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A Phase I Clinical Trial of Pazopanib in Combination With Escalating Doses of Radioactive 131I in Patients With Well-Differentiated Thyroid Carcinoma Refractory to Radioiodine, Despite Having Some Uptake


Phase 1
18 Years
N/A
Open (Enrolling)
Both
Recurrent Thyroid Cancer, Stage IVA Follicular Thyroid Cancer, Stage IVA Papillary Thyroid Cancer, Stage IVB Follicular Thyroid Cancer, Stage IVB Papillary Thyroid Cancer, Stage IVC Follicular Thyroid Cancer, Stage IVC Papillary Thyroid Cancer

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Trial Information

A Phase I Clinical Trial of Pazopanib in Combination With Escalating Doses of Radioactive 131I in Patients With Well-Differentiated Thyroid Carcinoma Refractory to Radioiodine, Despite Having Some Uptake


PRIMARY OBJECTIVES:

I. To determine the safety, tolerability and feasibility of administrating escalating doses
of 131I (iodine I 131) in combination with concurrent pazopanib (pazopanib hydrochloride)
therapy in order to define the maximum tolerated dose (MTD)/recommended phase II dose (RP2D)
in patients with radioiodine (RAI)-refractory disease with minor RAI-uptake.

SECONDARY OBJECTIVES:

I. To determine the effects of pazopanib in combination with 131I on RAI-avidity, uptake and
tumor response rate (Response Evaluation Criteria In Solid Tumors [RECIST] version 1.1).

II. To determine the time to tumor progression (TTP) or recurrence (progression will be
determined by RECIST criteria and by increases in suppressed thyroglobulin levels > 50% as
compared to tumor imaging and suppressed thyroglobulin levels performed within 1 week of the
last dose of pazopanib).

OUTLINE: This is a dose-escalation study of iodine I 131.

Patients receive iodine I 131 intramuscularly (IM) once daily (QD) 5 days a week in weeks
5-6. Patients also receive pazopanib hydrochloride orally (PO) QD beginning in week 1 and
continuing for 8 weeks post-radioactive iodine therapy.

After completion of study treatment, patients are followed up at 28 days.


Inclusion Criteria:



- Subjects must provide written informed consent prior to performance of study-specific
procedures or assessments, and must be willing to comply with treatment and follow
up; procedures conducted as part of the subject's routine clinical management (e.g.,
blood count, imaging study) and obtained prior to signing of informed consent may be
utilized for screening or baseline purposes provided these procedures are conducted
as specified in the protocol

- Histologically confirmed diagnosis of well-differentiated thyroid carcinoma (WDTC),
including papillary and follicular subtypes, and documented recurrent and/or
metastatic disease; patients must have unresectable disease: patients must not be
amenable to surgery but prior thyroidectomy is allowed

- Patient must have demonstrated evidence of disease progression by RECIST criteria
using site assessment of computed tomography (CT)/magnetic resonance imaging (MRI)
scans within 12 months (+1 month to allow for variances in patient scanning
intervals) prior to study entry or by > 50% increase in suppressed thyroglobulin
levels during this time period

- Patients with WDTC must be relatively 131I refractory/resistant as defined by at
least one of the following:

- One or more measurable lesions with low or absent 131I uptake on the most recent
pre-study radioiodine scans, based on a visual review of scans or RAI scan
reports

- One or more measurable lesions with disease progression by RECIST within 12
months (+ 1 month to allow for variances in patient scanning intervals) of 131I
therapy despite 131I uptake on RAI scan, based on site assessment of CT/MRI
scans or by > 50% increase in suppressed thyroglobulin levels during this time
period

- Evidence of at least one site of known disease with preserved 131I uptake above
background levels on a diagnostic post-therapy 131I scan prior to study entry

- Patients with WDTC must be receiving thyroxine suppression therapy and
thyroid-stimulating hormone (TSH) should not be elevated (TSH should be =< 5.50
mcu/mL)

- Eastern Cooperative Oncology Group (ECOG) performance status of 0-2

- Absolute neutrophil count (ANC) >= 1.5 X 10^9/L

- Hemoglobin >= 9 g/dL (5.6 mmol/L)

- Platelets >= 90 X 10^9/L

- International normalized ratio (INR) =< 1.2 X upper limit of normal (ULN); subjects
receiving anticoagulant therapy are eligible if their INR is stable and within the
recommended range for the desired level of anticoagulation

- Activated partial thromboplastin time (aPTT) =<1.2 X ULN

- Total bilirubin =< 1.5 X ULN

- Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) =< 2.5 X ULN, and
< 5 X ULN in the presence of liver metastases; concomitant elevations in bilirubin
and AST/ALT above 1.5 x ULN are not permitted

- Serum creatinine =< 2.0 mg/dL or, if serum creatinine > 2.0 mg/dL, calculate
creatinine clearance (CLCR) >= 30 mL/min

- Urine protein to creatinine ratio (UPC) < 1 or, 24-hour urine protein < 1 g; if UPC
>= 1, then a 24-hour urine protein must be assessed; subjects must have a 24-hour
urine protein value < 1 g to be eligible; use of urine dipstick for renal function
assessment is not acceptable

- Non-childbearing potential (i.e., physiologically incapable of becoming pregnant),
including any female who has had:

- A hysterectomy

- A bilateral oophorectomy (ovariectomy); a bilateral tubal ligation

- Is post-menopausal (subjects not using hormone replacement therapy [HRT] must
have experienced total cessation of menses for >= 1 year and be greater than 45
years in age, OR, in questionable cases, have a follicle stimulating hormone
[FSH] value > 40 mIU/mL and an estradiol value < 40pg/mL [< 140 pmol/L];
subjects using HRT must have experienced total cessation of menses for >= 1 year
and be greater than 45 years of age OR have had documented evidence of menopause
based on FSH and estradiol concentrations prior to initiation of HRT)

- Childbearing potential, including any female who has had a negative serum pregnancy
test within 2 weeks prior to the first dose of study treatment, preferably as close
to the first dose as possible, and agrees to use adequate contraception for at least
2 weeks following the last dose of the investigational product

- GlaxoSmithKline (GSK) acceptable contraceptive methods, when used consistently and in
accordance with both the product label and the instructions of the physician, are as
follow:

- Complete abstinence from sexual intercourse for 14 days before exposure to
investigational product, through the dosing period, and for at least 21 days
after the last dose of investigational product

- Oral contraceptive, either combined or progestogen alone

- Injectable progestogen

- Implants of levonorgestrel

- Estrogenic vaginal ring

- Percutaneous contraceptive patches

- Intrauterine device (IUD) or intrauterine system (IUS) with a documented failure
rate of less than 1% per year

- Male partner sterilization (vasectomy with documentation of azoospermia) prior
to the female subject's entry into the study, and this male is the sole partner
for that subject

- Double barrier method: condom and an occlusive cap (diaphragm or cervical/vault
caps) with a vaginal spermicidal agent (foam/gel/film/cream/suppository)

- Female subjects who are lactating should discontinue nursing prior to the first dose
of study drug and should refrain from nursing throughout the treatment period and for
14 days following the last dose of study drug

Exclusion Criteria:

- Patients with medullary thyroid cancer, thyroid lymphoma or anaplastic thyroid cancer
are excluded

- Resolution of all acute toxic effects of prior systemic therapy (including iodine
therapy or systemic therapy), radiotherapy or surgical procedure to National Cancer
Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) version 4.0
grade =< 1

- Patients with cumulative iodine I 131 exposure in excess of 1000 mCi

- Second primary malignancy that is of clinical significance, clinical detectable
and/or progressing at the time of consideration for study enrollment

- History or clinical evidence of central nervous system (CNS) metastases or
leptomeningeal carcinomatosis, except for individuals who have previously-treated CNS
metastases, are asymptomatic, and have had no requirement for steroids for 28 days
prior to first dose of study drug; screening with CNS imaging studies (CT or MRI) is
required only if clinically indicated or if the subject has a history of CNS
metastases; clinically significant gastrointestinal abnormalities that may increase
the risk for gastrointestinal bleeding including, but not limited to:

- Active peptic ulcer disease

- Known intraluminal metastatic lesion/s with risk of bleeding

- Inflammatory bowel disease (e.g. ulcerative colitis, Crohn's disease), or other
gastrointestinal conditions with increased risk of perforation

- History of abdominal fistula, gastrointestinal perforation, or intra abdominal
abscess within 28 days prior to beginning study treatment

- Clinically significant gastrointestinal abnormalities that may affect absorption of
investigational product including, but not limited to:

- Malabsorption syndrome

- Major resection of the stomach or small bowel

- Presence of uncontrolled infection

- Corrected QT interval (QTc) > 480 msecs using Bazett's formula

- History of any one or more of the following cardiovascular conditions within the past
6 months:

- Cardiac angioplasty or stenting

- Myocardial infarction

- Unstable angina

- Coronary artery bypass graft surgery

- Symptomatic peripheral vascular disease

- Class III or IV congestive heart failure, as defined by the New York Heart
Association (NYHA)

- Poorly controlled hypertension [defined as systolic blood pressure (SBP) of >= 140
mmHg or diastolic blood pressure (DBP) of >= 90mmHg]

- Note: initiation or adjustment of antihypertensive medication(s) is permitted
prior to study entry

- History of cerebrovascular accident including transient ischemic attack (TIA),
pulmonary embolism or untreated deep venous thrombosis (DVT) within the past 6
months; subjects with recent DVT who have been treated with therapeutic
anti-coagulating agents for at least 6 weeks are eligible

- Prior major surgery or trauma within 28 days prior to first dose of study drug and/or
presence of any non-healing wound, fracture, or ulcer (procedures such as catheter
placement not considered to be major)

- Evidence of active bleeding or bleeding diathesis

- Known endobronchial lesions and/or lesions infiltrating major pulmonary vessels that
increase the risk of pulmonary hemorrhage; Note: lesions infiltrating major pulmonary
vessels (contiguous tumor and vessels) are excluded; however, the presence of a tumor
that is touching, but not infiltrating (abutting) the vessels is acceptable (CT with
contrast is strongly recommended to evaluate such lesions)

- Recent Hemoptysis in excess of 15 ml of bright red blood in the 8 weeks prior to
study entry

- Any serious and/or unstable pre-existing medical, psychiatric, or other condition
that could interfere with subject's safety, provision of informed consent, or
compliance to study procedures

- Unable or unwilling to discontinue use of prohibited medications for at least 14 days
or five half-lives of a drug (whichever is longer) prior to the first dose of study
drug and for the duration of the study

- Treatment with any of the following anti-cancer therapies:

- Radiation therapy, surgery or tumor embolization within 14 days prior to the
first dose of pazopanib OR

- Chemotherapy, immunotherapy, biologic therapy, investigational therapy or
hormonal therapy within 14 days or five half-lives of a drug (whichever is
longer) prior to the first dose of pazopanib

Type of Study:

Interventional

Study Design:

Endpoint Classification: Safety Study, Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Treatment

Outcome Measure:

Toxicity and the occurrence of dose limiting toxicity (DLT) when pazopanib is given in conjunction with radioiodine to establish the MTD and RP2D in combination

Outcome Description:

Assessment of adverse events will include type, incidence, severity (graded by the National Cancer Institute [NCI] Common Terminology Criteria for Adverse Events [CTCAE], Version 4.03), timing, seriousness, and relatedness; and laboratory abnormalities. Descriptive statistics will be calculated for all variables and responses; continuous data will be expressed as their mean +/- standard deviation, median and range, and categorical data will be listed by frequency of occurrence and proportion of total (with 95% confidence intervals) for all enrolled patients and by dose cohort.

Outcome Time Frame:

8 weeks post radioactive iodine administration

Safety Issue:

Yes

Principal Investigator

Laura Chow

Investigator Role:

Principal Investigator

Investigator Affiliation:

Fred Hutchinson Cancer Research Center/University of Washington Cancer Consortium

Authority:

United States: Food and Drug Administration

Study ID:

7529

NCT ID:

NCT01413113

Start Date:

December 2011

Completion Date:

Related Keywords:

  • Recurrent Thyroid Cancer
  • Stage IVA Follicular Thyroid Cancer
  • Stage IVA Papillary Thyroid Cancer
  • Stage IVB Follicular Thyroid Cancer
  • Stage IVB Papillary Thyroid Cancer
  • Stage IVC Follicular Thyroid Cancer
  • Stage IVC Papillary Thyroid Cancer
  • Thyroid Neoplasms
  • Thyroid Diseases
  • Adenocarcinoma, Follicular

Name

Location

Fred Hutchinson Cancer Research Center/University of Washington Cancer ConsortiumSeattle, Washington  98109