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A Randomized, Multicenter, Open-label, Phase II Study of the Optimal Scheme of Administration of Pazopanib in Thyroid Carcinoma

Phase 2
18 Years
Not Enrolling
Thyroid Carcinoma

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Trial Information

A Randomized, Multicenter, Open-label, Phase II Study of the Optimal Scheme of Administration of Pazopanib in Thyroid Carcinoma

Total or near-total thyroidectomy is the primary treatment for differentiated thyroid
carcinoma. Postoperatively, DTC are treated with radioiodine (131I) and thyroid stimulating
hormone (TSH) suppressive levothyroxine therapy.

But 5% to 20% of patients with DTC develop distant metastases; some of them become
refractory to 131I therapy.

Targeted therapies have been studied in iodine refractory DTC for several years but none of
these treatments has yet been approved in DTC and clinicians continue to enroll patients in
clinical trials. The agents used so far in thyroid cancer are small molecules sharing the
property to inhibit various tyrosine kinase receptors such as Vascular Endothelial Growth
Factor Receptor (VEGFR), Epidermal Growth Factor Receptor (EGFR), RET or c-met.

The VEGF (Vascular Endothelial Growth Factor) is one of the several pro angiogenic molecules
that play a pivotal role in angiogenesis, one of the mechanisms involved in tumor growth and

VEGF expression is highly prevalent in Papillary Thyroid Carcinoma (PTCs) (79%), Follicular
Thyroid Carcinoma (FTCs) (50%) or Poorly Differentiated Thyroid Carcinoma (PDTCs) (37%) and
VEGFR is respectively expressed in 76%, 83% and 25% for VEGRF-1 and 68%, 56% and 37% for

Pazopanib (GW786034 - GlaxoSmithKline) is an orally administered, potent multitarget
tyrosine kinase inhibitor of VEGFR in particular (but also of PDGFR-α and -β, and stem cell
factor receptor c-Kit).

The results obtained in metastatic or locally advanced refractory DTC are currently
available (phase II study of 39 patients with metastatic, rapidly progressive RAI-refractory
DTC, treated with pazopanib 800mg daily, were published in Lancet Oncology in 2010 by KC
Bible), demonstrating the efficacy of these therapies in this indication. However, no clear
data is yet available indicating the optimal duration of treatment in first line therapy:
patients are currently treated until progression or until drug discontinuation due to
toxicity. Indeed, patients may have some difficulties to manage the chronic mild to moderate
(grade 1-2) side-effects related to long-term treatment, leading some asymptomatic patients
in whom tumor is controlled by TKI treatment to ask for treatment interruption.

The intermittent administration should avoid the occurrence of long-term adverse event and
subsequent dose reductions or discontinuation, thus allowing a longer control of underlying

All these considerations led our reflexion in the design of the present study, that is to
say to determine the feasibility of pazopanib treatment interruption with reintroduction at
progression in iodine refractory progressive DTC patients as compared to pazopanib
continuous administration, after 6 initial cycles of pazopanib 800 mg daily for all patients
included in the study, with a strong rationale for intermittent administration of pazopanib.

Inclusion Criteria:

- Age ≥ 18 years old,

- Histologically confirmed diagnosis of differentiated thyroid cancer (papillary,
follicular and poorly differentiated) (histological documentation of the diagnosis
approved by a regional referent pathologist of the TUTHYREF-PATH network, prior to
each patient's registration (Cf. appendix 5)),

- Archival tumor sample available. It will be provided for all subjects, for biomarker
analysis before and/or during study treatment.

- Patients must have been treated with therapeutic RAI. Patients may have received
prior treatment with either 1 line of chemotherapy and/or up to 1 Tyrosine Kinase

- Resistance to therapeutic radioiodine (RAI) (for DTC) as demonstrated at least by one
of the following:

- Absence of iodine uptake in at least one target lesion on a post-therapy
radioactive iodine scan,

- Presence of a target lesion after a cumulative radio-iodine activity of at least
600 mCi,

- Patient with uptake who have RAI treatment of at least 100 mCi within the last
12 months and have disease progression,

- Documented progression as per RECIST 1.1 based on 2 consecutives imaging performed
within the last 12 months,

- Measurable disease according to RECIST version 1.1,

- Eastern Cooperative Oncology Group (ECOG) Performance Status of 0 or 1,

- Adequate organ system function defined as the following:


- Absolute Neutrophils Count (ANC) ≥ 1.5 Gi/L

- Hemoglobin ≥ 9 g/dL (5.6µM) (transfusion is not allowed within 7 days of screening

- Platelets ≥ 100 Gi/L

- Prothrombin Time (PT) ≤ 1.2 x ULN or International Normalized Ratio (INR) ≤ 1.2
Subjects receiving anticoagulant therapy are eligible if their INR is stable and
within the recommended range for the desired target of anticoagulation

- Activated Partial Thromboplastin Time (aPTT) ≤ 1.2 x ULN

Electrolytes :

- Potassium within normal ranges.

Hepatic :

- Total bilirubin ≤ 1.5 x ULN

- Alanine AminoTansferase (ALAT) and Aspartate AminoTransferase (ASAT) ≤ 2.5 x ULN
Concomitant elevation in bilirubin and ASAT/ALAT above 1.0xULN is not allowed

Renal :

- Serum creatinine ≤ 1.5 mg/dL (133µM) or if serum creatinine> 1.5 mg/dL, calculated
creatinine clearance (ClCR) ≥ 50 mL/min (Cockcroft formula or MDRD formula for
patients older than 65 years old)

- Urine Protein to Creatinine Ratio (UPC) < 1; If UPC ratio ≥ 1, then a 24-hour urine
protein must be assessed. Subjects must have a 24-hour urine protein value < 1 gram
to be eligible Use of urine dipstick for renal function assessment is not acceptable

- Women of childbearing potential must have a negative urine or serum pregnancy
test within 7 days of first dose of pazopanib. They must be willing to use
effective contraception methods during the study and up to 7 days after the last
pazopanib administration.

- Affiliated to the French social security system.

- Subjects must provide written informed consent prior to perform any
study-specific procedure or assessment and must be willing to comply with
treatment and follow up.

Note: Procedures conducted as part of the subject's routine clinical management (e.g.,
blood count, imaging study such as bone scan) 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,

Exclusion Criteria:

- Other histological sub-types of thyroid tumors like medullar carcinoma, anaplastic
carcinoma, lymphoma or sarcoma,

- Prior treatment with pazopanib,

- Prior malignancy, Subjects who have had another malignancy and have been disease-free
for 5 years, or subjects with a history of completely resected non-melanomatous skin
carcinoma or successfully treated in situ carcinoma are eligible

- Symptomatic metastases of Central nervous system (CNS) requiring or having required
steroids or enzyme-inducing anticonvulsants within 4 weeks before inclusion ,

- 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 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 begin 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,

- Corrected QT interval (QTc) > 480 msec (correction method according to the Bazett's

- 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),

- Cerebrovascular accident including Transient Ischemic Attack (TIA), pulmonary
embolism or untreated Deep Venous Thrombosis (DVT), Subjects with recent DVT who
have been treated with therapeutic anti-coagulating agents for at least 6 weeks
are eligible,

- Poorly controlled hypertension (systolic blood pressure ≥ 140 mmHg or diastolic blood
pressure ≥ 90 mmHg) as described in the section 7.2 "Study requirements" of this
protocol, Initiation or adjustment of antihypertensive medication(s) is permitted
prior to study entry. At least one day after antihypertensive medication initiation
or adjustment, blood pressure (BP) must be re-assessed three times at approximately
2-minute intervals. These three values should be averaged to obtain the mean
diastolic blood pressure and the mean systolic blood pressure. The mean SBP / DBP
ratio must be <140/90 mmHg (OR 150/90 mm Hg, if this criterion is approved by the
coordination center) in order to be eligible.

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

- Evidence of active bleeding or bleeding diathesis,

- Known endobronchial lesions and/or lesions infiltrating major pulmonary vessels that
increase the risk of pulmonary hemorrhage, 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).

- Large protruding endobronchial lesions in the main or lobar bronchi are
excluded; however, endobronchial lesions in the segmented bronchi are allowed.

- Lesions extensively infiltrating the main or lobar bronchi are excluded;
however, minor infiltrations in the wall of the bronchi are allowed.

- Hemoptysis within the last 8 weeks before inclusion,

- Have a known immediate or delayed hypersensitivity reaction or idiosyncrasy to drug,

- 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 (analgesic radiation therapy is allowed if the radiation
field doesn't include a potential target lesion for tumor assessments),

- 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,

- Administration of other oncologic drug or any non-oncologic investigational drug
within 30 days (or 5 half lives whichever is longer) prior to receiving the first
dose of study treatment, or planned to be administered during the study

- Unable or unwilling to discontinue use of prohibited medications listed in Section
6.2.4.c "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,

- Any ongoing toxicity from prior anti-cancer therapy that is > Grade 1 and/or that is
progressing in severity (according to the NCI-CTC AE v4.0), except alopecia,

- 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.

Type of Study:


Study Design:

Allocation: Randomized, Endpoint Classification: Efficacy Study, Intervention Model: Parallel Assignment, Masking: Open Label, Primary Purpose: Treatment

Outcome Measure:

Time to treatment failure (TTF)

Outcome Description:

TTF is the time to permanent treatment discontinuation due to any cause after randomization in each arm

Outcome Time Frame:

up to 36 months

Safety Issue:


Principal Investigator

Christelle De La Fouchardière, MD

Investigator Role:

Principal Investigator

Investigator Affiliation:

Centre Léon Bérard; Lyon


France: ANSM (Agence Nationale de Sécurité du Medicament et des produits de santé) - French Health Products Safety Agency

Study ID:




Start Date:

March 2013

Completion Date:

March 2016

Related Keywords:

  • Thyroid Carcinoma
  • radioiodine refractory Differentiated Thyroid Carcinoma
  • pazopanib
  • intermittent administration
  • time to treatment failure
  • Carcinoma
  • Thyroid Neoplasms
  • Thyroid Diseases