The objective of this study is to determine the feasibility of pazopanib treatment interruption with reintroduction at progression in iodine refractory progressive Differentiated Thyroid Cancer (DTC) patients as compared to pazopanib continuous administration.

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 dissemination.

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 VEGRF-2.

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 disease.

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)

• 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 Inhibitor,

• 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:

Hematology:

• Absolute Neutrophils Count (ANC) ≥ 1.5 Gi/L
• Hemoglobin ≥ 9 g/dL (5.6µM) (transfusion is not allowed within 7 days of screening assessments)
• 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 method),

• 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 participation,

• 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.