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Daily oral administration of pazopanib 800mg (28 days cycles) from randomization until progression (according to RECIST 1.1) under treatment, after an initial period of 6 cycles (28 days) of daily administration of pazopanib 800mg from inclusion until randomization

Temporary discontinuation of pazopanib at randomization, after an initial period of 6 cycles (28 days) of daily administration of pazopanib 800mg from inclusion until randomization. Pazopanib will be reintroduced for 6 cycles of 28 days, with daily administration of pazopanib 800mg, as soon as the patient relapses (progressive disease according to RECIST 1.1). At the end of this additional 6 cycles, study drug will be stopped a second time.

This sequential scheme will be maintained until the patient experiences "on-treatment" progression

Continuous pazopanib (Arm A)

Intermittent pazopanib (Arm B)

Christelle De La Fouchardière, MD

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.

Phase II Study of the Optimal Scheme of Administration of Pazopanib in Thyroid Carcinoma

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

To study the correlation between clinical response and biomarkers (serum and tissue).

To perform gene expression profiling and to identify potential candidate genes.

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

Proportion of patients with a best overall response of Complete Response (CR) or a Partial Response (PR) at the end of the first 6 cycles, according to RECIST criteria 1.1

Proportion of patients with a best overall response of Complete Response, Partial Response or Stable Disease at the end of the first 6 cycles, according to RECIST criteria 1.1

Time from date of randomization to the date of event defined as the first documented progression under treatment or death due to any cause.

Best response observed from date of randomization

Time from the first documented response (CR or PR) to the first documented disease progression or death due to any cause, applies only to patients whose best overall response is CR or PR

Time from date of randomization to the date of death due to any cause

Proportion of patients with a CR or a PR after 6 cycles from randomization.

The proportion of patients with a SD, PR or CR after 6 cycles from randomization.

Adverse events (AE) experienced throughout the study and assessed according the NCI-CTC AE version 4.0.

The score obtained at the EORTC Quality of Life Questionnaire C30

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization	Link
Phase II Study of the Optimal Scheme of Administration of Pazopanib in Thyroid Carcinoma	NCT01813136	Thyroid Carcino...	Continuous pazo... Intermittent pa...	18 Years -	Centre Leon Berard
Phase II Study of the Optimal Scheme of Administration of Pazopanib in Thyroid Carcinoma	NCT01813136	Thyroid Carcino...	Continuous pazo... Intermittent pa...	18 Years -	Centre Leon Berard

Spots Global Cancer Trial Database for intermittent pazopanib (arm b)