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

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ClinicalTrials.gov Identifier: NCT01813136
Recruitment Status : Recruiting
First Posted : March 18, 2013
Last Update Posted : September 19, 2017
Sponsor:
Collaborator:
GlaxoSmithKline
Information provided by (Responsible Party):
Centre Leon Berard

Brief Summary:
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.

Condition or disease Intervention/treatment Phase
Thyroid Carcinoma Drug: Continuous pazopanib (Arm A) Drug: Intermittent pazopanib (Arm B) Phase 2

Detailed Description:

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.


Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 168 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: A Randomized, Multicenter, Open-label, Phase II Study of the Optimal Scheme of Administration of Pazopanib in Thyroid Carcinoma
Study Start Date : March 2013
Estimated Primary Completion Date : June 2018
Estimated Study Completion Date : June 2018

Resource links provided by the National Library of Medicine

Drug Information available for: Pazopanib

Arm Intervention/treatment
Active Comparator: Continuous pazopanib (Arm A)
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
Drug: Continuous pazopanib (Arm A)
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
Other Name: GW786034

Experimental: Intermittent pazopanib (Arm B)

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

Drug: Intermittent pazopanib (Arm B)

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

Other Name: GW786034




Primary Outcome Measures :
  1. Time to treatment failure (TTF) [ Time Frame: up to 36 months ]
    TTF is the time to permanent treatment discontinuation due to any cause after randomization in each arm


Secondary Outcome Measures :
  1. Objective Response Rate (ORR) [ Time Frame: 6 months after inclusion ]
    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

  2. Disease Control Rate (DCR) [ Time Frame: 6 months after inclusion ]
    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

  3. Progression-Free Survival (PFS) [ Time Frame: up to 36 months ]
    Time from date of randomization to the date of event defined as the first documented progression under treatment or death due to any cause.

  4. Best response rate [ Time Frame: up to 36 months ]
    Best response observed from date of randomization

  5. Duration of response [ Time Frame: up to 36 months ]
    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

  6. Overall Survival (OS) [ Time Frame: up to 36 months ]
    Time from date of randomization to the date of death due to any cause

  7. Objective Response Rate (ORR) [ Time Frame: 6 months after randomization ]
    Proportion of patients with a CR or a PR after 6 cycles from randomization.

  8. Disease Control Rate (SDR) [ Time Frame: 6 months after randomization ]
    The proportion of patients with a SD, PR or CR after 6 cycles from randomization.

  9. Safety profile of pazopanib [ Time Frame: up to 36 months ]
    Adverse events (AE) experienced throughout the study and assessed according the NCI-CTC AE version 4.0.

  10. Quality of Life (QoL) [ Time Frame: At inclusion, randomization and at the end of pazopanib treatment ]
    The score obtained at the EORTC Quality of Life Questionnaire C30


Other Outcome Measures:
  1. Identification of prognostic biomarkers of clinical outcome. [ Time Frame: At inclusion, day 56 and day 168 of treatment (before randomisation) ]
    To study the correlation between clinical response and biomarkers (serum and tissue).

  2. Tissue expression of Raf-1 kinase inhibitory protein, PAX8, BRAF, Pi3KCA and Ras. [ Time Frame: At inclusion, day 56 and day 168 of treatment (before randomization) ]
    To perform gene expression profiling and to identify potential candidate genes.



Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.


Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

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.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT01813136


Contacts
Contact: Julien Gautier +33426556829 julien.gautier@lyon.unicancer.fr

Locations
France
CHU Angers Recruiting
Angers, France, 49933
Principal Investigator: Vincent ROHMER, MD         
Sub-Investigator: Frédéric ILLOUZ, MD         
Sub-Investigator: Sandrine LABOUREAU-SOARES BARBOSA, MD         
Sub-Investigator: Patrice RODIEN, MD         
CHU Bordeaux Recruiting
Bordeaux, France, 33075
Principal Investigator: Alain RAVAUD, MD         
Sub-Investigator: Laurence DIGUE, MD         
Sub-Investigator: Marine GROSS-GOUPIL, MD         
Sub-Investigator: Amandine QUIVY, MD         
Sub-Investigator: Denis SMITH, MD         
Sub-Investigator: Nathalie TRUFLANDIER, MD         
Institut Bergonié Recruiting
Bordeaux, France, 33076
Principal Investigator: Yann GODBERT, MD         
Sub-Investigator: Françoise BONICHON, MD         
Sub-Investigator: Antoine ITALIANO, MD         
Centre François Baclesse Recruiting
Caen, France, 14076
Principal Investigator: Stéphane BARDET, MD         
Sub-Investigator: Renaud CIAPPUCCINI, MD         
CHRU Lille Hôpital Claude Huriez Recruiting
Lille, France, 59037
Principal Investigator: Christine DOCAO, MD         
Sub-Investigator: Maria-Claire MIGAUD, MD         
Centre Leon Berard Recruiting
Lyon, France, 69373
Principal Investigator: Christelle DE LA FOUCHARDIERE, MD         
Hôpital de la Timone APHM Recruiting
Marseille, France, 13385
Principal Investigator: Patricia NICCOLI, MD         
Sub-Investigator: Charlotte DUPUIS, MD         
Centre Antoine Lacassagne Recruiting
Nice, France, 06189
Principal Investigator: Danielle BENISVY, MD         
Sub-Investigator: Esma SAADA-BOUZID, MD         
Hôpital Saint-Louis APHP Recruiting
Paris, France, 75010
Principal Investigator: Damien POUESSEL, MD         
Sub-Investigator: Stéphane CULINE, MD         
Sub-Investigator: Marie-Elisabeth TOUBERT, MD         
Sub-Investigator: Cécile CHOUGNET, MD         
Hôpital de la Pitié Salpêtrière APHP Recruiting
Paris, France, 75651
Principal Investigator: Johanna WASSERMANN, MD         
Sub-Investigator: Laurence LEENHARDT, MD         
Sub-Investigator: Jean-Philippe SPANO, MD         
Sub-Investigator: Camille BUFFET, MD         
Institut Jean Godinot Recruiting
Reims, France, 51726
Principal Investigator: Audrey DALAC, MD         
Sub-Investigator: Sandrine FIEFFE-COQUET, MD         
Sub-Investigator: Jean-Marie POCHART, MD         
Sub-Investigator: Claire SCHVARTZ, MD         
Institut Claudius Régaud Recruiting
Toulouse, France, 31052
Principal Investigator: Slimane ZERDOUD, MD         
Sub-Investigator: Jean-Pierre DELORD, MD         
Institut Gustave Roussy Recruiting
Villejuif, France, 94805
Principal Investigator: Sophie LEBOULLEUX, MD         
Sub-Investigator: Eric BAUDIN, MD         
Sub-Investigator: Amandine BERDELOU, MD         
Sub-Investigator: Martin SCHLUMBERGER, MD         
Sponsors and Collaborators
Centre Leon Berard
GlaxoSmithKline
Investigators
Principal Investigator: Christelle De La Fouchardière, MD Centre Léon Bérard; Lyon

Publications:
Brose M. S., et al. Effect of BRAFV600E on response to sorafenib in advanced thyroid cancer patients. J Clin Oncol (meeting Abstracts) 27.15S (2009) : 6002.
GSK Laboratories. Investigator's Brochure of pazopanib, version 09 dated 25 Jan. 2012.Ref Type: Unpublished Work
Kaplan, E. L and P. Meier. Nonparametric estimation from incomplete observations. J Am Stat Assoc 53 (1958): 457-81.
Lan, K. K. G. and D. L. De Mets. Discrete sequential boundaries for clinical trials. Biometrika 70 (1983): 659-63
Leboulleux, S., Bastholt, L., and Krause TM. Vandetanib in locally advanced or metastatic differentiated thyroid cancer (papillary or follicular; DTC): a randomized, double-blind phase II trial. International Thyroid Conference;Paris, France; [ Sept 11.16, 2009. Abstr 0C.023.]. 2010. Ref Type: Abstract
Ravaud, A., et al. Sunitinib in patients with refractory advanced thyroid cancer: the THYSU phase II trial. J Clin Oncol (Meeting Abstracts) 26.15_suppl (2008): 6058.
Slamon D,. et al. Pazopanib + Lapatinib is more active than Lapatinib alone : Updated results from a randomized study in patients with first-line ErbB2-positive advanced or metastatic breast cancer [ESMO abstract 139P]. Ann Oncol. 2008c ;19 (supp 8) : viii 64-65.
Sleijfer, S., et al. Phase II study of pazopanib (GW786034) in patients (pts) with relapsed or refractory soft tissue sarcoma (STS): EORTC 62043. ASCO Meeting Abstracts 25.18_suppl (2007): 10031.

Responsible Party: Centre Leon Berard
ClinicalTrials.gov Identifier: NCT01813136     History of Changes
Other Study ID Numbers: PAZOTHYR
2012-003162-41 ( EudraCT Number )
First Posted: March 18, 2013    Key Record Dates
Last Update Posted: September 19, 2017
Last Verified: September 2017

Keywords provided by Centre Leon Berard:
radioiodine refractory Differentiated Thyroid Carcinoma
pazopanib
intermittent administration
time to treatment failure
TUTHYREF

Additional relevant MeSH terms:
Carcinoma
Thyroid Diseases
Thyroid Neoplasms
Neoplasms, Glandular and Epithelial
Neoplasms by Histologic Type
Neoplasms
Endocrine System Diseases
Endocrine Gland Neoplasms
Neoplasms by Site
Head and Neck Neoplasms