Study of the Efficacy of Lenvatinib Combined With Denosumab in the Treatment of Patients With Predominant Bone Metastatic Radioiodine Refractory Differentiated Thyroid Carcinomas

Study Overview
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Brief Summary
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This study evaluates the combination of lenvatinib with denosumab in bone-predominant metastatic Radioiodine Refractory Differentiated Thyroid Carcinomas. All patients will receive this combination of treatments.

Detailed Description
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Patients are usually considered for directed therapy (radiotherapy and/or surgery and/or thermo-ablation) in case of symptomatic lesions or at high risk of local complications. They also usually receive systemic bone-directed agents (bisphosphonate or denosumab), despite sparse available data in the context of differentiated thyroid carcinomas (DTC). As bone-directed agents have no antitumor activity, patients may require additional treatments. To date, only sorafenib and lenvatinib have been approved in the treatment of advanced Radioiodine Refractory Differentiated Thyroid Carcinomas (RR-DTC). Lenvatinib demonstrated efficacy in RR-DTC compared to placebo. While other kinase inhibitors appeared to be less effective in controlling bone metastatic disease compared to other soft tissue sites, lenvatinib showed, in a small number of patients, significant decrease in bone tumors size. Even if both study drugs are indicated in the treatment of patients suffering from RR-DTC with bone metastases, it is of essential importance to confirm that lenvatinib can provide clinical benefit and antitumor activity when combined with denosumab in this population.

Official Title
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A Prospective, Multicentre Phase II Study of the Efficacy of Lenvatinib Combined With Denosumab in the Treatment of Patients With Predominant Bone Metastatic Radioiodine Refractory Differentiated Thyroid Carcinomas (LENVOS)

Conditions
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Thyroid Cancer Metastatic

Intervention / Treatment
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* Drug: Lenvatinib + Denosumab


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Males or females of 18 years of age or older at the day of consenting to the study; I2. Patients with follicular cell-derived thyroid (papillary, vesicular or and poorly differentiated); Radioiodine-Refractory disease as defined by at least one of the following : Presence of malignant/metastatic tissue that does not concentrate radioiodine (RAI), Loss by the tumor tissue of the ability to concentrate RAI after previous evidence of RAI-avid disease, Concentration of RAI in some lesions but not in others, Progression of metastatic disease despite significant concentration of RAI; Predominant bone metastases (without threatening extra-bone metastasis) Patient at risk of Skeletal-Related Event defined by the occurrence of at least one of the following event within 12 months prior to inclusion: Skeletal-Related Event, including indication of loco regional procedure (i.e. radiation therapy, interventional radiology), Progressive disease with measurable metastatic bone lesion(s) as per the RECIST1.1; Nota Bene: bone lesions with soft tissue involvement are considered as measurable. Performance Status of the Eastern Cooperative Oncology Group (ECOG) ≤2; Adequate organ function within 14 days prior to treatment start, defined as the following: Neutrophils count ≥ 1.5 Gi/l Hemoglobin ≥ 9.0 g/dl Platelets count ≥ 100 Gi/l Prothrombin Time (PT) ≤ 1.2 x ULN or International Normalized Ratio ≤ 1.5 Nota bene: Subjects receiving anticoagulant therapy are eligible if their INR is stable and within the targeted anticoagulation. Serum transaminases (ASAT and ALAT) ≤ 3.0 x upper limit of the normal (ULN) (5.0 x ULN in case of liver metastases) Serum total bilirubin ≤ 2 x ULN Creatinine clearance ≥ 30ml/min; Absence of proteinuria Nota Bene: patients with proteinuria ≥1+ on dipstick urinalysis will have to undergo 24 hours urine collection. Subjects with urine protein ≥1g/24h will be ineligible; Albumin-adjusted serum calcium ≥ 2.0 mmol/l (8.0mg/dl) and ≤ 2.9 mmol/l (11.5mg/dl) Patient and his/her partner using 2 forms of effective contraception: For women of child-bearing potential: at least 4 weeks prior to study entry, during the study participation and for at least 1 month post-lenvatinib and at least 5 months post-denosumab, For men: at least 4 weeks prior to study entry and during the study participation; Patient must be covered by a medical insurance; Willingness and ability to comply with the study requirements; Signed and dated informed consent indicating that the patient has been informed of all the aspects of the trial prior to enrolment. Non-inclusion Criteria: Histological diagnosis of the following DTC subtypes: medullar, anaplastic, lymphoma or sarcoma; Prior history of malignancies other than study disease within the last 3 years, except locally curable disease with no sign of relapse; Prior or current treatment with denosumab or any other bone-directed agent (including bisphosphonates), regardless of the indication; Prior or current treatment with any tyrosine kinase inhibitor, including but not limited to lenvatinib and denosumab ; Patient with imminent or confirmed Skeletal-Related Event as defined in the protocol; Uncontrolled arterial hypertension (150mmHg/90mmHg) despite an optimal antihypertensive intervention; patients with high blood pressure can be enrolled provided that the hypertension is well controlled at a stable dose of antihypertensive therapy for at least 1 week prior to lenvatinib start; Any condition leading to an increased risk of bleeding or hemorrhage; Any other contraindication to lenvatinib and/or denosumab Major surgery within 3 weeks prior to the first study drug administration or major surgery planned during the course of the study; Unhealed lesion from dental or oral surgery; Any dental or jaw condition that may lead or already led to osteonecrosis of the jaw or to oral surgery; Nota Bene: a consultation with a specialist must confirm that dental and oral cavity assessment allows starting a treatment with denosumab. Any active infection, including known infection with HIV, Hepatitis B or Hepatitis C; Patient participating to a clinical trial that can interfere with the primary outcome assessment or treatment with any investigational drug within 4 weeks prior to the start date of study drugs or planned during the study participation; Any organic or psychiatric disorder that, in the opinion of the investigator, might prevent the subject from completing the study or interfere with the interpretation of the study results; Pregnant or breast feeding women. Women of childbearing potential* are required to have a negative serum pregnancy test within 72 hours prior to study treatment start. A positive urine test must be confirmed by a serum pregnancy test *: Female patients who meet at least one of the following criteria are defined as women of non-childbearing potential: ≥50 years old and naturally amenorrheic for ≥ 1 year Permanent premature ovarian failure confirmed by a specialist gynecologist Previous bilateral salpingo-oophrectomy XY genotype, Turner's syndrome, or uterine agenesis Female patients who do not meet at least one of the above criteria are defined as women of childbearing potential. Patient with impairment of gastrointestinal (GI) function or GI disease that may significantly alter the absorption of lenvatinib (e.g., ulcerative diseases, uncontrolled nausea, vomiting, diarrhea, malabsorption syndrome, or small bowel resection); Patient with history or active gastrointestinal or non-gastrointestinal fistula; Hypersensitivity or history of allergic reactions attributed to compounds of similar chemical or biologic composition of study drugs ; History or active significant cardiovascular impairment : congestive heart failure greater than New York Heart Association class II, unstable angina, myocardial infarction, stroke, or cardiac arrhythmia associated with impairment within 6 months of the first dose of study drug; Clinically significant electrocardiogram abnormality, including marked baseline prolonged QT/QTc interval (e.g., a repeated demonstration of a QTc interval > 500 msec); Clinically significant unrelated systemic illness (e.g., serious infection or significant cardiac, pulmonary, hepatic, or other organ dysfunction) that would compromise the patient's ability to tolerate study treatment or would likely interfere with study procedures or results. Patients using prohibited concomitant and/or concurrent medications. Patient requiring tutorship or curatorship.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Interventional Model Description: Patients with predominant bone metastases from Radioiodine-Refractory Differentiated Thyroid Carcinoma (RR-DTC)
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Trial arm<br>Lenvatinib and Denosumab will be used in the indication of their respective SmPCs. Study treatments will be divided in fictitious cycles of 28 days. Lenvatinib and Denosumab will be administered as per investigator's decision, based on the data from their SmPC, at starting doses of 24mg once daily and 120mg once every 4 weeks, respectively. Dose modification guidelines of their respective SmPCs will apply. Lenvatinib should be started the day after the inclusion. It will be taken every day at the same time, preferentially in the morning. As in routine practice, all patients will be supplemented with daily doses of at least 500mg Calcium and 400IU Vitamin D, unless hypercalcemia is present. Patients will be encouraged to maintain good oral hygiene during treatment with Denosumab. Study drugs will be continued until a treatment discontinuation criterion is met. | Drug: Lenvatinib + Denosumab<br>* Lenvatinib and Denosumab will be used in the indication of their respective SmPCs. Study treatments will be divided in fictitious cycles of 28 days. Lenvatinib and Denosumab will be administered as per investigator's decision, based on the data from their SmPC, at starting doses of 24mg once daily and 120mg once every 4 weeks, respectively. Dose modification guidelines of their respective SmPCs will apply. Lenvatinib should be started the day after the inclusion. It will be taken every day at the same time, preferentially in the morning. As in routine practice, all patients will be supplemented with daily doses of at least 500mg Calcium and 400IU Vitamin D, unless hypercalcemia is present. Patients will be encouraged to maintain good oral hygiene during treatment with Denosumab. Study drugs will be continued until a treatment discontinuation criterion is met<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Determination of the efficacy of lenvatinib associated with denosumab in the treatment of patients with predominant bone metastases from Radioiodine-Refractory Differentiated Thyroid Carcinoma | The 24-month Skeletal-Related Event-Free (24M-SREF) rate will be defined as the proportion of patients without occurrence of new bone metastatic lesions at 24 months | 24 months | 
| Determination of the efficacy of lenvatinib associated with denosumab in the treatment of patients with predominant bone metastases from Radioiodine-Refractory Differentiated Thyroid Carcinoma | The 24-month Skeletal-Related Event-Free (24M-SREF) rate will be defined as the proportion of patients without pathological bone fracture (either vertebral or non-vertebral) at 24 months | 24 months | 
| Determination of the efficacy of lenvatinib associated with denosumab in the treatment of patients with predominant bone metastases from Radioiodine-Refractory Differentiated Thyroid Carcinoma | The 24-month Skeletal-Related Event-Free (24M-SREF) rate will be defined as the proportion of patients without spinal cord compression at 24 months | 24 months | 
| Determination of the efficacy of lenvatinib associated with denosumab in the treatment of patients with predominant bone metastases from Radioiodine-Refractory Differentiated Thyroid Carcinoma | The 24-month Skeletal-Related Event-Free (24M-SREF) rate will be defined as the proportion of patients without bone-related orthopedic surgical intervention at 24 months | 24 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Determination of the progression free survival | Progression-Free Survival will be defined as the time from the date of inclusion to the date of first documented progression or death due to any cause | 24 months | 
| Determination of the objective response rate | Objective Response Rate will be defined as the proportion of patients with a best overall response of Complete Response or Partial Response during the study | 24 months | 
| Determination of the time to the first local procedure | Time to the first local procedure will be defined as the time from the date of inclusion to the date of any local procedure (external beam radiation therapy, thermoablation, cementoplasty…) aiming at relieving bone-related symptoms | 24 months | 
| Determination of the time to treatment failure | Time to Treatment Failure will be measured from the time of inclusion until discontinuation of treatment for any reason other than 'protocol deviation' or 'administrative problems', including SRE, clinical deterioration, treatment toxicity, and death. | 24 months | 
| Determination of the analgesic consumption | Analgesic consumption will be assessed and presented in morphine equivalent by 24 hours | 24 months | 
| Determination of the Quality of life using European Organisation for Research and Treatment of Cancer (EORTC) questionnaire | Using the EORTC QLQ-C30 (Quality of Life Questionnaire) - Scale range: 1 (better outcome) to 4 (worse outcome) for 28 variables and from 1 (better outcome) to 7 (worse outcome) for 2 variables | 24 months | 
| Determination of the Quality of life using European Organisation for Research and Treatment of Cancer (EORTC) questionnaire | Using the EORTC QLQ-BM22 (Bone Metastasis module) - Scale range 1 (better outcome) to 4 (worse outcome) for 22 items. | 24 months | 
| Determination of the tolerance profile | Tolerance profile will be described through the incidence and severity of drug-related adverse events (AE), AESI, SAE and deaths according to the last version of the NCI-CTC AE classification | 24 months |