Cabozantinib in Advanced Salivary Gland Cancer Patients

Study Overview
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Brief Summary
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Phase 2 clinical trial on the efficacy of cabozantinib in locally advanced, recurrent and/or metastatic salivary gland cancer patients.

Detailed Description
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Rationale: Salivary gland cancer (SGC) is a rare cancer with 24 histological subtypes. Treatment options for locally advanced and/or metastatic SGC are limited. The tyrosine kinase inhibitor cabozantinib suppresses tumor growth, angiogenesis, and metastasis, and has been approved for renal cell carcinoma and thyroid cancer. Cabozantinib may also be of value in advanced SGC because c-MET, one of the targets of cabozantinib, is frequently overexpressed in SGC. Objectives: To assess the objective response rate (ORR), progression free survival (PFS), overall survival (OS), duration of response (DoR), toxicity, and quality of life (QoL) of patients with advanced SGC treated with cabozantinib in 3 cohorts: salivary duct carcinoma (SDC), adenoid cystic carcinoma (ACC), other SGC's. Study design: Single arm, single center, phase II clinical trial in 3 cohorts: ACC, SDC and other SGC's. Study population: Patient with c-MET positive, locally advanced, recurrent, and/or metastatic SGC. Intervention: Cabozantinib tablets 60 mg once daily until progressive disease, intolerable toxicity, or investigator and/or patient decision to withdraw for a maximum duration of 2 years.

Official Title
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The Efficacy of Cabozantinib in Advanced SAlivary Gland Cancer Patients, a Phase II Clinical Trial

Conditions
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Salivary Gland Cancer

Intervention / Treatment
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* Drug: Cabozantinib


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Disease specific locally advanced, recurrent, and/or metastatic SGC (excluding sarcomas and mesenchymal tumors) c-MET positive disease Measurable disease per RECIST version 1.1 Cohort-specific criteria SDC cohort: direct inclusion (no objective tumor growth prior to inclusion needed) ACC cohort: inclusion after objective growth in the last three months or complaints due to the disease Other SGC's: inclusion after objective growth in the last three months or complaints due to the disease General conditions Age ≥18 years Eastern Cooperative Oncology Group performance status of 0 or 1. Normal number of neutrophils and thrombocytes Liver function: ALT and AST < 2.5 x upper limit of normal (ULN), total bilirubin ≤ 1.5 x ULN (except for Gilbert's syndrome), serum albumin ≥28 g/L Renal function: creatinine < 1.5 x ULN or calculated creatinine clearance ≥ 40 ml/min, Urine protein/creatinine ratio ≤113.1 mg/mmol (≤1 mg/mg) or 24-hour urine protein <1 g Hemoglobin A1c (HbA1c) ≤ 8% or a fasting serum glucose ≤ 9 mmol/l Exclusion Criteria: General conditions A known allergy for cabozantinib or its components Long QT-syndrome Pregnancy or lactation Patients (M/F) with reproductive potential not implementing adequate contraceptives measures Known brain metastases or cranial epidural disease unless adequately treated with radiotherapy and/or surgery and stable for at least 3 months before inclusion Major surgery within 3 months before randomization. Complete wound healing from major surgery must have occurred 1 month before inclusion and from minor surgery at least 10 days before inclusion Uncontrolled illness including, but not limited to cardiovascular disorders including symptomatic congestive heart failure, unstable angina pectoris, or serious cardiac arrhythmias, uncontrolled hypertension defined as sustained systolic BP > 150 mm Hg, or diastolic BP > 100 mm Hg, stroke (including TIA), myocardial infarction, or other ischemic event within 6 months before inclusion, serious active infections Concomitant treatments Concomitant (or within 4 weeks before inclusion) administration of any other experimental drug under investigation. Concurrent treatment with any other anti-cancer therapy. Concomitant anticoagulation. Low dose aspirin for cardioprotection and low dose LMWH are permitted. Radiation therapy within the last 4 weeks before inclusion

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: 3 cohorts: adenoid cystic carcinoma salivary duct carcinoma other subtypes of salivary gland cancer sample size: The Simon two-stage design will be used, The first stage consists of 9 patients per cohort ((1) SDC, (2) ACC) evaluable for response. If 0 responses out of the first 9 evaluable patients are observed, the study will be stopped. In any other situation, the study will be continued until 17 patients are evaluable for response per cohort. If ≤2 responses are observed the study will accept the null hypothesis. If >2 responses are observed, the null hypothesis will be rejected. In the third cohort (other SGC) 9 patients will be included to evaluate the efficacy of cabozantinib in other subtypes of c-MET positive SGC. Because different subtypes are included in this cohort, these results are hypothesis forming but will not be used for statistical analysis. Therefore, this study cohort will be closed after the first stage with 9 patients.
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: cabozantinib<br>cabozantinib 60 mg tablets OD | Drug: Cabozantinib<br>* cabozantinib tablets (Cabometyx®) once daily until progressive disease, intolerable toxicity, or investigator and/or patient decision to withdraw for a maximum duration of 2 years.<br>* Other names: cabometyx;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| overall response rate | Response will be measured according to RECIST version 1.1, the overall response rate is defined as the sum of the complete remissions plus partial responses. The best response will be used in each patient | every 8 weeks (first year of treatment) and every 12 weeks (second year of treatment) a CT/MRI scan will be made to asses the response rate until progressive disease | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| progression free survival | progression free survival is defined as time from study enrollment until disease progression or death. Outcome will be scored as 'progressed' or 'censored' according to the FDA guidance for industry of clinical trial endpoints. | every 8 weeks (first year of treatment) and every 12 weeks (second year of treatment) a CT/MRI scan will be made to asses PFS until progressive disease | 
| overall survival | overall survival is defined as time from study enrollment until date of death of any cause. Analysis of OS will be done at the end of the study (study related follow-up will be until 3 years after start of treatment) | Every OPD visit (starting with every 2 weeks, increasing to every 12 weeks after 1 year) | 
| duration of response | duration of response is defined as time from study enrollment until date of documented tumor progression or death. Only patients with a CR or PR will be included in the assessment of duration of response. | every 8 weeks (first year of treatment) and every 12 weeks (second year of treatment) a CT/MRI scan will be made to asses duration of response until progressive disease | 
| clinical benefit rate | defined as the sum of complete remissions, partial responses, and patients with stable disease for >6 months. | every 8 weeks (first year of treatment) and every 12 weeks (second year of treatment) a CT/MRI scan will be made to asses the clinical benefit rate until progressive disease | 
| Number of participants with treatment-related adverse events as assessed by CTCAE v5.0 | adverse events will be reported as descriptive statistics in a table | through study completion. At every visit AE's will be recorded. Scheduled visits will be planned 2, 4, 6, 8, 12, 16, 20, 24, 32, 40, 48, 56, 68, 80, 92 and 104 weeks after start of treatment | 
| quality of life based on the EORTC QLQ-C30 questionnaire |  | patients are asked to fill in the questionnaires in week 0 (before start of treatment), week 8, 16, 24, 40, 56, and at progressive disease (up to 104 weeks after start of study medication). | 
| quality of life based on the EORTC QLQ-H&N35 questionnaire |  | patients are asked to fill in the questionnaires in week 0 (before start of treatment), week 8, 16, 24, 40, 56, and at progressive disease (up to 104 weeks after start of study medication). | 
| quality of life based on the PSSHN questionnaire |  | patients are asked to fill in the questionnaire in week 0 (before start of treatment), week 8, 16, 24, 40, 56, and at progressive disease (up to 104 weeks after start of study medication).. | 
| pain level assessed by the VAS(visual analog scale) questionnaire | scale range 0-10, in which a higher score represents more pain | patients are asked to fill in the questionnaire in week 0 (before start of treatment), week 8, 16, 24, 40, 56, and at progressive disease (up to 104 weeks after start of study medication). | 
| response rate with continues tumor shrinkage end-points | response rate depicted in a waterfall plot | every 8 weeks (first year of treatment) and every 12 weeks (second year of treatment) a CT/MRI scan will be made to asses the response rate until progressive disease | 
| circulating tumor DNA levels | circulating tumor DNA levels will be assessed to evaluate whether treatment response and disease progression can be predicted. | circulating tumor DNA levels will be measured at baseline, at week 2, week 4 and before every evaluation CT/MRI scan. | 
| correlation of c-MET immunohistochemical score with treatment response | c-MET immunohistochemical score ranges from 0 to 300. | c-MET will be measured once (before treatment). Response will be measured every 8 weeks (first year) and every 12 weeks (second year of treatment) | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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salivary gland cancer, adenoid cystic carcinoma, salivary duct carcinoma, cabozantinib, progression free survival, overall survival, phase 2 clinical trial