safety issues

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

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.

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