everolimus 5 mg vs 10 mg/daily for patients with neuroendocrine tumors

Conditions: Neuroendocrine Tumors; Progression; Neuroendocrine Tumor Grade 1; Neuroendocrine Tumor Grade 2; Neuroendocrine Tumor of Pancreas; Neuroendocrine Tumor of the Lung; Neuroendocrine Tumor Carcinoid

Summary: everolimus is approved in many countries to treat patients with advanced/metastatic well-differentiated neuroendocrine tumors (net), providing median progression-free survival times of approximately 12 months across different types of net. however, it is can cause severe adverse effects. phase i trial demonstrated that a dose of 5mg/day/week was sufficient to inhibit cell proliferation by blocking the mtor pathway. this is a randomized, open-label, phase ii near-equivalence clinical trial of oral everolimus 5 mg vs 10 mg oral/daily and continuously in patients with grade 1 or grade 2 metastatic net, with tumor progression or intolerance to at least one line of treatment and with radiological disease progression within 6 months.

everolimus toxicity can also be serious, requiring hospital medical assistance. in a study with more than 100 latin american patients led by our group, approximately 20% of patients with net treated with everolimus 10mg/day had serious infections, such as pneumonia, abscesses, pyelonephritis, with 7% developing opportunistic infections, such as toxoplasmosis and pneumocystosis, requiring hospital admissions. the rationale for testing 5mg/day comes from the results of phase i trials of everolimus, where a dose of 5mg/day was sufficient to inhibit cell proliferation by blocking the mtor pathway. therefore, everolimus 5mg/day appears to have antitumor effects equivalent to 10mg/day, but it is less toxic than 10mg/day. retrospective data from our center also suggest that 5mg is similar to 10mg/daily in terms of time to treatment failure in patients with advanced nets (unpublished data). objectives: * to evaluate whether everolimus at a dose of 5 mg/day may be as effective, but safer, as 10 mg/day in the treatment of patients with advanced net. * to compare progression-free survival and time to treatment failure between study arms * to compare radiological response using recist v.1.1 criteria. * to compare the frequency of grade \> 1 toxicities using ctcae v.5.0. * to assess tolerability by measuring the frequency and intensity of adverse events measured by the ctcae version 5.0 criteria and the need for temporary or permanent interruption of everolimus. methods: randomized, open-label, phase ii near-equivalence clinical trial of oral everolimus 5 mg vs 10 mg oral/daily and continuously in patients with grade 1 or grade 2 metastatic net, with tumor progression or intolerance to at least one line of treatment and with radiological disease progression within 6 months. eligibility criteria: inclusion: * histological confirmation of well-differentiated grade 1/grade 2 net from gastrointestinal, pancreatic, pulmonary or unknown primary sites. * metastatic or locally advanced and unresectable disease, measurable by images * disease progression by recist 1.1 in the last 6 months assessed by local investigators * at least one previous line of systemic treatment (suspended for more than 3 weeks). * eastern cooperative oncology group (ecog) 0-2 * good organ function: * hemoglobin \> 8 g/dl * neutrophils ≥ 1,500/mm³ * platelets \> 90,000/mm³ * aspartate aminotransferase (ast) and alanine aminotransferase (alt) ≤ 2.5 x uln \[upper limit of normal\] or ≤ 5 x uln for patients with liver metastases * bilirubin ≤ 1.5 x uln, creatinine \< 1.5 mg/dl concomitant use of somatostatin analogues is allowed for patients with functioning net. exclusion: * aggressive disease requiring cytotoxic therapy * severe/uncontrolled comorbid conditions that deem participant unfit for everolimus therapy, as per investigators' judgement. * minen procedures: randomization 1:1 will be performed centrally by redcap software at ac camargo cancer center, sao paulo, brasil. * group 5 mg: participants will receive everolimus at a dose of 5 mg, orally, per day, continuously * group 10 mg group: participants will receive everolimus at a dose of 10 mg, orally, per day, continuously the participant will receive everolimus 5mg or 10mg and must take 1 (one) tablet, orally, once a day, after breakfast, starting within 4 weeks from randomization. every 4 weeks of treatment will correspond to 1 treatment cycle. before starting each cycle, participants will undergo a medical visit to evaluate undesirable effects, medical history, physical examination and check the results of blood tests. ct scans (or mri, if applicable) will be performed at every 3 cycles to assess treatment antitumor effect until progression. the treatment will last until tumor progression by recist 1.1, intolerance/ severe adverse effects or consent withdrawal. participants will be evaluated clinically and with laboratory tests every 4 weeks until resolution of any adverse effects of the treatment. patients who receive at least one dose of everolimus will be evaluated for the occurrence of toxicities sample size: n=100 patients (50 per arm) h0= 50% progression free at 12 months h1= 42% progression free at 12 months (inferior value of the 95% ci, based on radiant trials) alpha error (one-sided) = 5% beta error = 10% attrition rate = 20%

Eligibility criteria:
inclusion criteria: * histological confirmation of well-differentiated grade 1/grade 2 net from gastrointestinal, pancreatic, pulmonary or unknown primary sites. * metastatic or locally advanced and unresectable disease, measurable by images * disease progression by recist 1.1 in the last 6 months assessed by local investigators * at least one previous line of systemic treatment (suspended for more than 3 weeks). * eastern cooperative oncology group (ecog) 0-2 o good organ function: * hemoglobin \> 8 g/dl * neutrophils ≥ 1,500/mm³ * platelets \> 90,000/mm³ * aspartate aminotransferase (ast) and alanine aminotransferase (alt) ≤ 2.5 x uln \[upper limit of normal\] or ≤ 5 x uln for patients with liver metastases * bilirubin ≤ 1.5 x uln, creatinine \< 1.5 mg/dl exclusion criteria: * aggressive disease requiring cytotoxic therapy * severe/uncontrolled comorbid conditions that deem participant unfit for everolimus therapy, as per investigators' judgement. * minen