Everolimus 5 mg vs 10 mg/Daily for Patients With Neuroendocrine Tumors
- Conditions
- Neuroendocrine Tumor CarcinoidNeuroendocrine Tumor of the LungNeuroendocrine TumorsProgressionNeuroendocrine Tumor Grade 2Neuroendocrine Tumor Grade 1Neuroendocrine Tumor of Pancreas
- Interventions
- Registration Number
- NCT06472388
- Lead Sponsor
- AC Camargo Cancer Center
- Brief 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.
- Detailed Description
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also suggest that 5mg is similar to 10mg/daily in terms of time to treatment failure in patients with advanced NETs (unpublished data).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%
Recruitment & Eligibility
- Status
- RECRUITING
- Sex
- All
- Target Recruitment
- 100
-
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
- Aggressive disease requiring cytotoxic therapy
- Severe/uncontrolled comorbid conditions that deem participant unfit for everolimus therapy, as per investigators' judgement.
- MiNEN
Study & Design
- Study Type
- INTERVENTIONAL
- Study Design
- PARALLEL
- Arm && Interventions
Group Intervention Description Everolimus 5 Everolimus 5 MG oral everolimus 5 mg/daily continuously until progression or intolerance or consent withdrawal. dose reduction for toxicity is allowed. Everolimus 10 Everolimus 5 MG oral everolimus 10 mg/daily continuously until progression or intolerance or consent withdrawal. dose reduction for toxicity is allowed.
- Primary Outcome Measures
Name Time Method Progression free survival rate at 12 months 12 months Proportion of patients without radiological progression or death at 12 months from first day of everolimus
- Secondary Outcome Measures
Name Time Method progression free survival 12 months Time from first day of everolimus until radiological progression or death (time to event)
time to treatment failure 12 months fTime from first day of everolimus until progression, treatment discontinuation for toxicity or death
Trial Locations
- Locations (1)
AC Camargo Cancer Center
🇧🇷Sao Paulo, Brazil