Everolimus 5 mg vs 10 mg/Daily for Patients With Neuroendocrine Tumors (EVENET)

Randomized Phase II Trial of Everolimus 5 mg vs 10 mg/Daily for Patients With Advanced Neuroendocrine Tumors

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.

Study Overview

• Status: Recruiting
• Conditions: Progression; Neuroendocrine Tumors; Neuroendocrine Tumor of the Lung; Neuroendocrine Tumor Grade 2; Neuroendocrine Tumor Grade 1; Neuroendocrine Tumor of Pancreas; Neuroendocrine Tumor Carcinoid
• Intervention / Treatment: Drug: Everolimus 5 MG

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also suggest that 5mg is similar to 10mg/daily in terms of time to treatment failure in patients with advanced NETs (unpublished data).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%

• Study Type: Interventional
• Enrollment (Estimated): 100
• Phase: Phase 2

Contacts and Locations

• Study Contact: Name: Rachel P Riechelmann, MD; Phone Number: +55112189500; Email: rachel.riechelmann@accamargo.org.br

Study Locations

• Brazil
  • Sao Paulo, Brazil, 01509010
    • Recruiting
    • AC Camargo Cancer Center
    • Contact: Rachel P Riechelmann, MD; Email: rachel.riechelmann@accamargo.org.br
  • SP
    • São Paulo, SP, Brazil, 01509010
      • Recruiting
      • AC Camargo Cancer Center
      • Contact: Rachel P Riechelmann, MD; Phone Number: 2776 +5521895000; Email: rachel.riechelmann@accamargo.org.br

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Child; Adult; Older Adult
• Accepts Healthy Volunteers: No

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Everolimus 5; oral everolimus 5 mg/daily continuously until progression or intolerance or consent withdrawal. dose reduction for toxicity is allowed.	Drug: Everolimus 5 MG; oral everolimus 5 mg/daily
Active Comparator: Everolimus 10; oral everolimus 10 mg/daily continuously until progression or intolerance or consent withdrawal. dose reduction for toxicity is allowed.	Drug: Everolimus 5 MG; oral everolimus 5 mg/daily

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Progression free survival rate at 12 months	Proportion of patients without radiological progression or death at 12 months from first day of everolimus	12 months

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
progression free survival	Time from first day of everolimus until radiological progression or death (time to event)	12 months
time to treatment failure	fTime from first day of everolimus until progression, treatment discontinuation for toxicity or death	12 months

Collaborators and Investigators

• Sponsor: AC Camargo Cancer Center

Study record dates

Study Major Dates

• Study Start (Actual): April 24, 2024
• Primary Completion (Estimated): May 20, 2026
• Study Completion (Estimated): December 31, 2026

Study Registration Dates

• First Submitted: May 3, 2024
• First Submitted That Met QC Criteria: June 18, 2024
• First Posted (Actual): June 25, 2024

Study Record Updates

• Last Update Posted (Actual): June 25, 2024
• Last Update Submitted That Met QC Criteria: June 18, 2024
• Last Verified: June 1, 2024

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Digestive System Diseases; Respiratory Tract Diseases; Neoplasms by Histologic Type; Lung Diseases; Neoplasms by Site; Adenocarcinoma; Carcinoma; Neoplasms, Glandular and Epithelial; Endocrine System Diseases; Digestive System Neoplasms; Endocrine Gland Neoplasms; Respiratory Tract Neoplasms; Thoracic Neoplasms; Neuroectodermal Tumors; Neoplasms, Germ Cell and Embryonal; Neoplasms, Nerve Tissue; Pancreatic Diseases; Neoplasms; Lung Neoplasms; Pancreatic Neoplasms; Neuroendocrine Tumors; Carcinoid Tumor; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Enzyme Inhibitors; Antineoplastic Agents; Immunosuppressive Agents; Immunologic Factors; Protein Kinase Inhibitors; MTOR Inhibitors; Everolimus
• Other Study ID Numbers: 67420523.4.1001.5432

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO
• IPD Plan Description: No plan yet

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: Yes