Everolimus Plus Best Supportive Care vs Placebo Plus Best Supportive Care in the Treatment of Patients With Advanced Neuroendocrine Tumors (GI or Lung Origin) (RADIANT-4)

Novartis

Status and phase: Completed; Phase 3

Conditions: Neuroendocrine Tumors; Advanced NET of GI Origin; Advanced NET of Lung Origin

Treatments: Drug: Placebo; Drug: Everolimus; Other: Best suportive care (BSC)

Study type: Interventional

Funder types: Industry

Identifiers

NCT01524783

2011-002887-26 (Registry Identifier)

CRAD001T2302

Details and patient eligibility

About

The purpose of this study is to compare the antitumor activity of everolimus plus best supportive care versus placebo plus best supportive care in patients with progressive nonfunctional neuroendocrine tumor (NET) of gastrointestinal (GI) or lung origin without a history of, or current symptoms of carcinoid syndrome.

Full description

This was a prospective, multi-center, randomized, double-blind, parallel-group, placebo-controlled, two-arm Phase III study comparing the efficacy and safety of everolimus 10 mg daily to placebo in patients with advanced NET of GI or lung origin without a history of, or current symptoms of carcinoid syndrome.

After assessment of eligibility, participants qualifying for the study were randomized in a 2:1 ratio to receive either everolimus or matching placebo. Participants received daily oral doses of 10 mg everolimus or matching placebo as study drug. In both arms, the study drug was combined with best supportive care and treatment cycles were defined as 28 days. Participants were treated until disease progression as per Response Evaluation Criteria In Solid Tumors (RECIST) 1.0, intolerable toxicity, death, lost to follow-up or consent withdrawal. Regardless of the reason for study drug discontinuation, participants had a safety follow-up visit scheduled 30 days after the last dose of the study drug.

Per data monitoring committee recommendation, all participants on treatment with placebo were allowed to crossover to open-label treatment with everolimus. This change was implemented through protocol amendment 3 (issued on 06-May-2016) after which remaining participants entered into open-label phase of the study.

Enrollment: 302 patients

Sex: All

Ages: 18+ years old

Volunteers: No Healthy Volunteers

Inclusion criteria

• Pathologically confirmed, well differentiated (G1 or G2), advanced (unresectable or metastatic), neuroendocrine tumor of GI or lung origin
• No history of and no active symptoms related to carcinoid syndrome
• In addition to treatment-naive patients, patients previously treated with SSA, Interferon (IFN), one prior line of chemotherapy, and/or PRRT were allowed into the study. Pretreated patients had to have progressed on or after the last treatment
• Radiological documented disease progression within 6 months prior to randomization
• Measurable disease
• WHO performance status ≤1
• Adequate bone marrow, liver and renal function

Exclusion criteria

• Patients with poorly differentiated neuroendocrine carcinoma, high-grade neuroendocrine carcinoma, adenocarcinoid, pancreatic islet cell carcinoma, insulinoma, glucagonoma, gastrinoma, goblet cell carcinoid, large cell neuroendocrine carcinoma and small cell carcinoma

• Patients with pancreatic NET or NET of origins other than GI or Lung

• Patients with history of or active symptoms of carcinoid syndrome (e.g. flushing, diarrhea)

• Patients with more than one line of prior chemotherapy

• Prior targeted therapy

• Hepatic intra-arterial embolization within the last 6 months. Cryoablation or radiofrequency ablation of hepatic metastases within 2 months of randomization

• Prior therapy with mTOR inhibitors (e.g. sirolimus, temsirolimus, deforolimus)

• Known intolerance or hypersensitivity to everolimus or other rapamycin analogs (e.g. sirolimus, temsirolimus)

• Known impairment of gastrointestinal (GI) function or GI disease that may significantly alter the absorption of oral everolimus

• Uncontrolled diabetes mellitus as defined by HbA1c >8% despite adequate therapy

• Patients who had any severe and/or uncontrolled medical conditions such as:

  • unstable angina pectoris, symptomatic congestive heart failure, myocardial infarction ≤6 months prior to randomization, serious uncontrolled cardiac arrhythmia
  • active or uncontrolled severe infection
  • liver disease such as cirrhosis, decompensated liver disease, and chronic hepatitis (i.e. quantifiable HBV-DNA and/or positive HbsAg, quantifiable HCV-RNA)

• Chronic treatment with corticosteroids or other immunosuppressive agents

• Known history of HIV seropositivity

• Pregnant or nursing (lactating) women

Other protocol-defined inclusion/exclusion criteria might apply.

Trial design

Primary purpose: Treatment

Allocation: Randomized

Interventional model: Parallel Assignment

Masking: Quadruple Blind

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302 participants in 2 patient groups, including a placebo group

Everolimus + BSC

Experimental group

Description:

Participants received everolimus 10 mg once daily plus best supportive care (BSC) throughout the study

Treatment:

Other: Best suportive care (BSC)

Drug: Everolimus

Placebo + BSC

Placebo Comparator group

Description:

Participants received matching placebo once daily plus best supportive care (BSC) during the blinded period. Participants were allowed to crossover to treatment with everolimus 10mg once daily plus BSC during the open-label period.

Treatment:

Drug: Placebo

Other: Best suportive care (BSC)