Durvalumab (MEDI4736) Plus Tremelimumab for Advanced Neuroendocrine Neoplasms of Gastroenteropancreatic or Lung Origin

NCT03095274 | Completed Phase 2 Results

• 2 other identifiers: ESR 15-11561-61-DUNE2016-002858-20
• Study Type: interventional
• Target: 126
• Locations: 1 country
• Sites: 19

Brief Summary

Well-differentiated gastroenteropancreatic and lung neuroendocrine tumors are generally malignancies with a prolonged natural history. However, clinical behavior is heterogeneous and when tumor progression is observed, treatment options are limited. The most used therapy for neuroendocrine tumors management are somatostatin analogs. However, even the use in lung carcinoids is quite usual, no antitumoral activity has been demonstrated. Tremelimumab and Durvalumab combination could be more efficient drugs to improve immune system activation and could obtain a significantly higher clinical benefit in these patients. Tremelimumab and Durvalumab would be the first immune combination agents showing efficacy in neuroendocrine neoplasms of different origins.

Conditions

Neuroendocrine Tumors; Neuroendocrine Neoplasm of Lung

Outcome Measures

Primary Outcomes (2)

• Clinical Benefit Rate (CBR)

  by Response Evaluation Criteria In Solid Tumors (RECIST) version 1.1, which is defined as the percentage of patients achieving complete response (CR), partial response (PR), or stable disease (SD) at month 9 after durvalumab plus tremelimumab was started. Assessed by Computed tomography scan (CT) or magnetic resonance imaging (MRI) CR is defined as disappearance of all target lesions; PR as \>=30% decrease in the sum of the longest diameter of target lesions; SD as no changes in target lesions (i.e. \<20% growth and \<30% decrease). CBR = CR + PR +SD. Some patients were not evaluable as they had no tumor assessments.

  9 months

• Overall Survival

  Time between start of treatment and death. Here we report the median time to death from any cause, estimated by Kaplan Meier method. The times reported in here are the median time to event estimated by Kaplan Meier and that is why the number of months might be higher or lower than the overall and patient-specific follow-up.

  Throughout the study period. Each patients has been followed approximately 24 months, up to 30 months.

Secondary Outcomes (7)

• Overall Response Rate

  9 months

• Duration of Response

  Throughout the study period, approximately 24 months

• Progression Free Survival

  Throughout the study period, approximately 24 months

• Safety - Toxicities as Defined by CTCAE, v4.0

  9 months

• Response Status

  12 months

Study Arms (2)

Durvalumab

EXPERIMENTAL

Durvalumab, 1500 mg Q4W (equivalent to 20 mg/kg Q4W) for 12 months in patients ≥ 30kg. Weight-based dosing should be used for patients \<30 kg: durvalumab 20 mg/kg.

Drug: Durvalumab

Tremelimumab

EXPERIMENTAL

Tremelimumab 75 mg Q4W (equivalent to 1 mg/kg Q4W) for up to 4 doses/cycles in patients ≥ 30kg. Weight-based dosing should be used for patients \<30 kg: tremelimumab 1 mg/kg Q4.

Drug: Tremelimumab

Interventions

Durvalumab DRUG

Durvalumab, 1500 mg Q4W for 12 months.

Also known as: MEDI4736

Durvalumab

Tremelimumab DRUG

Tremelimumab 75 mg Q4W for up to 4 doses/cycles.

Also known as: CP-675,206

Tremelimumab

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Written informed consent obtained from the subject prior to performing any protocol-related procedures.
• Age \>18 years at time of study entry.
• Subjects must have histologically confirmed diagnosis of one of the following advanced/metastatic neuroendocrine tumor types:
• Cohort 1: Well-moderately differentiated neuroendocrine tumors of the lung ( mitotic count ≤10 mitoses x 10 HPF), also known as typical and atypical lung carcinoids, that have progressed to prior somatostatin analog therapy and/or one prior targeted therapy or chemotherapy (only one prior systemic therapy, with the exception of patients that have been treated with somatostatin analogues and other systemic treatment, when two prior treatments are allowed).
• Cohort 2: Well-moderately differentiated G1/G2 (WHO grade 1 and 2) gastrointestinal neuroendocrine tumors after progression to somatostatin analogs and one targeted therapy (prior targeted therapy could be everolimus or a multikinase inhibitor). Prior therapies with interferon alpha-2b or radionucleotide therapy are allowed.
• Cohort 3: Well-moderately differentiated neuroendocrine tumors G1/G2 (WHO grade 1 and 2) from pancreatic origin after progression to standard therapies (chemotherapy, somatostatin analogs and target therapy); patients must be treated with at least two prior systemic treatment lines and a maximum of four previous treatment lines.
• Cohort 4: Neuroendocrine neoplasms (WHO grade 3) of gastroenteropancreatic origin of unknown primary site (excluding lung primary tumors) after progression to first-line chemotherapy with a platinum based regimen.
• For patients included in cohorts 1, 2 and 3: WHO Classification G1/G2 (mitotic count ≤10 mitoses x 10 HPF) lung typical and atypical carcinoids for cohort 1, G1/G2 (Ki67≤20% and mitotic count ≤20 mitoses x 10 HPF) gastrointestinal for cohort 2 (including stomach, small intestine and colorectal origins), G1/G2 (Ki67≤20% and mitotic count ≤20 mitoses x 10 HPF) pancreatic for cohort 3.
• For patients included in cohort 4: WHO classification G3 (Ki67\>20% or mitotic count \>20 mitoses x 10 HPF) gastroenteropancreatic neuroendocrine carcinomas (NEC) or liver metastases of G3 NEC of unknown primary site.
• Subjects must have evidence of measurable disease meeting the following criteria:
• In case of more than one target lesion, it should be identified at least 1 lesion of ≥ 1.0 cm in the longest diameter for a non lymph node, or ≥ 1.5 cm in the short-axis diameter for a lymph node, which is serially measurable according to RECIST 1.1 using computerized tomography/magnetic resonance imaging (CT/MRI). If there is only one target lesion and it is a non-lymph node, it should have a longest diameter of ≥ 1.5 cm.
• Lesions that have had external beam radiotherapy (EBRT) or loco-regional therapies such as radiofrequency (RF) ablation or liver embolization must show evidence of progressive disease based on RECIST 1.1 to be deemed a target lesion.
• Subjects must show evidence of disease progression by radiologic image techniques within 12 months (an additional month will be allowed to accommodate actual dates of performance of scans, i.e., within ≤ 13 months) prior to signing informed consent, according to RECIST 1.1 .
• Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1.
• Life expectancy of at least 12 weeks.

You may not qualify if:

• Involvement in the planning and/or conduct of the study.
• Participation in another clinical study with an investigational product during the last 4 weeks.
• WHO Classification G3 neuroendocrine neoplasms of lung origin (oat cell/large cell lung cancer).
• Prior treatment with anti-PDL-1/anti-PD-1 or anti-CTL-4 therapy.
• Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, symptomatic congestive heart failure, uncontrolled hypertension, unstable angina pectoris, cardiac arrhythmia, active peptic ulcer disease or gastritis, active bleeding diatheses including any subject known to have evidence of acute or chronic hepatitis B (e.g., HBsAg reactive), hepatitis C (e.g., HCV RNA \[qualitative\] is detected) or known history of Human Immunodeficiency Virus (HIV) (HIV 1/2 antibodies), or psychiatric illness/social situations that would limit compliance with study requirements or compromise the ability of the subject to give written informed consent.
• Known history of previous clinical diagnosis of tuberculosis.
• Current or prior use of immunosuppressive medication within 28 days before the first dose of durvalumab or tremelimumab, with the exceptions of intranasal and inhaled corticosteroids or systemic corticosteroids at physiological doses, which are not to exceed 10 mg/day of prednisone, or an equivalent corticosteroid.
• Active or prior documented autoimmune disease within the past 2 years NOTE: Subjects with vitiligo, Grave's disease, or psoriasis not requiring systemic treatment (within the past 2 years) are not excluded.
• Active or prior documented inflammatory bowel disease (e.g., Crohn's disease, ulcerative colitis).
• History of allogeneic organ transplant.
• History of hypersensitivity to durvalumab, tremelimumab or any excipient.
• Subjects having a diagnosis of immunodeficiency or are receiving systemic steroid therapy or any other form of immunosuppressive therapy within 28 days prior to the first dose of trial treatment.
• Knowledge of active central nervous system (CNS) metastases and/or carcinomatous meningitis. Subjects with previously treated brain metastases may participate provided they have stable brain metastases \[without evidence of progression by imaging confirmed \[by magnetic resonance imaging (MRI) if MRI was used at prior imaging, or confirmed by computed tomography (CT) imaging if CT used at prior imaging\] for at least four weeks prior to the first dose of trial treatment; also, any neurologic symptoms must have returned to baseline\], have no evidence of new or enlarging brain metastases,and have not used steroids for brain metastases for at least 7 days prior to trial treatment. This exception does not include carcinomatous meningitis, as subjects with carcinomatous meningitis are excluded regardless of clinical stability.
• Receipt of live attenuated vaccination within 30 days prior to study entry or within 30 days of receiving durvalumab or tremelimumab. Note: The killed virus vaccines used for seasonal influenza vaccines for injection are allowed; however intranasal influenza vaccines (e.g., FluMist®) are live attenuated vaccines, and are not allowed.
• Subjects having known history of, or any evidence of interstitial lung disease or active, noninfectious pneumonitis.

Sponsors & Collaborators

• Grupo Espanol de Tumores Neuroendocrinos: lead

Study Sites (19)

Instituto Catalán de Oncología Badalona

Badalona, Barcelona, Spain

Location

Complejo Hospitalario de Navarra

Pamplona, Navarre, Spain

Location

Hospital Universitario Marqués de Valdecilla

Santander, Principality of Asturias, Spain

Location

Hospital Duran i Reynals/ICO L'Hospitalet

Barcelona, Spain

Location

Hospital Universitari Vall d'Hebron

Barcelona, Spain

Location

Hospital Universitario de Burgos

Burgos, Spain

Location

Hospital Universitario Donostia

Donostia / San Sebastian, Spain

Location

Hospital Universitario Virgen de las Nieves

Granada, Spain

Location

Hospital Universitario 12 de Octubre

Madrid, Spain

Location

Hospital Universitario Gregorio Marañón

Madrid, Spain

Location

Hospital Universitario HM Sanchinarro

Madrid, Spain

Location

Hospital Universitario La Paz

Madrid, Spain

Location

Hospital Universitario Ramón y Cajal

Madrid, Spain

Location

Hospital Universitario Virgen de la Victoria

Málaga, Spain

Location

Hospital General Universitario Morales Meseguer

Murcia, Spain

Location

Hospital Universitario de Canarias

Santa Cruz de Tenerife, Spain

Location

Hospital Universitario Virgen del Rocío

Seville, Spain

Location

Hospital Universitario y Politécnico La Fe

Valencia, Spain

Location

Hospital Universitario Miguel Servet

Zaragoza, Spain

Location

Related Publications (1)

• Capdevila J, Hernando J, Teule A, Lopez C, Garcia-Carbonero R, Benavent M, Custodio A, Garcia-Alvarez A, Cubillo A, Alonso V, Carmona-Bayonas A, Alonso-Gordoa T, Crespo G, Jimenez-Fonseca P, Blanco M, Viudez A, La Casta A, Sevilla I, Segura A, Llanos M, Landolfi S, Nuciforo P, Manzano JL. Durvalumab plus tremelimumab for the treatment of advanced neuroendocrine neoplasms of gastroenteropancreatic and lung origin. Nat Commun. 2023 May 23;14(1):2973. doi: 10.1038/s41467-023-38611-5.

  PMID: 37221181 DERIVED

MeSH Terms

Conditions

Neuroendocrine Tumors

Interventions

durvalumab; tremelimumab

Condition Hierarchy (Ancestors)

Neuroectodermal Tumors; Neoplasms, Germ Cell and Embryonal; Neoplasms by Histologic Type; Neoplasms; Neoplasms, Nerve Tissue

Results Point of Contact

• Title: A responsibility person designate by sponsor
• Organization: MFAR

investigacion@mfar.net

934344412

Study Officials

• Jaume Capdevila, M.D., Ph.D.

  Hospital Universitari Vall d'Hebron, Barcelona

  STUDY CHAIR

Publication Agreements

• PI is Sponsor Employee: No
• Restrictive Agreement: No

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: NON RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Model Details: The study includes a combined treatment of Durvalumab plus Tremelimumab

Study Record Dates

• First Submitted: March 23, 2017
• First Posted: March 29, 2017
• Study Start: April 11, 2017
• Primary Completion: November 30, 2019
• Study Completion: May 23, 2022
• Last Updated: January 9, 2025
• Results First Posted: January 9, 2025

Record last verified: 2024-11

Data Sharing

• IPD Sharing: Will not share

Locations

ES (19)