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Trial record 62 of 2732 for:    Neoplasms | Neuroendocrine Tumors

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

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ClinicalTrials.gov Identifier: NCT03095274
Recruitment Status : Recruiting
First Posted : March 29, 2017
Last Update Posted : November 28, 2018
Sponsor:
Information provided by (Responsible Party):
Grupo Espanol de Tumores Neuroendocrinos

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.

Condition or disease Intervention/treatment Phase
Neuroendocrine Tumors Neuroendocrine Neoplasm of Lung Drug: Durvalumab Drug: Tremelimumab Phase 2

Detailed Description:
Prospective, multi-center, open label, stratified, exploratory, phase II study evaluating the efficacy and safety of durvalumab plus tremelimumab in different cohorts of patients with advanced/metastatic, histologically confirmed, grade 1/2 (G1/G2) of the 2010 WHO classification neuroendocrine tumors of the pancreas, gastrointestinal tract and lung origins and grade 3 (G3) of gastroenteropancreactic system or unknown primary site (excluding lung primaries) after progression to previous therapies.

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 126 participants
Allocation: Non-Randomized
Intervention Model: Single Group Assignment
Intervention Model Description: The study includes a combined treatment of Durvalumab plus Tremelimumab
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: A Phase II Study of Durvalumab (MEDI4736) Plus Tremelimumab for the Treatment of Patients With Advanced Neuroendocrine Neoplasms of Gastroenteropancreatic or Lung Origin (the DUNE Trial)
Actual Study Start Date : April 11, 2017
Estimated Primary Completion Date : April 2020
Estimated Study Completion Date : April 2020

Resource links provided by the National Library of Medicine

Drug Information available for: Durvalumab

Arm Intervention/treatment
Experimental: Durvalumab

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
Durvalumab, 1500 mg Q4W for 12 months.
Other Name: MEDI4736

Experimental: Tremelimumab

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
Tremelimumab 75 mg Q4W for up to 4 doses/cycles.
Other Name: CP-675,206




Primary Outcome Measures :
  1. Clinical Benefit Rate [ Time Frame: 9 months ]
    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.


Secondary Outcome Measures :
  1. Overall Response Rate [ Time Frame: 9 months ]
    by immune-related Response Evaluation Criteria In Solid Tumors (irRECIST) criteria

  2. Duration of response [ Time Frame: 9 months ]
    by immune-related Response Evaluation Criteria In Solid Tumors (irRECIST) criteria

  3. Progression Free Survival [ Time Frame: 9 months ]
    by immune-related Response Evaluation Criteria In Solid Tumors (irRECIST) criteria

  4. Safety - toxicities as defined by CTCAE, v4.0 [ Time Frame: 9 months ]
    Based on subjects who experienced toxicities as defined by CTCAE, v4.0 The attribution to drug, time-of-onset, duration of the event, its resolution, and any concomitant medications.

  5. Overall Survival [ Time Frame: 9 months ]
    Time between start of treatment and death.

  6. Response Status [ Time Frame: 12 months ]
    by irRECIST criteria, at 6, 9 and 12 months after start of study treatment.


Other Outcome Measures:
  1. Biochemical Response [ Time Frame: 9 months ]
    Changes in CgA and NSE levels and its association with response rate and progression-free survival.

  2. Tumor and blood biomarkers [ Time Frame: 9 months ]
    Whether baseline tumor and blood biomarkers may be predictive of response to durvalumab and tremelimumab therapy.



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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  1. Written informed consent obtained from the subject prior to performing any protocol-related procedures.
  2. Age >18 years at time of study entry.
  3. Subjects must have histologically confirmed diagnosis of one of the following advanced/metastatic neuroendocrine tumor types:

    1. 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).
    2. 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.
    3. 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.
    4. 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.
  4. 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.
  5. 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.
  6. Subjects must have evidence of measurable disease meeting the following criteria:

    1. 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.
    2. 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.
    3. 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 .
  7. Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1.
  8. Life expectancy of at least 12 weeks.
  9. Adequate normal organ and marrow function as defined below: Haemoglobin ≥ 9.0 g/dL; Absolute neutrophil count (ANC) ≥ 1.5 x 109/L (> 1500 per mm3); Platelet count ≥ 100 x 109/L (>100,000 per mm3).
  10. Serum bilirubin ≤ 1.5 x institutional upper limit of normal (ULN). This will not apply to subjects with confirmed Gilbert's syndrome (persistent or recurrent hyperbilirubinemia that is predominantly unconjugated in the absence of hemolysis or hepatic pathology), who will be allowed only in consultation with their physician.
  11. AST (SGOT)/ALT (SGPT) ≤ 2.5 x institutional upper limit of normal unless liver metastases are present, in which case it must be ≤ 5x ULN.
  12. Serum creatinine CL>40 mL/min by the Cockcroft-Gault formula (Cockcroft and Gault 1976) or by 24-hour urine collection for determination of creatinine clearance.
  13. Female subjects must either be of non-reproductive potential (ie, post-menopausal by history: ≥60 years old and no menses for ≥1 year without an alternative medical cause; OR history of hysterectomy, OR history of bilateral tubal ligation, OR history of bilateral oophorectomy) or must have a negative serum pregnancy test upon study entry.
  14. Subject is willing and able to comply with the protocol for the duration of the study including undergoing treatment and scheduled visits and examinations including follow up.

Exclusion Criteria:

  1. Involvement in the planning and/or conduct of the study.
  2. Participation in another clinical study with an investigational product during the last 4 weeks.
  3. WHO Classification G3 neuroendocrine neoplasms of lung origin (oat cell/large cell lung cancer).
  4. Prior treatment with anti-PDL-1/anti-PD-1 or anti-CTL-4 therapy.
  5. 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.
  6. Known history of previous clinical diagnosis of tuberculosis.
  7. 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.
  8. 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.
  9. Active or prior documented inflammatory bowel disease (e.g., Crohn's disease, ulcerative colitis).
  10. History of allogeneic organ transplant.
  11. History of hypersensitivity to durvalumab, tremelimumab or any excipient.
  12. 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.
  13. 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.
  14. 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.
  15. Subjects having known history of, or any evidence of interstitial lung disease or active, noninfectious pneumonitis.
  16. Any prior Grade ≥3 immune-related adverse event (irAE) while receiving any previous immunotherapy agent, or any unresolved irAE >Grade 1.
  17. Subjects who have received any anti-cancer treatment within 21 days or any investigational agent within 30 days prior to the first dose of study drug and should have recovered from any toxicity related to previous anti-cancer treatment. This does not apply to the use of somatostatin analogues for symptomatic therapy.
  18. Major surgery within 3 weeks prior to the first dose of study drug.
  19. Subjects having > 1+ proteinuria on urine dipstick testing will undergo 24h urine collection for quantitative assessment of proteinuria. Subjects with urine protein ≥ 1 g/24h will be ineligible.
  20. Significant cardiovascular impairment: history of congestive heart failure greater than New York Heart Association (NYHA) Class II, unstable angina; myocardial infarction or stroke within 6 months of the first dose of study drug, or cardiac arrhythmia requiring medical treatment.
  21. Mean QT interval corrected for heart rate (QTc) ≥470 ms calculated from 3 electrocardiograms (ECGs) using Fredericia's Correction.
  22. Bleeding or thrombotic disorders or use of anticoagulants, such as warfarin, or similar agents requiring therapeutic international normalized ration (INR)monitoring. Treatment with low molecular weight heparin (LMWH) is allowed.
  23. Active hemoptysis (bright red blood of at least 0.5 teaspoon) within 3 weeks prior to the first dose of study drug.
  24. Patients with tumoral disease in the head and neck region, such as paratracheal or periesophageal lymph node involvement, or with infiltration of structures in the digestive tract, or vascular pathways that represent a risk of increased bleeding.
  25. Patients of cohort 1 with neuroendocrine tumors of pulmonary origin or pulmonary metastases with evidence of active bleeding.
  26. Patients with evidence of digestive bleeding.
  27. Active infection (any infection requiring treatment).
  28. Active malignancy (except for differentiated thyroid carcinoma, or definitively treated melanoma in-situ, basal or squamous cell carcinoma of the skin, or carcinoma in-situ of the cervix) within the past 24 months.
  29. Female patients who are pregnant or breastfeeding or male or female patients of reproductive potential who are not willing to employ highly effective birth control from screening to 180 days after the last dose of durvalumab + tremelimumab combination therapy or 90 days after the last dose of durvalumab monotherapy, whichever is the longer time period.
  30. Documented active alcohol or drug abuse.
  31. Patients with a prior history of non-compliance with medical regimens.
  32. Any condition that, in the opinion of the investigator, would interfere with evaluation of study treatment or interpretation of patient safety or study results.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03095274


Contacts
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Contact: Jaume Capdevila, M.D. +34 932746085 jacapdevila@vhebron.net

Locations
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Spain
Hospital Universitario Marqués de Valdecilla Recruiting
Santander, Asturias, Spain
Contact: Carlos López López, M.D.    +34 942202515    clopez@humv.es   
Principal Investigator: Carlos López López, M.D.         
Instituto Catalán de Oncología Badalona Recruiting
Badalona, Barcelona, Spain
Contact: José Luis Manzano Mozo, M.D.    +34 934978925    jmanzano@iconcologia.net   
Principal Investigator: José Luis Manzano Mozo, M.D.         
Complejo Hospitalario de Navarra Recruiting
Pamplona, Navarra, Spain
Contact: Antonio Viudez Berral, M.D.    +34 848 42 22 22    antonio.viudez.berral@navarra.es   
Principal Investigator: Antonio Viudez Berral, M.D.         
Hospital Duran i Reynals/ICO L'Hospitalet Recruiting
Barcelona, Spain
Contact: Alexandre Teulé Vega, M.D.    +34 932607744    ateule@iconcologia.net   
Principal Investigator: Alexandre Teulé Vega, M.D.         
Hospital Universitari Vall d'Hebron Recruiting
Barcelona, Spain
Contact: Jaume Capdevila, M.D., Ph.D.    +34 932746085    jacapdevila@vhebron.net   
Principal Investigator: Jaume Capdevila, M.D.         
Hospital Universitario de Burgos Recruiting
Burgos, Spain
Contact: Guillermo Crespo Herrero, M.D.    +34 947281800    gcrespoherrero@hotmail.com   
Principal Investigator: Guillermo Crespo Herrero, M.D.         
Hospital Universitario Donostia Recruiting
Donostia San Sebastian, Spain
Contact: Adelaida La Casta Muñoa, M.D.    +34 943007000    adelaida.lacastamunoa@osakidetza.net   
Principal Investigator: Adelaida La Casta Muñoa, M.D.         
Hospital Universitario Virgen de las Nieves Recruiting
Granada, Spain
Contact: Encarnación González Flores, M.D.    +34 958020000    encarna.gonzalez@hotmail.es   
Principal Investigator: Encarnación González Flores, M.D.         
Hospital Universitario 12 de Octubre Recruiting
Madrid, Spain
Contact: Rocío García-Carbonero, M.D.    +34 913908307    rgcarbonero@gmail.com   
Principal Investigator: Rocío García-Carbonero, M.D.         
Hospital Universitario Gregorio Marañón Recruiting
Madrid, Spain
Contact: Montserrat Blanco Codesido, M.D.    +34 915868000    montseblancocodesido@yahoo.es   
Principal Investigator: Montserrat Blanco Codesido, M.D.         
Hospital Universitario HM Sanchinarro Recruiting
Madrid, Spain
Contact: Antonio Cubillo Gracián, M.D.    +34 902089800    acubillo@hmhospitales.com   
Principal Investigator: Antonio Cubillo Gracián, M.D.         
Hospital Universitario La Paz Recruiting
Madrid, Spain
Contact: Paula Jiménez Fonseca, M.D.    +34 985106121    palucaji@hotmail.com   
Principal Investigator: Paula Jiménez Fonseca, M.D.         
Hospital Universitario Ramón y Cajal Recruiting
Madrid, Spain
Contact: Teresa Alonso, M.D.    +34913368000    talonso@oncologiahrc.com   
Principal Investigator: Teresa Alonso Gordoa, M.D.         
Hospital General Universitario Morales Meseguer Recruiting
Murcia, Spain
Contact: Alberto Carmona Bayonas, M.D.    +34 968 36 09 00    alberto.carmonabayonas@gmail.com   
Principal Investigator: Alberto Carmona Bayonas, M.D.         
Hospital Universitario Virgen de la Victoria Recruiting
Málaga, Spain
Contact: Isabel Sevilla García, M.D.    +34 951032466    isevilla02@yahoo.es   
Principal Investigator: Isabel Sevilla García, M.D.         
Hospital Universitario de Canarias Recruiting
Santa Cruz de Tenerife, Spain
Contact: Marta Llanos Muñoz, M.D.    +34 922677351    martallanosmunoz@gmail.com   
Principal Investigator: Marta Llanos Muñoz, M.D.         
Hospital Universitario Virgen del Rocío Recruiting
Sevilla, Spain
Contact: Marta Benavent Viñuales, M.D.    +34 955002113    martabenaventv@gmail.com   
Principal Investigator: Marta Benavent Viñuales, M.D.         
Hospital Universitario y Politécnico La Fe Recruiting
Valencia, Spain
Contact: Ángel Segura Huerta, M.D.    +34 961244000    segura_ang@gva.es   
Principal Investigator: Ángel Segura Huerta, M.D.         
Hospital Universitario Miguel Servet Recruiting
Zaragoza, Spain
Contact: Vicente Alonso Orduña, M.D.    +34 976765500    valonsoo@salud.aragon.es   
Principal Investigator: Vicente Alonso Orduña, M.D.         
Sponsors and Collaborators
Grupo Espanol de Tumores Neuroendocrinos
Investigators
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Study Chair: Jaume Capdevila, M.D. Hospital Vall d'Hebron

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Responsible Party: Grupo Espanol de Tumores Neuroendocrinos
ClinicalTrials.gov Identifier: NCT03095274     History of Changes
Other Study ID Numbers: ESR 15-11561-61-DUNE
2016-002858-20 ( EudraCT Number )
First Posted: March 29, 2017    Key Record Dates
Last Update Posted: November 28, 2018
Last Verified: November 2018
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No

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Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No

Additional relevant MeSH terms:
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Neoplasms
Neuroendocrine Tumors
Lung Neoplasms
Neuroectodermal Tumors
Neoplasms, Germ Cell and Embryonal
Neoplasms by Histologic Type
Neoplasms, Nerve Tissue
Respiratory Tract Neoplasms
Thoracic Neoplasms
Neoplasms by Site
Lung Diseases
Respiratory Tract Diseases
Durvalumab
Tremelimumab
Antibodies, Monoclonal
Antineoplastic Agents, Immunological
Antineoplastic Agents
Immunologic Factors
Physiological Effects of Drugs