Immunotherapy, Chemotherapy, Radiotherapy and Surgery for Synchronous Oligo-metastatic NSCLC

NCT03965468 | Active Not Recruiting Phase 2 DMC

• 3 other identifiers: ETOP 14-182018-003011-22ESR-17-13224
• Study Type: interventional
• Target: 96
• Locations: 4 countries
• Sites: 15

Brief Summary

A multicentre single arm phase II trial assessing the efficacy of immunotherapy, chemotherapy plus stereotactic radiotherapy to metastases followed by definitive surgery or radiotherapy to the locoregional primary tumour, in patients with histologically-confirmed synchronous oligo-metastatic non-small cell lung cancer (NSCLC).

Conditions

Stage IV; Oligometastasis; Non-small Cell Lung Cancer

Keywords

NSCLC

Outcome Measures

Primary Outcomes (1)

• Progression-free survival at 12 months

  The PFS rate at 1-year is the primary endpoint of this trial and it is defined as the rate of patients without a PFS event at 1-year after enrolment. The rate will be estimated as the percentage of patients without a PFS event over the total number of patients who have completed a 1-year follow-up period after the enrolment. PFS is defined as the time from the date of enrolment until documented progression or death, if progression is not documented. Progression is defined as the development of new metastatic lesions or local progression of resected or irradiated metastases or primary tumour, assessed according to RECIST criteria version 1.1

  Assessed from the date of enrolment to completion of treatment at 12 months.

Secondary Outcomes (8)

• Overall survival

  Time from date of enrolment until death from any cause. Assessed for up to 30 months.

• Pattern of disease progression

  Assessed from the date of enrolment until progression, from enrolment up to 12 months.

• Response to induction therapy

  Assessed from the start of protocol treatment until the 3-month restaging

• Distant progression-free survival

  Assessed from the date of enrolment for up to 12 months.

• Overall response

  Assessed from the start of protocol treatment across all time points until the end of follow-up, assessed for up to 30 months.

Study Arms (1)

Immunotherapy, chemotherapy, radiotherapy and surgery

EXPERIMENTAL

Durvalumab 1500 mg administered intravenously every 3 weeks for the first 4-6 cycles (during chemotherapy); Tremelimumab 75mg administered intravenously every 3 weeks for the first 4-6 cycles (only cohort 2) 4-6 cycles of chemotherapy, carboplatin AUC5 every 3 weeks plus paclitaxel 175 mg/m2, every 3 weeks; Stereotactic body radiotherapy (SBRT) of all oligo-metastatic lesions, in a maximum of 10 treatment fractions over 2 weeks, starting after week one of chemotherapy cycle 1 and completed within four weeks after start of durvalumab treatment; Restaging at 3 months; if no disease progression, proceed to definitive local treatment (surgical resection of primary tumour or radiotherapy at a minimum dose of 60-66Gy to the primary tumour). Durvalumab continues at 1500 mg intravenously every 4 weeks until progression of disease or for a maximum of 1 year from start of treatment.

Drug: Durvalumab; Drug: Carboplatin; Drug: Paclitaxel; Radiation: Stereotactic body radiation therapy (SBRT); Procedure: Surgical resection - definitive local treatment.; Radiation: Radical radiotherapy - definitive local treatment.; Drug: Tremelimumab

Interventions

Surgical resection - definitive local treatment. PROCEDURE

Surgical resection of primary tumour for patients with single station, non-bulky tumours.

Immunotherapy, chemotherapy, radiotherapy and surgery

Radical radiotherapy - definitive local treatment. RADIATION

Conventional or moderately hypo-fractionated radiotherapy to the primary tumour for other tumour stages, or in case of medical inoperability.

Immunotherapy, chemotherapy, radiotherapy and surgery

Tremelimumab DRUG

Tremelimumab is a human mAb of the IgG 2 subclass that is directed against CTLA-4 (CD152), a cell surface receptor that is expressed primarily on activated T-cells and acts to inhibit their activation. Tremelimumab completely blocks the interaction of human CTLA-4 with CD80 and CD86, resulting in increased release of cytokines (interleukin-2 and IFN-γ) from human T-cells, peripheral blood mononuclear cells and whole blood.

Immunotherapy, chemotherapy, radiotherapy and surgery

Carboplatin DRUG

Carboplatin belongs to the group of medicines known as alkylating agents. Carboplatin interferes with the growth of cancer cells, which eventually are destroyed.

Immunotherapy, chemotherapy, radiotherapy and surgery

Paclitaxel DRUG

A compound extracted from the Pacific yew tree Taxus brevifolia with antineoplastic activity. Paclitaxel binds to tubulin and inhibits the disassembly of microtubules, thereby resulting in the inhibition of cell division. This agent also induces apoptosis by binding to and blocking the function of the apoptosis inhibitor protein Bcl-2 (B-cell Leukemia 2).

Immunotherapy, chemotherapy, radiotherapy and surgery

Stereotactic body radiation therapy (SBRT) RADIATION

SBRT of all oligo-metastatic lesions

Immunotherapy, chemotherapy, radiotherapy and surgery

Durvalumab DRUG

Durvalumab is a human monoclonal antibody (mAb) of the immunoglobulin G (IgG) 1 kappa subclass that inhibits binding of PD-L1. Durvalumab is expected to stimulate the patient's antitumour immune response by binding to PD L1 and shifting the balance toward an antitumour response.

Also known as: Imfinzi

Immunotherapy, chemotherapy, radiotherapy and surgery

Eligibility Criteria

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

You may qualify if:

• Histologically confirmed non-small cell lung cancer
• Able to understand and give written informed consent and comply with study procedures
• Age ≥18 years
• ECOG Performance Status 0-1
• Availability of tumour tissue for translational research
• Adequate haematological, renal and liver function

You may not qualify if:

• Prior chemotherapy, radiotherapy or therapeutic surgery for NSCLC (an exception is the resection of one single CNS or adrenal metastasis, as above)
• Activating driver mutation: epidermal growth factor receptor (EGFR), anaplastic lymphoma kinase (ALK), proto-oncogene receptor tyrosine kinase (ROS1)
• More than three distant metastases
• Brain metastases not amendable for radiosurgery or neurosurgery
• Extracranial metastatic locations such as malignant ascites, pleural or pericardial effusion, diffuse lymphangiomatosis of skin or lung, diffuse bone marrow metastasis, abdominal masses/abdominal organomegaly, identified by physical exam that is not measurable by reproducible imaging techniques.
• Primary lung cancer not suitable for radical therapy (pneumonectomy excluded)
• History of leptomeningeal carcinomatosis
• Major surgery or significant traumatic injury from which the patient has not recovered at least 28 days before enrolment
• Any uncontrolled intercurrent illness, including but not limited to: ongoing or active infection, symptomatic congestive heart failure, uncontrolled hypertension, unstable angina pectoris, cardiac arrhythmia, interstitial lung disease or serious chronic gastrointestinal conditions associated with diarrhea, which in the investigator's opinion makes it undesirable for the patient to participate in the trial or which would jeopardise compliance with the protocol
• Known active hepatitis infection, positive hepatitis C virus (HCV) antibody, hepatitis B virus (HBV) surface antigen (HBsAg) or HBV core antibody (anti-HBc) at screening.
• Known positivity for human immunodeficiency virus (positive HIV 1/2 antibodies) or active tuberculosis infection (clinical evaluation that includes clinical history, physical examination and radiographic findings, and TB testing in line with local practice)
• Active autoimmune disease requiring systemic treatment
• Severe or uncontrolled cardiac disease requiring treatment
• History of active primary immunodeficiency
• History of allogeneic organ transplant

Sponsors & Collaborators

• AstraZeneca: collaborator
• ETOP IBCSG Partners Foundation: lead

Study Sites (15)

European Institute of Oncology

Milan, Italy

Location

Istituto Oncologico Veneto - Irccs

Padua, Italy

Location

IRCCS Istituto Nazionale Tumori Regina Elena

Roma, Italy

Location

Maastricht University Medical Center

Maastricht, Netherlands

Location

Erasmus Medical Centre

Rotterdam, Netherlands

Location

Hosp. De la Santa Creu i Sant Pau

Barcelona, Spain

Location

Hosp. Uni. Virgen de las Nieves

Granada, Spain

Location

Hosp. Sanchinarro- Centro Integral Oncología Clara Campal

Madrid, Spain

Location

Vall d'Hebron University Hospital

Madrid, Spain

Location

Hosp. Uni. Politécnico La Fe

Valencia, Spain

Location

Inselspital Bern

Bern, Switzerland

Location

Geneva University Hospital

Geneva, Switzerland

Location

Centre Hospitalier Universitaire Vaudois (CHUV)

Lausanne, Switzerland

Location

Kantonsspital Winterthur

Winterthur, Switzerland

Location

University Hospital Zurich

Zurich, Switzerland

Location

Related Publications (10)

• Reck M, Rodriguez-Abreu D, Robinson AG, Hui R, Csoszi T, Fulop A, Gottfried M, Peled N, Tafreshi A, Cuffe S, O'Brien M, Rao S, Hotta K, Leiby MA, Lubiniecki GM, Shentu Y, Rangwala R, Brahmer JR; KEYNOTE-024 Investigators. Pembrolizumab versus Chemotherapy for PD-L1-Positive Non-Small-Cell Lung Cancer. N Engl J Med. 2016 Nov 10;375(19):1823-1833. doi: 10.1056/NEJMoa1606774. Epub 2016 Oct 8.

  PMID: 27718847 BACKGROUND

• Galluzzi L, Buque A, Kepp O, Zitvogel L, Kroemer G. Immunogenic cell death in cancer and infectious disease. Nat Rev Immunol. 2017 Feb;17(2):97-111. doi: 10.1038/nri.2016.107. Epub 2016 Oct 17.

  PMID: 27748397 BACKGROUND

• Langer CJ, Gadgeel SM, Borghaei H, Papadimitrakopoulou VA, Patnaik A, Powell SF, Gentzler RD, Martins RG, Stevenson JP, Jalal SI, Panwalkar A, Yang JC, Gubens M, Sequist LV, Awad MM, Fiore J, Ge Y, Raftopoulos H, Gandhi L; KEYNOTE-021 investigators. Carboplatin and pemetrexed with or without pembrolizumab for advanced, non-squamous non-small-cell lung cancer: a randomised, phase 2 cohort of the open-label KEYNOTE-021 study. Lancet Oncol. 2016 Nov;17(11):1497-1508. doi: 10.1016/S1470-2045(16)30498-3. Epub 2016 Oct 10.

  PMID: 27745820 BACKGROUND

• Rizvi NA, Hellmann MD, Brahmer JR, Juergens RA, Borghaei H, Gettinger S, Chow LQ, Gerber DE, Laurie SA, Goldman JW, Shepherd FA, Chen AC, Shen Y, Nathan FE, Harbison CT, Antonia S. Nivolumab in Combination With Platinum-Based Doublet Chemotherapy for First-Line Treatment of Advanced Non-Small-Cell Lung Cancer. J Clin Oncol. 2016 Sep 1;34(25):2969-79. doi: 10.1200/JCO.2016.66.9861. Epub 2016 Jun 27.

  PMID: 27354481 BACKGROUND

• Twyman-Saint Victor C, Rech AJ, Maity A, Rengan R, Pauken KE, Stelekati E, Benci JL, Xu B, Dada H, Odorizzi PM, Herati RS, Mansfield KD, Patsch D, Amaravadi RK, Schuchter LM, Ishwaran H, Mick R, Pryma DA, Xu X, Feldman MD, Gangadhar TC, Hahn SM, Wherry EJ, Vonderheide RH, Minn AJ. Radiation and dual checkpoint blockade activate non-redundant immune mechanisms in cancer. Nature. 2015 Apr 16;520(7547):373-7. doi: 10.1038/nature14292. Epub 2015 Mar 9.

  PMID: 25754329 BACKGROUND

• Kang J, Demaria S, Formenti S. Current clinical trials testing the combination of immunotherapy with radiotherapy. J Immunother Cancer. 2016 Sep 20;4:51. doi: 10.1186/s40425-016-0156-7. eCollection 2016.

  PMID: 27660705 BACKGROUND

• Bernstein MB, Krishnan S, Hodge JW, Chang JY. Immunotherapy and stereotactic ablative radiotherapy (ISABR): a curative approach? Nat Rev Clin Oncol. 2016 Aug;13(8):516-24. doi: 10.1038/nrclinonc.2016.30. Epub 2016 Mar 8.

  PMID: 26951040 BACKGROUND

• Golden EB, Chhabra A, Chachoua A, Adams S, Donach M, Fenton-Kerimian M, Friedman K, Ponzo F, Babb JS, Goldberg J, Demaria S, Formenti SC. Local radiotherapy and granulocyte-macrophage colony-stimulating factor to generate abscopal responses in patients with metastatic solid tumours: a proof-of-principle trial. Lancet Oncol. 2015 Jul;16(7):795-803. doi: 10.1016/S1470-2045(15)00054-6. Epub 2015 Jun 18.

  PMID: 26095785 BACKGROUND

• Hellman S, Weichselbaum RR. Oligometastases. J Clin Oncol. 1995 Jan;13(1):8-10. doi: 10.1200/JCO.1995.13.1.8. No abstract available.

  PMID: 7799047 BACKGROUND

• Weichselbaum RR, Hellman S. Oligometastases revisited. Nat Rev Clin Oncol. 2011 Jun;8(6):378-82. doi: 10.1038/nrclinonc.2011.44. Epub 2011 Mar 22.

  PMID: 21423255 BACKGROUND

MeSH Terms

Conditions

Carcinoma, Non-Small-Cell Lung

Interventions

durvalumab; Carboplatin; Paclitaxel; Radiosurgery; tremelimumab

Condition Hierarchy (Ancestors)

Carcinoma, Bronchogenic; Bronchial Neoplasms; Lung Neoplasms; Respiratory Tract Neoplasms; Thoracic Neoplasms; Neoplasms by Site; Neoplasms; Lung Diseases; Respiratory Tract Diseases

Intervention Hierarchy (Ancestors)

Coordination Complexes; Organic Chemicals; Taxoids; Cyclodecanes; Cycloparaffins; Hydrocarbons, Alicyclic; Hydrocarbons, Cyclic; Hydrocarbons; Diterpenes; Terpenes; Radiotherapy; Therapeutics; Stereotaxic Techniques; Neurosurgical Procedures; Surgical Procedures, Operative; Investigative Techniques

Study Officials

• Matthias Guckenberger, MD-PhD

  University Hospital, Zürich

  STUDY CHAIR

• Isabelle Schmitt-Opitz, MD

  University Hospital, Zürich

  STUDY CHAIR

Study Design

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

Study Record Dates

• First Submitted: May 24, 2019
• First Posted: May 29, 2019
• Study Start: November 19, 2019
• Primary Completion (Estimated): August 1, 2026
• Study Completion (Estimated): December 1, 2026
• Last Updated: February 9, 2026

Record last verified: 2026-02

Data Sharing

• IPD Sharing: Will not share

Locations

IT (3); CH (5); NL (2); ES (5)