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

• ClinicalTrials.gov Identifier: NCT03965468
• Recruitment Status: Recruiting
• First Posted: May 29, 2019
• Last Update Posted: December 2, 2019
• Sponsor: European Thoracic Oncology Platform
• Collaborator: AstraZeneca
• Information provided by (Responsible Party): European Thoracic Oncology Platform

Study Description

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).

Condition or disease	Intervention/treatment	Phase
Non-small Cell Lung Cancer; Stage IV; Oligometastasis	Drug: Durvalumab; Drug: Carboplatin; Drug: Paclitaxel; Radiation: Stereotactic body radiation therapy (SBRT); Procedure: Surgical resection - definitive local treatment.; Radiation: Radical radiotherapy - definitive local treatment.	Phase 2

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Study Design

• Study Type: Interventional (Clinical Trial)
• Estimated Enrollment: 47 participants
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: A Multicentre Single Arm Phase II Trial Assessing the Efficacy of Immunotherapy, Chemotherapy and Stereotactic Radiotherapy to Metastases Followed by Definitive Surgery or Radiotherapy to the Primary Tumour, in Patients With Synchronous Oligo-metastatic Non-small Cell Lung Cancer
• Actual Study Start Date: November 19, 2019
• Estimated Primary Completion Date: December 2021
• Estimated Study Completion Date: December 2021

Arms and Interventions

Arm

Intervention/treatment

Experimental: Immunotherapy, chemotherapy, radiotherapy and surgery; Durvalumab 1500 mg administered intravenously every 3 weeks for the first 4-6 cycles (during chemotherapy); 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; 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.; Other Name: Imfinzi; Drug: Carboplatin; Carboplatin belongs to the group of medicines known as alkylating agents. Carboplatin interferes with the growth of cancer cells, which eventually are destroyed.; Drug: Paclitaxel; 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).; Radiation: Stereotactic body radiation therapy (SBRT); SBRT of all oligo-metastatic lesions; Procedure: Surgical resection - definitive local treatment.; Surgical resection of primary tumour for patients with single station, non-bulky tumours.; Radiation: Radical radiotherapy - definitive local treatment.; Conventional or moderately hypo-fractionated radiotherapy to the primary tumour for other tumour stages, or in case of medical inoperability.

Outcome Measures

Primary Outcome Measures :

1. Progression-free survival at 12 months [ Time Frame: Assessed from the date of enrolment to completion of treatment at 12 months. ]
   Defined as time from date of enrollment until documented progression. 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 1.1 criteria.

Secondary Outcome Measures :

1. Overall survival [ Time Frame: Time from date of enrolment until death from any cause. Assessed for up to 30 months. ]
   Defined as the time from date of enrolment until death from any cause. Censoring will occur at the last follow-up date.
2. Pattern of disease progression [ Time Frame: Assessed from the date of enrolment until progression, from enrolment up to 12 months. ]
   Defined as the site of first progression. None, locoregional, distant, or both locoregional and distant.
3. Response to induction therapy [ Time Frame: Assessed from the start of protocol treatment until the end of the induction phase (restaging at 3-month tumour assessment). ]
   Defined as the best overall response [complete response (CR) or partial response (PR)] according to RECIST 1.1 criteria.
4. Distant progression-free survival [ Time Frame: Assessed from the date of enrolment for up to 12 months. ]
   Defined as the date of development of new metastases, excluding oligometastasis diagnosed at enrolment.
5. Overall response [ Time Frame: Assessed from the start of protocol treatment across all time points until the end of protocol treatment, for up to 12 months. ]
   Defined as best overall response [complete response (CR) or partial response (PR) according to RECIST 1.1 criteria.
6. Duration of response [ Time Frame: Assessed from the date of enrolment for up to 12 months. ]
   Defined as the interval from the date of first documentation of objective response (CR or PR), according to RECIST 1.1 criteria to the date of first documented progression or response.
7. Symptom-specific and global quality of life: The Lung Cancer Symptom Scale [ Time Frame: Assessed at trial entry, until 6 months after treatment start and at 12 months from enrolment. ]
   The Lung Cancer Symptom Scale, a 9-item one page questionnaire will be used to assess change in total score (average of all 9 items).
8. Toxicity before and after surgery/radiotherapy [ Time Frame: Adverse events will be collected from the date of consent until 90 days after the completion of treatment. ]
   Safety parameters will be assessed in terms of adverse events graded by CTCAE v5.0 including events leading to dose interruptions, withdrawals of protocol treatment and death; severe, serious and selected adverse events; deaths; laboratory parameters and abnormalities, and vital signs.

Eligibility Criteria

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

Criteria

Inclusion Criteria:

• Histologically confirmed non-small cell lung cancer
• Synchronous oligo-metastatic stage IV disease: maximum of three distant metastases, one of which must be extra-cerebral for stereotactic body radiotherapy (SBRT); Initial mediastinal staging is recommended (except for lymph nodes <1 cm on CT and PET-negative) preferentially by endobronchial ultrasound (EBUS); Neurosurgical resection of one single central nervous system (CNS) metastasis or laparoscopic resection of one adrenal metastasis before study inclusion is allowed (one extra-cerebral metastasis must be available for SBRT)
• 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

Exclusion Criteria:

• 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 lymphangitiosis 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
• Active tuberculosis, hepatitis B, hepatitis C or human immunodeficiency virus (HIV) infection
• Active autoimmune disease requiring systemic treatment
• Severe or uncontrolled cardiac disease requiring treatment
• History of primary immunodeficiency
• History of allogeneic organ transplant
• Receipt of live attenuated vaccines within 30 days prior to enrolment
• Known allergies or hypersensitivity to trial drugs or to any excipient.
• Women who are pregnant or in the period of lactation.
• Sexually active men and women of childbearing potential who are not willing to use an effective contraceptive method during the trial and for up to 90 days after last dose of durvalumab.

Contacts and Locations

Contacts

Contact: Barbara Ruepp, PharmD; +41315119400; barbara.ruepp@ibcsg.org

Locations

Netherlands

Maastricht University Medical Center; Not yet recruiting

Maastricht, Netherlands

Contact: Dirk De Ruysscher, MD dirk.deruysscher@maastro.nl

Principal Investigator: Dirk De Ruysscher, MD

Erasmus Medical Centre; Not yet recruiting

Rotterdam, Netherlands

Contact: Joachim Aerts, MD j.aerts@erasmusmc.nl

Principal Investigator: Joachim Aerts, MD

Spain

Hosp. De la Santa Creu i Sant Pau; Not yet recruiting

Barcelona, Spain

Contact: Ivana Sullivan, MD

Principal Investigator: Ivana Sullivan, MD

Hosp. Uni. Virgen de las Nieves; Not yet recruiting

Granada, Spain

Contact: Javier Valdivia, MD

Principal Investigator: Javier Valdivia, MD

Hosp. Sanchinarro- Centro Integral Oncología Clara Campal; Not yet recruiting

Madrid, Spain

Contact: Ana Collazo, MD

Principal Investigator: Ana Collazo, MD

Hosp. Uni. Politécnico La Fe; Not yet recruiting

Valencia, Spain

Contact: Oscar Juan-Vidal, MD

Principal Investigator: Oscar Juan-Vidal, MD

Switzerland

Inselspital Bern; Recruiting

Bern, Switzerland

Contact: Amina Scherz, MD amina.scherz@insel.ch

Principal Investigator: Amina Scherz, MD

HFR Fribourg; Not yet recruiting

Fribourg, Switzerland

Contact: Daniel Betticher daniel.betticher@h-fr.ch

Principal Investigator: Daniel Betticher, MD

Geneva University Hospital; Not yet recruiting

Geneva, Switzerland

Contact: Alfredo Addeo, MD alfredo.addeo@hcuge.ch

Principal Investigator: Alfredo Addeo, MD

Centre Hospitalier Universitaire Vaudois (CHUV); Not yet recruiting

Lausanne, Switzerland

Contact: Solage Peters

Principal Investigator: Solange Peters, MD

University Hospital Zurich; Recruiting

Zurich, Switzerland

Contact: Matthias Guckenberger, MD Matthias.Guckenberger@usz.ch

Principal Investigator: Matthias Guckenberger, MD

Sponsors and Collaborators

European Thoracic Oncology Platform

AstraZeneca

Investigators

• Study Chair: Matthias Guckenberger, MD-PhD; University Hospital, Zürich
• Study Chair: Isabelle Schmitt-Opitz, MD; University Hospital, Zürich

More Information

Publications:

Reck M, Rodríguez-Abreu D, Robinson AG, Hui R, Csőszi T, Fülöp 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. Epub 2016 Oct 8.

Galluzzi L, Buqué 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. Review.

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.

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.

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.

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.

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. Review.

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.

Hellman S, Weichselbaum RR. Oligometastases. J Clin Oncol. 1995 Jan;13(1):8-10.

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. Review.

• Responsible Party: European Thoracic Oncology Platform
• ClinicalTrials.gov Identifier: NCT03965468 History of Changes
• Other Study ID Numbers: ETOP 14-18; 2018-003011-22 ( EudraCT Number ); ESR-17-13224 ( Other Identifier: AstraZeneca )
• First Posted: May 29, 2019
• Last Update Posted: December 2, 2019
• Last Verified: November 2019

Individual Participant Data (IPD) Sharing Statement:

• Plan to Share IPD: No

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

Keywords provided by European Thoracic Oncology Platform:

NSCLC

Additional relevant MeSH terms:

Lung Neoplasms; Carcinoma, Non-Small-Cell Lung; Respiratory Tract Neoplasms; Thoracic Neoplasms; Neoplasms by Site; Neoplasms; Lung Diseases; Respiratory Tract Diseases; Carcinoma, Bronchogenic; Bronchial Neoplasms; Paclitaxel; Albumin-Bound Paclitaxel; Carboplatin; Durvalumab; Antibodies, Monoclonal; Antineoplastic Agents, Phytogenic; Antineoplastic Agents; Tubulin Modulators; Antimitotic Agents; Mitosis Modulators; Molecular Mechanisms of Pharmacological Action; Immunologic Factors; Physiological Effects of Drugs; Antineoplastic Agents, Immunological