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

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ClinicalTrials.gov Identifier: NCT03965468

Recruitment Status : Active, not recruiting

First Posted : May 29, 2019

Last Update Posted : December 15, 2022

View this study on Beta.ClinicalTrials.gov

Sponsor:

Collaborator:

AstraZeneca

Information provided by (Responsible Party):

ETOP IBCSG Partners Foundation

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. Drug: Tremelimumab	Phase 2

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Detailed Description:

Non-small cell lung cancer (NSCLC) continues to be the leading cause of cancer-related mortality worldwide. Even with adjustment for age NSCLC is responsible for almost 20% of cancer-related deaths. Recent years have brought tremendous progress in the understanding of the disease, its underlying biology and the development of effective therapies. Traditionally, NSCLC has been treated with surgery, platinum-based chemotherapy or radiotherapy alone or in combination, depending on tumour stage, tolerability of expected side effects and prognosis. Various strategies are currently being pursued in order to increase the patient population that may benefit from immunotherapy and to further improve the outcome of patients with NSCLC.

The CHESS clinical trial is for patients with NSCLC that has progressed to a small number of other parts of the body (oligo-metastatic) and has not been previously treated, or after surgical resection of a single metastasis (central nervous system or adrenal). The trial aims to reduce the risk of systemic progression and thereby improve progression free survival. Participants will receive induction treatment consisting of immunotherapy combined with platinum-based doublet chemotherapy and stereotactic body radiotherapy (SBRT) that will be given to all oligo-metastatic locations. SBRT started early and concurrently with immunotherapy aims at enhancing a postulated immune effect and simultaneously effectively control the macro-metastases.

Preclinical data have shown a strong immune-enhancing effect of radiotherapy, especially when delivered to small volumes, in high-single fraction doses and over a short period of time. Consequently, stereotactic body radiotherapy (SBRT) is currently being intensively investigated as a partner for systemic immunotherapy. Earlier clinical studies generated proof-of-principle data for the synergistic effects of combined radiotherapy and immunotherapy. Chemotherapy and high-dose radiotherapy are well known triggers of immunogenic cell death and are therefore highly promising partners for combination with immunotherapy.

The sub-group of patients with "oligometastatic" disease was originally described by Hellman and Weichselbaum in 1995. In line with this concept, the current NCCN and ESMO guidelines describe that Stage IV NSCLC patients presenting with solitary metastases can be treated with curative intent using local surgery and/or radiotherapy. Local treatment for oligo-metastatic NSCLC has been adopted rapidly in the oncological community and one reason is the progress made in the fields of surgery and radiotherapy, both becoming less toxic (minimally invasive surgery) and simultaneously less toxic and more effective (precision radiotherapy), respectively. SBRT allows treatment of small peripheral primaries and metastases at virtually all anatomical locations with a favourable therapeutic ratio of local tumour control rates >90% and low rates of toxicity. Simultaneously, minimally invasive surgery for early and locally advanced NSCLC today achieves excellent local tumour control with low rates of toxicity.

Patients with a limited number of metastases - oligometastatic disease - are currently treated with combined radical local treatment for all active lesions (locoregional primary and metastases) and their prognosis is better as compared to patients who receive systemic treatment only for widespread metastatic disease. However, the majority of patients still develop systemic disease progression indicating the urgent clinical need for more effective systemic treatment to control subclinical disease.

All CHESS trial participants will receive induction treatment with the immunotherapy drug durvalumab, standard platinum-chemotherapy and radiation therapy of the lung cancer metastases (SBRT). Durvalumab is a human monoclonal antibody carefully engineered to attach to immune cells to stimulate their activity against cancer cells. There are now several approved antibodies for the treatment of cancer or other diseases. Standard platinum-chemotherapy includes treatment with carboplatin and paclitaxel.

After three months of induction treatment the status of the lung cancer will be restaged. If the primary lung cancer is stable or has not increased in size it will be surgically removed if possible or, alternatively, treated with radiation therapy. Treatment with durvalumab will continue until the disease relapses or for a maximum of one year from the start of induction treatment. If the lung cancer has increased in size at the time of the three month restaging all trial treatment will stop and the study doctor will discuss other treatment options that are available.

The efficacy, safety and tolerability of combining immunotherapy with standard platinum-chemotherapy and SBRT will be evaluated in the CHESS clinical trial.

Encouraged by the positive results of the POSEIDON trial, we amended the CHESS protocol to include a second cohort of additional 47 patients who will receive tremelimumab, in addition to the protocol treatment of the original CHESS protocol (e.g., durvalumab, platinum-based doublet chemotherapy, and SRBT to the oligo-metastatic lesions, followed by definitive local treatment for patients that have not progressed at the time of restaging).

Objectives and endpoints, patient selection and statistical assumption remain the same as for cohort 1 in the original protocol.

Study Design

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Study Type :	Interventional (Clinical Trial)
Estimated Enrollment :	96 participants
Allocation:	N/A
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 :	August 2026
Estimated Study Completion Date :	December 2026

Resource links provided by the National Library of Medicine

MedlinePlus Genetics related topics: Lung cancer

Drug Information available for: Durvalumab

U.S. FDA Resources

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); 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 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. Drug: Tremelimumab 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.

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);

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

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.

Drug: Tremelimumab

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.

Outcome Measures

Primary Outcome Measures :

Progression-free survival at 12 months [ Time Frame: Assessed from the date of enrolment to completion of treatment 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

Secondary Outcome Measures :

Overall survival [ Time Frame: Time from date of enrolment until death from any cause. Assessed for up to 30 months. ]
Overall survival (OS) is defined as the time from the date of enrolment until death from any cause. Censoring for OS (patients without reported death) will occur at the last follow-up date.
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.
Response to induction therapy [ Time Frame: Assessed from the start of protocol treatment until the 3-month restaging ]
Defined as the best overall response [complete response (CR) or partial response (PR)] according to RECIST 1.1 criteria.
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.
Overall response [ Time Frame: Assessed from the start of protocol treatment across all time points until the end of follow-up, assessed for up to 30 months. ]
Defined as best overall response [complete response (CR) or partial response (PR) according to RECIST 1.1 criteria.
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, relapse or death from any cause.
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).
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; clinically significant laboratory parameters and abnormalities, and vital signs.

Eligibility Criteria

Information from the National Library of Medicine

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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:

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 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
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 a highly effective contraceptive method during the trial and up to 90 days after last dose of durvalumab monotherapy or 180 days after the last dose of durvalumab and tremelimumab combination therapy

Contacts and Locations

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): NCT03965468

Locations

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Italy
European Institute of Oncology
Milano, Italy
Istituto Oncologico Veneto - Irccs
Padova, Italy
Netherlands
Maastricht University Medical Center
Maastricht, Netherlands
Erasmus Medical Centre
Rotterdam, Netherlands
Spain
Hosp. De la Santa Creu i Sant Pau
Barcelona, Spain
Hosp. Uni. Virgen de las Nieves
Granada, Spain
Hosp. Sanchinarro- Centro Integral Oncología Clara Campal
Madrid, Spain
Vall d'Hebron University Hospital
Madrid, Spain
Hosp. Uni. Politécnico La Fe
Valencia, Spain
Switzerland
Inselspital Bern
Bern, Switzerland
Geneva University Hospital
Geneva, Switzerland
Centre Hospitalier Universitaire Vaudois (CHUV)
Lausanne, Switzerland
University Hospital Zurich
Zurich, Switzerland

Sponsors and Collaborators

ETOP IBCSG Partners Foundation

AstraZeneca

Investigators

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

More Information

Publications:

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.

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.

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.

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. doi: 10.1200/JCO.1995.13.1.8. No abstract available.

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.

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Responsible Party:	ETOP IBCSG Partners Foundation
ClinicalTrials.gov Identifier:	NCT03965468
Other Study ID Numbers:	ETOP 14-18 2018-003011-22 ( EudraCT Number ) ESR-17-13224 ( Other Identifier: AstraZeneca )
First Posted:	May 29, 2019 Key Record Dates
Last Update Posted:	December 15, 2022
Last Verified:	December 2022
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

Keywords provided by ETOP IBCSG Partners Foundation:


NSCLC

Additional relevant MeSH terms:

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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	Carboplatin Durvalumab Tremelimumab Antineoplastic Agents, Phytogenic Antineoplastic Agents Tubulin Modulators Antimitotic Agents Mitosis Modulators Molecular Mechanisms of Pharmacological Action Antineoplastic Agents, Immunological

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