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JOURNAL ONKOLOGIE – STUDIE
CHESS

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

Rekrutierend

NCT-Nummer:
NCT03965468

Studienbeginn:
November 2019

Letztes Update:
28.02.2024

Wirkstoff:
Durvalumab, Carboplatin, Paclitaxel, Tremelimumab

Indikation (Clinical Trials):
Lung Neoplasms, Carcinoma, Non-Small-Cell Lung

Geschlecht:
Alle

Altersgruppe:
Erwachsene (18+)

Phase:
Phase 2

Sponsor:
ETOP IBCSG Partners Foundation

Collaborator:
AstraZeneca

Studienleiter

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

Kontakt

Studienlocations
(3 von 13)

European Institute of Oncology
Milano
ItalyAktiv, nicht rekrutierend» Google-Maps
Istituto Oncologico Veneto - Irccs
Padova
ItalyAktiv, nicht rekrutierend» Google-Maps
Maastricht University Medical Center
Maastricht
NetherlandsAktiv, nicht rekrutierend» Google-Maps
Erasmus Medical Centre
Rotterdam
NetherlandsAktiv, nicht rekrutierend» Google-Maps
Centre Hospitalier Universitaire Vaudois (CHUV)
Lausanne
SwitzerlandAktiv, nicht rekrutierend» Google-Maps
Alle anzeigen

Studien-Informationen

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.

Ein-/Ausschlusskriterien

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

Studien-Rationale

Primary outcome:

1. 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:

1. 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.

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 3-month restaging):
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 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.

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, relapse or death from any cause.

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; clinically significant laboratory parameters and abnormalities, and vital signs.

Geprüfte Regime

  • Durvalumab (Imfinzi):
    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.
  • Carboplatin:
    Carboplatin belongs to the group of medicines known as alkylating agents. Carboplatin interferes with the growth of cancer cells, which eventually are destroyed.
  • 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).
  • Stereotactic body radiation therapy (SBRT):
    SBRT of all oligo-metastatic lesions
  • Surgical resection - definitive local treatment.:
    Surgical resection of primary tumour for patients with single station, non-bulky tumours.
  • 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.
  • 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.

Quelle: ClinicalTrials.gov


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