Clinical trial NCT06219317: Immunotherapy Consolidation After Radical Treatment of Synchronous Oligo-metastatic NSCLC
Official title: Immunotherapy Consolidation After Radical Treatment of Synchronous Oligo-metastatic NSCLC
Study type: INTERVENTIONAL
Overall status: RECRUITING
Phase: PHASE2
Conditions: NSCLC Stage IV
Keywords: NSCLC
cemiplimab
immunotherapy
oligometastatic disease
radical treatment
Lead sponsor: European Organisation for Research and Treatment of Cancer - EORTC
Sponsor class: NETWORK
First posted: 2024-01-23
Enrollment: 136
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: This is a multi-center, double-blind, placebo-controlled randomized phase II study to assess whether continuation of cemiplimab treatment (for up to 12 months) increases progression-free survival (PFS) as compared to placebo in patients with a stage IV, synchronous, oligometastatic non-small cell lung cancer (NSCLC) who have not progressed following 4 cycles of cemiplimab with our without platinum-based chemotherapy and radical treatment.

Eligible patients are randomized with a 1:1 ratio to either the cemiplimab or placebo group and will undergo disease assessment (e.g. imaging, blood tests) at regular follow-up visits.


Eligibility criteria: 1. Registration phase

   Inclusion criteria
   * Histologic or cytologic confirmation of NSCLC. If small-cell elements present, participant will be ineligible.
   * Synchronous oligometastatic disease at diagnosis - and still oligometastatic at registration into the study - defined as maximum 5 metastases, in maximum 3 organs. Hilar, mediastinal and/or supraclavicular lymph nodes are not considered as metastases.
   * Age at registration ≥18 years
   * Eastern Cooperative Oncology Group performance status (ECOG PS)/ World Health Organization (WHO) 0-1.
   * Hepatic function:
   * Serum total bilirubin ≤1.5x upper limit of normal (ULN), or ≤3x ULN, if liver metastases or in patients with history of Gilbert syndrome
   * Aspartate aminotransferase (AST) and/or alanine aminotransferase (ALT) ≤3x ULN (or ≤5x ULN, if liver metastases)
   * Renal function:
   * Glomerular filtration rate (GFR) based on the modification of diet in renal disease (MDRD) equation ≥30 mL/min
   * Bone marrow function:
   * Hemoglobin ≥9.0 g/dL
   * Absolute neutrophil count (ANC) ≥1.5 x 109/L
   * Platelet count ≥100 x 109/L
   * Women of childbearing potential (WOCBP) must have a negative serum or highly sensitive urine pregnancy test within 7 days prior to the first dose of treatment.

   Note: Women of childbearing potential are defined as premenopausal females capable of becoming pregnant (i.e., females who have had any evidence of menses in the past 12 months, with the exception of those who had prior hysterectomy). However, women who have been amenorrhoeic for 12 or more months are still considered to be of childbearing potential if the amenorrhea is possibly due to prior chemotherapy, antiestrogens, low body weight, ovarian suppression, or other reasons.
   * Patients of childbearing / reproductive potential should agree to use adequate birth control measures, as defined by the protocol, during the study treatment period and for:
   * At least 6 months after the last dose of pemetrexed-if pemetrexed was administered.
   * At least 6 months after the last dose of cemiplimab/placebo. A highly effective method of birth control is defined as a method which results in a low failure rate (i.e., less than 1% per year) when used consistently and correctly. Such methods are detailed in Appendix Y.
   * Women who are breast feeding should discontinue nursing prior to the first dose of study treatment and until:
   * At least 6 months after the last dose of pemetrexed, if pemetrexed was administered.
   * At least 6 months after the last dose of cemiplimab/placebo.
   * Capable of giving signed informed consent which includes compliance with the requirements and restrictions listed in the informed consent form (ICF) and in this protocol.

   Exclusion criteria
   * Presence of malignant pleural, pericardial and/or peritoneal effusion.
   * Presence of leptomeningeal carcinomatosis.
   * Tumour known to be positive for EGFR exon 19 or 21 mutations, ALK translocations or ROS1 fusions.
   * Prior pneumonectomy, radiotherapy (including mediastinal radiotherapy), chemotherapy, immune-check inhibitors or targeted therapy for lung cancer within the last 3 years before registration.
   * Previously treated brain metastases that are radiologically non-stable.

   Notes:
   * Patients with previously treated brain metastases, i.e., without evidence of progression for at least 4 weeks by repeat imaging (note that the repeat imaging should be performed during study screening), clinically stable and without requirement of steroid treatment for at least 14 days prior to first dose of study intervention, can participate. These treated brain metastasis will count as metastasis in the definition of oligometastatic disease.
   * Symptomatic brain metastases should be treated with surgery and/or stereotactic radiotherapy/ radiosurgery as soon as possible after diagnosis. If surgery is considered it must be applied before enrolment. Radiotherapy can be performed at any time.
   * History of any solid or hematological malignancy in the past 3 years before registration.

   Exceptions include patients who underwent successful definitive treatment of basal or squamous cell carcinoma of the skin, or any in-situ carcinoma(s).
   * Any uncontrolled, intercurrent illness or clinical situation that would, in the judgment of investigator, limit compliance with study requirements.
   * Any uncontrolled active infection, defined as an infection ≥ grade 3 according to CTCAE version 5.0.
   * Any autoimmune disease that has required systemic treatment in the past 2 years (defined as any use of disease modifying agents, corticosteroids or immunosuppressive drugs).

   Replacement therapy (e.g., thyroxine for hypothyroidism or insulin for type I diabetes) is not considered a form of systemic treatment.

   The following treatments are allowed:
   * Intranasal, inhaled and topical steroids as well as local steroid injections (e.g., intra articular injection).
   * Systemic corticosteroids at physiologic doses not to exceed 10 mg/day of prednisone or its equivalent.
   * Systemic corticosteroid replacement therapy for adrenal or pituitary insufficiency.
   * Steroids as premedication for hypersensitivity reactions (e.g., CT scan premedication)

     * Known active hepatitis B or C, defined as a positive HBV surface antigen (HBsAg) result or positive HCV RNA.
     * Known active HIV infection, defined as \>200 copies of HIV per ml of blood.
     * History of interstitial lung disease (e.g., idiopathic pulmonary fibrosis, organizing pneumonia) or history of non-infectious pneumonitis that required systemic glucocorticoids to assist with management.

   A history of radiation pneumonitis in the radiation field is permitted as long as pneumonitis resolved ≥12 months prior to registration.

   • Immunosuppressive corticosteroid doses (\>10 mg prednisone daily or equivalent) within 2 weeks prior to the first dose of cemiplimab.

   Patients who require brief courses of steroids (e.g., as prophylaxis for imaging studies due to hypersensitivity to contrast agents) can be included.
   * Participation in any other clinical study involving an investigational drug or device within 4 weeks before registration.
   * History of documented allergic reaction or acute hypersensitivity reaction attributed to antibody treatments.
   * Sensitivity to any of the study interventions, or components thereof, or other allergy that, in the opinion of the investigator, contraindicates participation in the study.
   * Any psychological, familial, sociological or geographical condition potentially hampering compliance with the study protocol, understanding and completion of questionnaires and follow-up schedule; those conditions should be assessed and discussed with the patient before the enrolment in the trial
2. At randomization Prior to treatment allocation for the consolidation phase an additional set of selection criteria need to be met and stratification factors provided.

Inclusion criteria

* Stable disease, partial or complete response according to RECIST v.1.1 after 4 cycles of induction treatment and radical treatment of all residual disease (if applicable). Patients with progressive disease will be excluded.
* Anticipated life expectancy \>12 weeks
* Hepatic function:
* Serum total bilirubin ≤1.5x ULN (or ≤3x ULN, if liver metastases or in patients with history of Gilbert syndrome)
* AST and/or ALT ≤3x ULN (or ≤5x ULN, if liver metastases)
* Renal function:
* GFR based on MDRD equation ≥30 mL/min
* Bone marrow function:
* Hemoglobin ≥9.0 g/dL
* ANC ≥1.5 x 109/L
* Platelet count ≥100 x 109/L
* WOCBP must have a negative serum or highly negative urine pregnancy test within 7 days prior to the first dose of consolidation treatment.

Exclusion criteria

• Use of immunosuppressive corticosteroid doses (\>10 mg prednisone daily or equivalent) within 2 weeks prior to the first dose of cemiplimab/placebo. Patients who require brief courses of steroids (e.g., as prophylaxis for imaging studies due to hypersensitivity to contrast agents) can be included.

Primary outcomes:
measure: Progression-free survival (PFS)
timeFrame: 9 years from first patient randomized
Secondary outcomes:
measure: Overall survival (OS)
timeFrame: 6 years from first patient randomized
measure: Time to disease progression
timeFrame: 6 years from first patient randomized
measure: Time to development of new metastatic lesions
timeFrame: 6 years from first patient randomized
measure: Time to progression in oligometastatic lesions initially present at registration
timeFrame: 6 years from first patient randomized
measure: AEs according to NCI-CTCAE v5.0 and SAEs
timeFrame: 9 years from first patient randomized
measure: Patient reported QoL as measured by the EORTC QLQ-C30 questionnaire
timeFrame: 9 weeks from last patient last treatment
measure: Patient reported QoL as measured by the IL316 questionnaire - self assessment of treatment side effects
timeFrame: 9 weeks from last patient last treatment
measure: Patient reported QoL as measured by the IL316 questionnaire - questions from EORTC QLQ-LC29 questionnaire
timeFrame: 9 weeks from last patient last treatment
measure: Patient reported QoL as measured by the IL316 questionnaire - questions from EORTC QLQ-ELD14 questionnaire
timeFrame: 9 weeks from last patient last treatment
Other outcomes:
measure: Tumour molecular profile (NGS panel, WES (including germline), RNAseq)
timeFrame: 6 years from first patient randomized
measure: ctDNA analysis
timeFrame: 6 years from first patient randomized
measure: Circulating biomarkers such as cytokines, or auto-Ab
timeFrame: 6 years from first patient randomized
measure: Biomarker assessment of the tumour microenvironment
timeFrame: 6 years from first patient randomized
Locations:
city: Brussels
country: Belgium
facility: Cliniques Universitaires Saint-Luc
city: Haine-Saint-Paul
country: Belgium
facility: CHU Helora Pole Hospitalier Jolimont
city: Yvoir
country: Belgium
facility: CHU Mont Godinne - UCL Namur
city: Bayonne
country: France
facility: CH de La Cote Basque - Saint Leon
city: Marseille
country: France
facility: Institut Paoli-Calmettes
city: Paris
country: France
facility: Groupe Hospitalier Paris Saint Joseph
city: Legnano
country: Italy
facility: ASST Ovest Milanese - Legnano
city: Legnano
country: Italy
facility: Azienda Unita Locale Socio-Sanitaria N. 9-Mater Salutis Hospital
city: Pavia
country: Italy
facility: Fondazione IRCCS - Policlinico San Matteo
city: Ravenna
country: Italy
facility: AUSL Della Romagna - Ospedale Santa Maria delle Croci
city: Rozzano
country: Italy
facility: Istituto Clinico Humanitas
city: Udine
country: Italy
facility: Azienda Ospedaliero - Universitaria "Santa Maria della Misericordia" di Udine
city: Maastricht
country: Netherlands
facility: Academisch Ziekenhuis Maastricht
city: Barcelona
country: Spain
facility: Hospital De La Santa Creu I Sant Pau
city: Barcelona
country: Spain
facility: UOMi Cancer Center
city: Sevilla
country: Spain
facility: Hospital Quironsalud Sagrado Corazon
city: Sevilla
country: Spain
facility: University Hospital Virgen del Rocio
Study officials:
affiliation: Maastro Clinic - Maastricht Radiation Oncology, Maastricht, Netherlands
name: Dirk de Ruysscher, MD
role: STUDY_CHAIR
affiliation: Cliniques Universitaires Saint-Luc, Brussels, Belgium
name: Frank Aboubakar Nana, MD
role: STUDY_CHAIR
References: