Clinical trial NCT02654587: OSE2101 Versus Chemotherapy in HLA-A2 Positive Patients With Advanced NSCLC After Immune Checkpoint Inhibitor Failure
Official title: A Randomized Phase III Trial of OSE2101 Compared With Chemotherapy (Docetaxel or Pemetrexed) in HLA-A2 Positive Patients With Advanced Non-Small Cell Lung Cancer With Progressive Disease After Immune Checkpoint Inhibitors
Study type: INTERVENTIONAL
Overall status: TERMINATED
Phase: PHASE3
Conditions: Non Small Cell Lung Cancer
Keywords: Advanced Non-Small-Cell Lung Cancer
Therapeutic Cancer Vaccine
Resistance to Immunotherapy
Quality of Life
Lead sponsor: OSE Immunotherapeutics
Sponsor class: INDUSTRY
First posted: 2016-01-13
Enrollment: 219
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Intervention model description: Two-step open-label study with a planned interim OS futility in experimental arm per Fleming design (Step1) Central randomisation (2:1) with stratification by histology (non-squamous versus squamous), best response to first-line treatment \[complete response (CR) or partial response (PR) versus stable disease (SD) or PD\] and line of prior anti-PD(L)1 treatment (first-line when combined with platinum-based chemotherapy versus second-line when administered as sequential treatment after first-line platinum-based chemotherapy).
Primary purpose: TREATMENT

Brief summary: The aim of this clinical trial was to determine if the therapeutic cancer vaccine OSE2101 (TEDOPI) was more effective than standard chemotherapy (docetaxel or pemetrexed) in treating HLA-A2 positive patients with metastatic NSCLC who progressed after sequential or concurrent chemotherapy and immune checkpoint inhibitor given in first or second-line treatment.

The main questions were to compare the survival, the tolerance to treatment and the quality of life of patients between the two arms of treatment (OSE2101 versus standard chemotherapy)

Detailed description: The study was a two-step randomized (2:1) study. Patients were stratified by histology (non-squamous versus squamous), best response to first-line treatment \[complete response or partial response versus stable disease or progressive disease\] and line of treatment with prior ICI (first-line ICI when combined with platinum-based chemotherapy versus second-line ICI when administered as sequential treatment). Primary endpoint was overall survival (OS). Interim OS futility analysis was planned as per Fleming design. In April 2020 at the time of the interim analysis, a decision was taken to early stop the accrual due to COVID-19 after 219 out of 363 patients were randomized. It led to a decrease of the study power from 80% to 62%. At the time of the interim analysis, a subgroup of patients was identified from stratification factor based on a clinical and biological rationale: those who received ICI second line and having received at least 12 weeks ICI. This subgroup was defined as ICI secondary resistance. The final analysis was carried out in the subgroup of patients with ICI secondary resistance and in all patients (ICI primary and secondary resistance).

Eligibility criteria: Inclusion Criteria:

1. Signed and dated informed consent
2. Willingness and ability to comply with the clinical study procedures.
3. Female or male, 18 years of age or older
4. Histologically or cytologically proven diagnosis of Non-Small Cell Lung Cancer (NSCLC) that is locally advanced (stage III) unsuitable for radiotherapy or metastatic (stage IV) according to the 8th edition of tumor, node, metastasis (TNM) in Lung Cancer
5. Subjects with disease recurrence or progression after immune checkpoint inhibitor and platinum-based chemotherapy:

   i) either 1st line chemotherapy followed by 2nd line immune checkpoint inhibitor, or ii) 1st line combination of immune checkpoint inhibitor and chemotherapy Patients with progression during or within 12 months after the end of immune checkpoint inhibitor given as sequential or concomitant platinum-based chemotherapy ± radiation for locally advanced disease (stage III) were eligible
6. Subjects with measurable or non-measurable lesions according to RECIST 1.1
7. Subjects must express HLA-A2 phenotype (central test in blood)
8. Subjects must be considered suitable for chemotherapy with single-agent pemetrexed or single-agent docetaxel
9. Subjects with brain metastases were eligible if treated (whole brain radiotherapy, stereotaxic radiotherapy, surgery) at least 3 weeks prior to initiation of study treatment and have no symptoms related to brain metastases for at least 2 weeks before initiation of study treatment and are not taking any forbidden medications
10. Any prior chemotherapy, immunotherapy, hormonal therapy, radiation therapy or surgeries must have been completed at least 3 weeks prior to initiation of study treatment.
11. Any toxicity from prior therapy must have recovered to ≤ Grade 1 (except alopecia)
12. Eastern Cooperative Oncology Group (ECOG) performance status 0-1
13. Adequate organ function as defined by all the following criteria:

    * Albuminemia \> 25g/L
    * Serum aspartate transaminase (AST) and serum alanine transaminase (ALT) ≤ 1.5 x upper limit of normal (ULN) with alkaline phosphatase ≤ 2.5 x ULN, or AST and ALT ≤ 5 x ULN if liver function abnormalities are due to liver metastases
    * Total serum bilirubin ≤ 1.5 x ULN
    * Absolute neutrophil count (ANC) ≥ 1500/L
    * Platelets ≥ 100000/L
    * Hemoglobin ≥ 9.0 g/dL (in the absence of transfusion within 2 weeks before randomization)
    * Creatinine clearance (based on modified Cockcroft-Gault formula) ≥ 45 ml/min.

Exclusion Criteria:

1. Small-cell lung cancer/mixed NSCLC with small cell component or other neuroendocrine lung cancers (typical and atypical carcinoids, large-cell neuroendocrine carcinomas)
2. Patients with squamous cell carcinoma histology, and who had docetaxel as part of his prior chemotherapy
3. Current or previous treatment with investigational therapy in another therapeutic clinical trial (interrupted less than 4 weeks before study treatment initiation)
4. Patients whose tumor harbors EGFR gene mutation that sensitizes tumors to Tyrosine-Kinase Inhibitor (TKI) (EGFR exon 18-21) or Anaplastic Lymphoma Kinase (ALK) rearrangement
5. Ongoing immunotherapy (checkpoint inhibition, antigen immunotherapy that would be scheduled to continue concomitantly to the study)
6. Spinal cord compression (unless treated with the patient attaining good pain control and stable or recovered neurologic function), carcinomatous meningitis, or leptomeningeal disease
7. Patients with squamous cell histology or non-squamous cell histology previously treated by pemetrexed with a contraindication for docetaxel with grade ≥ 2 neuropathy or hypersensitivity reaction to medications formulated with polysorbate 80 (Tween 80)
8. Patients with a condition requiring systemic treatment with either corticosteroids or other immunosuppressive medications
9. Treatment with corticosteroids in the last 3-week period before inclusion, except for topical, ocular, intra-articular, intranasal, and inhaled corticosteroids with minimal systemic absorption (e.g. with a dose ≤ 500 microgram beclomethasone equivalent for inhaled steroids), or steroid doses ≤ 10 mg daily prednisone equivalent which are permitted
10. A recognized immunodeficiency disease including human immunodeficiency virus (HIV) infection (and other cellular immunodeficiencies, hypogammaglobulinemia or dysgammaglobulinemia; subjects who have hereditary, congenital or acquired immunodeficiencies)
11. Patients with auto-immune disease, with the exception of type I diabetes or treated hypothyroidism
12. Patients with interstitial lung disease
13. Patients with active B or C hepatitis
14. Other malignancy: patients will not be eligible if they have evidence of other active invasive cancer(s) (other than NSCLC) within 5 years prior to screening (except appropriately treated non-melanoma skin cancer or localized cervical cancer, or other local tumors considered cured (e.g.localized and presumed cured prostate cancer)
15. Other severe acute or chronic medical or psychiatric conditions, or laboratory abnormalities that would impart, in the judgment of the investigator and/or sponsor, excess risk associated with study participation or study drug administration, and which would, therefore, make the patient inappropriate for entry into this study
16. Female patients must be surgically sterile or be postmenopausal, or must agree to use effective contraception during the period of the trial and for at least 90 days after completion of treatment
17. Male patients sexually active with a woman of childbearing potential must be surgically sterile or must agree to use effective contraception during the period of the trial and for at least 90 days after completion of treatment. The decision of effective contraception will be based on the judgment of the principal investigator
18. Breastfeeding women
19. Women with a positive pregnancy test.

Primary outcomes:
measure: Overall Survival (OS)
timeFrame: Approx. 24 months
Secondary outcomes:
measure: Post-Progression Survival
timeFrame: approximately 24 months
measure: Time to Worsening ECOG PS
timeFrame: Approx. 24 months
measure: Mean Changes in Functional Subscales of European Organization for Research and Treatment of Cancer (EORTC) Quality of Life Core Questionnaire (QLQ-C30) From Baseline to Treatment Discontinuation in Patients With ICI Secondary Resistance
timeFrame: Approx. 24 months
measure: Mean Changes in Symptoms Subscales of the European Organization for Research and Treatment of Cancer (EORTC) Quality of Life Core Questionnaire (QLQ-C30) From Baseline to Treatment Discontinuation in Patients With ICI Secondary Resistance
timeFrame: Approx. 24 months
measure: Mean Changes in Symptoms Subscales of European Organization for Research and Treatment of Cancer (EORTC) Quality of Life Core Lung Cancer (QLQ-LC13) From Baseline to Treatment Discontinuation in Patients With ICI Secondary Resistance
timeFrame: Approx. 24 months
measure: Disease Control Rate (DCR) at 6 Months
timeFrame: Approx. 6 months
measure: Progression Free Survival (PFS) in Patients With ICI Secondary Resistance
timeFrame: Approx. 24 months
Other outcomes:
measure: Objective Response Rate (ORR) in ICI Secondary Resistance
timeFrame: Approx. 24 months
measure: Percentage of Patients With Objective Response at 6 Months in ICI Secondary Resistance
timeFrame: Approx. 6 months
measure: Time to Next Lung Cancer Therapy in ICI Secondary Resistance
timeFrame: Approx. 24 months
Locations:
city: Burbank
country: United States
facility: East Valley Hematology and Oncology medical Group
state: California
city: Washington
country: United States
facility: Georgetown University Hospital
state: District of Columbia
city: Boca Raton
country: United States
facility: BRCR Medical Center, Inc
state: Florida
city: Covington
country: United States
facility: Pontchartrain Cancer Center
state: Louisiana
city: New York
country: United States
facility: Meyer Cancer Center, Weill Cornell Medecine
state: New York
city: Canton
country: United States
facility: Gabrail Cancer Center Research
state: Ohio
city: Oklahoma City
country: United States
facility: Stephenson Cancer Center
state: Oklahoma
city: Portland
country: United States
facility: Robert W. Franz Cancer Center
state: Oregon
city: Danville
country: United States
facility: Gesinger Medical Center
state: Pennsylvania
city: Houston
country: United States
facility: Millenium Oncology
state: Texas
city: Jihlava
country: Czechia
facility: Nemocnice Jihlava, Onkologické oddelení
city: Praha
country: Czechia
facility: Všeobecná Fakultní nemocnice
city: Avignon
country: France
facility: Institut Saint Catherine
city: Bobigny
country: France
facility: Hôpital Avicenne
city: Bordeaux
country: France
facility: Institut Bergonié
city: Brest
country: France
facility: CHGU Morvan - Brest
city: Bron
country: France
facility: Hôpital Louis Pradel
city: Cholet
country: France
facility: Centre Hospitalier de Cholet
city: Créteil
country: France
facility: Hôpital intercommunal de Créteil
city: Grenoble
country: France
facility: CHU Grenoble
city: Le Mans
country: France
facility: Clinique Victor Hugo
city: Le Mans
country: France
facility: Centre Hospitalier du Mans
city: Lille
country: France
facility: Hopital Albert Calmette
city: Marseille
country: France
facility: Paoli-Calmettes Institute
city: Montpellier
country: France
facility: CHU Montpellier
city: Mulhouse
country: France
facility: Hôpital Emile Muller
city: Nantes
country: France
facility: Centre Catherine de Sienne
city: Paris
country: France
facility: Hôpital Saint-Louis
city: Paris
country: France
facility: Hôpital Bichat - Claude-Bernard
city: Paris
country: France
facility: Hôpital Tenon
city: Saint Mandé
country: France
facility: Hôpital d'Instruction des Armées Bégin
city: Strasbourg
country: France
facility: CHU de Strasbourg - Hôpital Civil
city: Toulouse
country: France
facility: Hôpital Larrey - CHU de Toulouse
city: Tours
country: France
facility: Centre Hospitalier Régional Universitaire de Tours
city: Troyes
country: France
facility: Centre Hospitalier Troyes
city: Villejuif
country: France
facility: Institut Gustave Roussy (IGR)
city: Cologne
country: Germany
facility: Krankenhaus Mehrheit - Kliniken der Stadt Köln - Lungenklinik
city: Halle
country: Germany
facility: Klinik für Innere Medizin II Hospital Martha-Maria Halle-Dölau gGmbH
city: Tubingen
country: Germany
facility: Universitätsklinikum Tübingen Medizinische Klinik II
city: Ulm
country: Germany
facility: Klinik für Innere Medizin II Universitätsklinikum Ulm
city: Budapest
country: Hungary
facility: Magyar Honvedseg Egeszsegugyi Kozpont II szamu telephely
city: Budapest
country: Hungary
facility: Országos Korányi TBC és Pulmonológiai Intézet XI Tüdőbelosztály
city: Budapest
country: Hungary
facility: Országos Korányi TBC és Pulmonológiai Intézet XIV Tüdőbelosztály
city: Budapest
country: Hungary
facility: Semmelweis Egyetem Altalanos Orvostudományi Kar Pulmonologiai Klinika
city: Deszk
country: Hungary
facility: Csongrad Megyei Mellkasi Betegsegek Szakkorháza I Tüdőosztály
city: Mátraháza
country: Hungary
facility: Matrai Gyogyintézet
city: Be'er Sheva
country: Israel
facility: Soroka University Medical Center
city: Haifa
country: Israel
facility: Rambam Health Care Campus
city: Jerusalem
country: Israel
facility: Hadassah Campus Ein Kerem
city: Kefar Saba
country: Israel
facility: Meir Medical Center
city: Petah tikva
country: Israel
facility: Rabin (Belinson) Medical Center
city: Bari
country: Italy
facility: IRCCS Oncologico Giovanni Paolo II
city: Lecce
country: Italy
facility: Unità Operativa di Oncologia dell'Ospedale Vito Fazzi di Lecce, Piazza Muratore
city: Legnano
country: Italy
facility: Oncologia medica
city: Lucca
country: Italy
facility: Azienda USL 2 Lucca - Dipartimento Oncologico
city: Meldola
country: Italy
facility: Istituto Scientifico Romagnolo per lo Studio e la Cura dei Tumori (I.R.S.T)
city: Napoli
country: Italy
facility: U.O.C. Pneumologia a indirizzo oncologico, Presidio Ospedaliero Monaldi - Azienda Ospedaliera dei Colli - Via Leonardo Bianchi
city: Padova
country: Italy
facility: Istituto Oncologico Veneto, IRCCS
city: Perugia
country: Italy
facility: Ospedale di Perugia - Oncologia medica
city: Rimini
country: Italy
facility: U.O. Oncologia Ospedale Infermi
city: Roma
country: Italy
facility: UOC di Oncologia Medica, Policlinico Universitario Campus Biomedico
city: Roma
country: Italy
facility: IRCCS Regina Elena National Cancer Institute
city: Siena
country: Italy
facility: Policlinico Santa Maria alle Scotte
city: Verona
country: Italy
facility: Ospedale Civile Maggiore
city: Gdańsk
country: Poland
facility: Klinika Onkologii i Radioterapii , Uniwersyteckie Centrum Kliniczne
city: Konin
country: Poland
facility: Przychodnia Lekarska "KOMED"
city: Otwock
country: Poland
facility: Mazowieckie Centrum Leczenia chorób Płuc i Gruźlicy
city: Toruń
country: Poland
facility: Wojewódzki Szpital Zespolony , Oddział Chemioterapii Nowotworów
city: Barcelona
country: Spain
facility: Hospital Universitari Quirón Dexeus
city: Barcelona
country: Spain
facility: Hospital Universitari Vall D'Hebron
city: Barcelona
country: Spain
facility: Hospital de Mataro
city: Barcelona
country: Spain
facility: Hospital Universitario Germans Trias i Pujol
city: La Coruña
country: Spain
facility: "Complejo Hospitalario Universitario A Coruna (CHUAC)"
city: Madrid
country: Spain
facility: Hospital Universitario La Paz Servicio de Oncología Médica
city: Madrid
country: Spain
facility: Hospital Universitario Puerta de Hierro Majadahonda Servicio de Oncología Médica Consultas externas, 2ª planta
city: Mataró
country: Spain
facility: Hospital de Mataro
city: Málaga
country: Spain
facility: Hospital Universitario Carlos Haya
city: Milton Keynes
country: United Kingdom
facility: Milton Keynes Hospital
Study officials:
affiliation: OSE Immunotherapeutics
name: Dominique Costantini, Dr
role: STUDY_DIRECTOR
References:
citation: Besse B, Felip E, Garcia Campelo R, Cobo M, Mascaux C, Madroszyk A, Cappuzzo F, Hilgers W, Romano G, Denis F, Viteri S, Debieuvre D, Galetta D, Baldini E, Razaq M, Robinet G, Maio M, Delmonte A, Roch B, Masson P, Schuette W, Zer A, Remon J, Costantini D, Vasseur B, Dziadziuszko R, Giaccone G; ATALANTE-1 study group. Randomized open-label controlled study of cancer vaccine OSE2101 versus chemotherapy in HLA-A2-positive patients with advanced non-small-cell lung cancer with resistance to immunotherapy: ATALANTE-1. Ann Oncol. 2023 Oct;34(10):920-933. doi: 10.1016/j.annonc.2023.07.006. Epub 2023 Sep 11.