Phase 3 Randomized Open-Label Trial of OSE2101 Versus Docetaxel in HLA-A2 Positive Metastatic NSCLC Patients with Secondary Resistance to Immune Checkpoint Inhibitors

Trial ID: 2023-509340-10-00
Protocol: OSE2101C302
Sponsor: OSE Immunotherapeutics

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Diseases & Conditions

Squamous cell carcinoma of lung Non-small cell lung cancer Non-small cell lung cancer stage IV

Objectives

The primary objective of this phase 3 trial is to confirm the **superiority** of OSE2101 over docetaxel in terms of **Overall Survival (OS)** in patients with metastatic Non-Small Cell Lung Cancer (NSCLC) who are HLA-A2 positive and have developed secondary resistance to immune checkpoint inhibitors. This objective is clinically relevant as it aims to establish a more effective treatment option for this patient population, potentially improving survival outcomes.

Secondary objectives include confirming the clinical benefit of OSE2101 compared to docetaxel, with a focus on **Patient Reported Outcomes (PROs)**. This evaluation is important for understanding the broader impact of the treatment on patients' quality of life and overall treatment experience.

Participants

The clinical trial involves a total of **69 participants** diagnosed with metastatic **Non-Small Cell Lung Cancer** (NSCLC) who express the HLA-A2 positive phenotype. The study population includes both male and female subjects aged 18 years and older. Participants were selected based on specific criteria, including the absence of EGFR, ALK, and ROS1 gene alterations, and progression after at least 24 weeks of first-line chemotherapy-immunotherapy (CT-ICI). The trial excludes vulnerable populations and requires participants to have an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1, indicating they are fully active or restricted in physically strenuous activity but ambulatory. Participants must have adequate organ function and no significant ongoing toxicity from prior therapies. Lifestyle considerations such as diet and physical activity are not specified, but participants must adhere to contraception guidelines if applicable. The trial aims to evaluate the efficacy of OSE2101 compared to docetaxel in improving overall survival.

Plans and Procedures

The clinical trial is designed as a **randomized**, open-label, phase 3 study to evaluate the efficacy and safety of OSE2101 compared to **docetaxel** in patients with metastatic Non-Small Cell Lung Cancer (NSCLC) who are HLA-A2 positive and have developed secondary resistance to immune checkpoint inhibitors. The primary objective is to confirm the superiority of OSE2101 over docetaxel in terms of overall survival. The trial is expected to commence recruitment on September 2, 2024, and conclude by December 31, 2027.

Participants will be randomly assigned to receive either OSE2101, administered as a subcutaneous injection, or docetaxel, administered intravenously. The maximum treatment period for both interventions is 24 weeks. The study will include several key visits: an initial screening visit to confirm eligibility, regular follow-up visits to monitor treatment response and safety, and an end-of-study visit to assess final outcomes. The inclusion visit will involve comprehensive assessments to ensure participants meet all eligibility criteria, including confirmation of the HLA-A2 phenotype and metastatic NSCLC status.

Participants are expected to be involved in the study for the entire duration of the treatment period, with additional follow-up as required. Conditions that may lead to early termination from the study include significant adverse events, withdrawal of consent, or any other medical condition that, in the investigator's opinion, warrants discontinuation. The primary endpoint of the study is overall survival, defined as the time from randomization to death from any cause. The trial will adhere to rigorous scientific and ethical standards to ensure the validity and reliability of the results.

Treatment

The clinical trial involves the administration of two primary treatments: **DOCETAXEL** and **TEDOPI**. **DOCETAXEL** is utilized as a comparator treatment in this study. It is a **concentrate for solution for infusion** and is administered via the **intravenous** route. The dosage is calculated based on body surface area, with a maximum daily dose of 75 mg/m² and a cumulative maximum dose of 2625 mg/m² over the treatment period. The treatment duration is set for a maximum of 24 weeks. **DOCETAXEL** is a chemical substance and is commonly used in chemotherapy protocols. Participant compliance with the dosing schedule is monitored throughout the trial to ensure adherence to the treatment regimen.

**TEDOPI**, also known by its sponsor product code OSE2101, is the experimental medication in this trial. It is an **emulsion for injection** and is administered via **subcutaneous injection**. The maximum daily dose is 5 mg, with a total maximum dose of 75 mg over the course of the treatment period, which also spans up to 24 weeks. **TEDOPI** is a cancer vaccine composed of multiple protein-based active substances, including MPS-112, MPS-106, MPS-213, MPS-102, MPS-216, MPS-103, MPS-215, MPS-214, D-ALA-LYS-CHA-VAL-ALA-ALA-TRP-THR-LEU-LYS-ALA-ALA-D-ALA, and MPS-200. These components are designed to elicit an immune response against specific cancer antigens. The administration schedule and participant adherence are closely monitored to ensure the integrity of the trial data.

Efficacy

The efficacy of the clinical trial will be assessed by comparing the **Overall Survival (OS)** between the two treatment groups: OSE2101 and docetaxel. The primary endpoint is defined as the time from randomization to death from any cause. This endpoint will be measured and analyzed to determine the superiority of OSE2101 over docetaxel in patients with metastatic Non-Small Cell Lung Cancer (NSCLC) who have developed secondary resistance to Immune Checkpoint Inhibitors.

Inclusion and Exclusion Criteria

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Inclusion Criteria

Male or female, aged ≥ 18 years
Patients expressing HLA-A2 phenotype in blood by pre-screening central laboratory
Patients with histologically or cytologically squamous or non-squamous documented NSCLC, metastatic stage at study entry, not eligible for definite surgery or radiation, without EGFR, ALK and ROS1 gene alterations eligible for targeted therapy; for patients with squamous NSCLC, the molecular tests are not mandatory if age ≥ 50 years old and smoker ≥ 15 pack years; other sensitizing mutations known to be immunosensitive are eligible in case of lack of local access to targeted therapy (i.e.; KRAS G12C and BRAF mutations) after Sponsor’ agreement
Patients with metastatic NSCLC who received only one prior line of systemic therapy with CT and ICI, with ICI lasting ≥ 24 weeks, including ≥ 12 weeks of anti-PD(L)1 as monotherapy or in combination with another ICI or an anti-angiogenic prior to randomization (i.e.; ICI secondary resistance); induction treatment with first-line CT-ICI should contain platinum-based CT
Patients that experience a radiologically documented PD (assessed by the Investigator) ≥ 24 weeks of ICI, including ≥ 12-weeks of anti-PD(L)1 as monotherapy or in combination with another ICI or an anti-angiogenic prior to randomization; patients who permanently stopped ICI after a protocol specified cessation of ICI according to site’ practice and patients after having permanently stopped ICI due to prior toxicity that is resolved or not clinically significant at time of study entry are authorized
Patients with ECOG performance status (PS) 0 or 1
Patients with measurable or non-measurable lesions per RECIST 1.1
Patients with adequate organ functions defined as: Albumin ≥ 2.8 g/dL ; AST and ALT up to 3.0 x ULN associated with Alkaline Phosphatase (ALKP) ≤ 2.5 x ULN, or ALPK ≥ 2.5 x ULN up to 5.0 x ULN associated with AST and ALT ≤ 1.5 x ULN ; Total serum bilirubin ≤ 1 x ULN; for patients with Gilbert’s syndrome, total bilirubin ≤ 3 ULN or direct bilirubin ≤ 1.5 ULN ; Absolute neutrophil count (ANC) ≥ 1.5 x 109/L ; Platelets ≥ 100 x 109/L ; Haemoglobin ≥ 9 g/dL (in the absence of transfusion within 2 weeks before randomization) ; Creatinine clearance (CrCl) according to CKD-EPI (Chronic Kidney Disease – EPIdemiology) formula ≥ 30 ml/min/1.73m2
Patients without clinically significant ongoing toxicity from prior therapy (severity ≤ Grade 1; except alopecia) ; patients with disease necessitating a replacement treatment and well balanced are authorized (e.g., hypo or hyperthyroidism, adrenal insufficiency, diabetes treated by oral anti-glycemic agent and/or insulin therapy…)
If applicable, before study treatment (OSE2101 or docetaxel) administration, a wash out of at least 21 days or 5 half-lives (whichever is shorter) since the last anticancer treatment or investigational therapy; a wash out of at least 28 days after definitive radiation or prior major surgery; wash out after palliative radiation of at least 2 weeks
Women of childbearing potential (WOCBP) participating in the study must agree to use highly effective methods of contraception (i.e., one that results in a less than 1% per year failure rate when used consistently and correctly) prior to study entry, during the study, and for 180 days after the last dose of study treatment. Highly effective methods of contraception are defined as one of the following methods: combined (oestrogen and progestogen containing) hormonal contraception associated with inhibition of ovulation (oral, intravaginal, transdermal), progestogen-only hormonal contraception associated with inhibition of ovulation (oral, injectable, implantable), intrauterine device (IUD), intrauterine hormone-releasing system (IUS), bilateral tubal occlusion, vasectomised partner, sexual abstinence
Male patient with WOCBP partner must be willing to use male contraception (condoms) during the study, and for 90 days after the last dose of study treatment. WOCBP partners of male subjects participating in the study may use hormone-based contraceptives as one of the acceptable methods of contraception since they will not be receiving the study treatment (i.e.; oral hormonal contraception, cap, diaphragm, or sponge with spermicide)
WOCBP must have a highly sensitive or serum pregnancy negative test during screening and within 24 hours prior to each administration of the study treatment (OSE2101 or docetaxel). Women who are postmenopausal for at least 1 year (defined as more than 12 months since last menses) or are surgically sterilised do not require this test
Patients having signed and dated informed consent (IC) prior to any trial-specific procedures
Patients must be affiliated to a social security system per local regulation (such as in France).

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Exclusion Criteria

Small-cell lung cancer/mixed NSCLC with small cell component or other neuroendocrine lung cancers (typical and atypical carcinoids, large-cell neuroendocrine carcinomas)
Patients with active auto-immune disease and/or immune-related disease due to prior immunotherapy or other condition requiring systemic immunosuppressive treatments or chronic administration of corticosteroids > 10 mg daily prednisolone equivalent (except as replacement if adrenal insufficiency); short course of corticosteroids > 10 mg daily prednisolone equivalent is allowed if ≤ 10 days continuous duration (e.g. premedication to prevent contrast allergy, drug reaction…); topical, ocular, intra-articular, intranasal, and inhaled corticosteroids with minimal systemic absorption are allowed
Patients with interstitial lung disease or active non-infectious pneumonitis
Patients who have known hereditary, congenital or acquired immunodeficiencies; for human immunodeficiency virus (HIV) infection, patient may be eligible if CD4+ count ≥ 350 cells/μL, and no history of acquired immunodeficiency syndrome (AIDS) infections within 12 months prior to start of study treatment, and receiving an established antiretroviral therapy with NO known drug-drug interaction with docetaxel for at least 4 weeks prior to starting the study treatment, and have a viral load ≤ 400 copies/μL (local laboratory)
Patients with an active infection requiring anti-infective therapy until all signs of infection have resolved before randomization
Patients with PD during induction first-line CT-ICI (to exclude hyper progression and fast progression to CT-ICI) or with PD within 24 weeks of ICI; chemotherapy or other cytotoxic agents in combination with ICI within 12 weeks prior to randomization are not authorized;
Patients with chronic Hepatitis B (HBV) infection who meet the criteria for antiviral therapy (according to local/international guidelines) and not treated prior to starting the study treatment; patients with an active Hepatitis C (HCV) with HCV viral load (by local laboratory) above the limit of quantification; patients who received a prior antiviral HCV treatment or no prior treatment but HCV natural resolution with HCV RNA not detectable are eligible
Patients with other active cancer(s) within 3 years prior to randomization (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)
Patients with severe acute or chronic medical (i.e., severe liver impairment) or psychiatric or incapacitated conditions, or laboratory abnormalities that would expose to an excess risk associated with study participation or study drug administration in the opinion of the Investigator and/or the Sponsor
Patient participating in another clinical trial with an investigational medicinal product
Patient is the Principal Investigator or Investigator, research assistant, pharmacist, study coordinator, other staff directly involved in the conduct of the study
Patients with known hypersensitivity to the active substances or to any of the excipients of OSE2101 or docetaxel
Patients with current brain metastases, leptomeningeal metastases or carcinomatous meningitis, or previously treated brain metastases, leptomeningeal metastases, or carcinomatous meningitis; patients with spinal cord compression except if due to external causes and duly treated (e.g.; radiation for bone metastasis)
Patients with AST and/or ALT >1.5 × ULN concomitant with ALPK > 2.5 × ULN
Pregnant or breastfeeding woman.

Trial Status by Country

Country	Status	Start of Recruitment	Planned Patients
Belgium	Recruiting	02 Sept 2024	35
France	Recruiting	02 Sept 2024	77
Germany	Recruiting	02 Sept 2024	26
Greece	Recruiting	02 Sept 2024	36
Hungary	Recruiting	02 Sept 2024	15
Italy	Recruiting	02 Sept 2024	37
The Netherlands	Recruiting	02 Sept 2024	—
Poland	Recruiting	02 Sept 2024	25
Portugal	Recruiting	02 Sept 2024	10
Romania	Recruiting	02 Sept 2024	16