A randomized, phase II, open-label, multicenter study investigating efficacy and safety of anti-PD-1/PD-L1 treatment +/- UV1 vaccination as first line treatment in patients with inoperable advanced or metastatic non-small cell lung cancer

Trial ID: 2022-502437-25-00
Sponsor: Vestre Viken HF

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Diseases & Conditions

Non-small cell lung cancer Lung neoplasm malignant

Objectives

The primary objective of this study is to evaluate and compare the **efficacy** of PD-1/PD-L1 inhibitor treatment with or without UV1 vaccination in patients with stage IIIB/IIIC or stage IV non-small cell lung cancer (NSCLC). This is clinically relevant as it aims to determine whether the addition of UV1 vaccination can enhance the therapeutic outcomes of standard PD-1/PD-L1 inhibitor therapy in advanced or metastatic NSCLC, potentially leading to improved treatment protocols.

Secondary objectives include:

Comparing overall survival (OS), objective response rate (ORR), disease control rate (DCR), time to response (TTR), and duration of response (DOR) according to Response Evaluation Criteria in Solid Tumours, version 1.1 (RECIST 1.1), between patients receiving PD-1/PD-L1 inhibitor treatment alone and those receiving it in combination with UV1 vaccination.
Determining the safety and tolerability of PD-1/PD-L1 inhibitor treatment compared to its combination with UV1 vaccination.
Investigating possible biological markers for response, resistance, and toxicity.

These secondary objectives are crucial for understanding the broader implications of combining UV1 vaccination with PD-1/PD-L1 inhibitors, including potential benefits in survival and response rates, as well as identifying biomarkers that could guide personalized treatment strategies.

Participants

The clinical trial involves participants diagnosed with **advanced or metastatic non-small cell lung cancer** (NSCLC), specifically those with stage IIIB/IIIC or stage IV disease. The study population includes both male and female subjects aged 18 years and older, with an Eastern Cooperative Oncology Group (ECOG) performance status of 0-2, indicating they are ambulatory and capable of self-care. Participants must have adequate organ function and a histologically confirmed diagnosis of NSCLC that is not amenable to curative treatment. The trial does not include a vulnerable population. The sponsor has not provided the total number of participants. Selection criteria require participants to have a PD-L1 expression of 50% or greater, and they must be eligible for PD-1/PD-L1 inhibitor monotherapy as a first-line treatment. Lifestyle factors such as diet and physical activity are not specified as part of the selection criteria. The trial excludes individuals who have received immunotherapies as part of previous neo-adjuvant or adjuvant systemic therapy unless completed at least 12 months prior to the development of metastatic disease. Participants must provide written informed consent before any study-specific procedures are conducted.

Plans and Procedures

The clinical trial is designed to evaluate the efficacy and safety of a combination treatment involving **PD-1/PD-L1 inhibitors** with or without UV1 vaccination in patients diagnosed with advanced or metastatic non-small cell lung cancer (NSCLC). This study is structured as a randomized, phase II, open-label, multicenter trial. The trial aims to compare the outcomes of patients receiving the combination therapy against those receiving standard care. The primary endpoint is progression-free survival as assessed by Blinded Independent Central Review, while secondary endpoints include overall survival, objective response rate, disease control rate, time to recurrence, and duration of response.

The trial is expected to run from August 15, 2022, to July 1, 2027, with recruitment having commenced on March 15, 2022. Participants will be involved in the study for a maximum treatment period of 13 weeks. The study includes several key visits: an initial screening visit to confirm eligibility based on criteria such as histologically confirmed NSCLC stage IIIB/IIIC or IV, adequate organ function, and an ECOG performance status of 0-2. Follow-up visits will be scheduled to monitor the participants' response to treatment and any adverse effects. The end-of-study visit will conclude the participant's involvement, assessing the final outcomes and any long-term effects of the treatment.

Participants may be withdrawn from the study early if they experience unacceptable toxicity, disease progression, or if they withdraw consent. The trial is conducted under strict ethical guidelines, ensuring that all participants provide informed consent before any study-specific procedures are initiated. The investigational products, Leukine and UV1, are administered intradermally in the form of a powder for solution for injection. The trial is not categorized as low intervention due to the use of non-authorized products. The study is conducted in compliance with regulatory standards to ensure the safety and well-being of all participants.

Treatment

The clinical trial involves the administration of two experimental medications, **Leukine** and **UV1**, both formulated as a **powder for solution for injection**. **Leukine** contains the active substance **sargramostim**, a protein classified under "Protein - Other". It is administered via **intradermal use**. The maximum daily dose of **Leukine** is 250 µg, with a total maximum dose of 2000 µg over a treatment period of up to 13 weeks. The administration schedule and participant compliance are monitored to ensure adherence to the dosing regimen.

**UV1** is another investigational product in this study, containing a combination of active substances: **alrefimotide**, **riletamotide**, and **tapderimotide**, all categorized as "Protein - Other". Similar to **Leukine**, **UV1** is also administered via **intradermal use**. The maximum daily dose for **UV1** is 300 µg, with a total maximum dose of 2400 µg over a 13-week treatment period. The administration of **UV1** is carefully monitored to ensure compliance with the dosing schedule.

In this trial, no non-experimental treatments such as standard-of-care therapy, placebo, or comparator treatments are utilized. The focus is on evaluating the efficacy and safety of the experimental medications in patients with inoperable advanced or metastatic non-small cell lung cancer. The trial is designed to assess the impact of these treatments on the specified patient population, with rigorous monitoring of drug administration and participant adherence to the treatment protocol.

Efficacy

The efficacy of the clinical trial will be assessed using several key endpoints. The primary endpoint is **Progression-Free Survival (PFS)**, which will be evaluated according to the Response Evaluation Criteria in Solid Tumours (RECIST v1.1) and determined by a Blinded Independent Central Review (BICR). Secondary endpoints include Overall Survival (OS), Objective Response Rate (ORR), Disease Control Rate (DCR), Time To Recurrence (TtR), and Duration of Response (DoR). These endpoints will provide a comprehensive evaluation of the treatment's efficacy in patients with inoperable advanced or metastatic non-small cell lung cancer (NSCLC).

Inclusion and Exclusion Criteria

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Inclusion Criteria

Histologically confirmed NSCLC stage IIIB/IIIC or IV not amenable for curative treatment, with PD-L1 ≥ 50% measured by a validated method, and eligible for PD-1/PD-L1 inhibitor monotherapy in the first-line setting
At least one lesion, not previously irradiated and not chosen for biopsy during the study screening period, that can be accurately measured at baseline according to RECIST 1.1
Subjects who received previous neo-adjuvant or adjuvant systemic therapy (other than immunotherapies) will be eligible if neo-adjuvant or adjuvant therapy was completed at least 12 months prior to the development of metastatic disease. Last dose of neoadjuvant or adjuvant therapy must be more than 12 months prior to enrollment/randomization
Available unstained archived tumour tissue sample in sufficient quantity to allow for analyses. At least fifteen unstained slides or a tumour block (preferred)
Male and female age ≥ 18 years at time of signing the ICF
Eastern Cooperative Oncology Group (ECOG) performance status of 0-2
Adequate organ function as defined below − Haemoglobin ≥9.0 g/dL− Absolute neutrophil count (ANC) 1.5 x (> 1500 per mm3) − Platelet count ≥100 x 109/L (>75,000 per mm3) − Serum bilirubin ≤1.5 x institutional upper limit of normal (ULN). − AST (SGOT)/ALT (SGPT) ≤2.5 x institutional upper limit of normal unless liver metastases are present, in which case it must be ≤5x ULN − Measured creatinine clearance (CL) >40 mL/min or Calculated creatinine CL >40 mL/min by the Cockcroft-Gault formula (Cockcroft and Gault 1976) or by 24-hour urine collection for determination of creatinine clearance: Males: Creatinine CL (mL/min) = Weight (kg) x (140 – Age) 72 x serum creatinine (mg/dL) Females: Creatinine CL (mL/min) = Weight (kg) x (140 – Age) x 0.85 72 x serum creatinine (mg/dL)
Written informed consent obtained prior to any study specific procedure

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Exclusion Criteria

Previous treatment with a PD-1 or PD-L1 inhibitor, or any other agent targeting immune checkpoints
Previous malignancy (except non-melanoma skin cancer and the following in situ cancers: bladder, gastric, esophageal, colon, endometrial, cervical, melanoma or breast) unless a complete remission was achieved at least 2 years prior to study entry
Symptomatic or uncontrolled brain metastases requiring concurrent treatment, inclusive of but not limited to surgery, radiation and/or corticosteroids (prednisone >10 mg or equivalent). Surgery, radiation and/or corticosteroids (any dose >10 mg prednisone equivalent) must have been completed ≥ 2 weeks prior to randomization.
Known history of leptomeningeal carcinomatosis
Uncontrolled seizures.
Current or prior use of immunosuppressive medication within 28 days before the first dose of PD-1/PD-L1 inhibitor, with the exceptions of intranasal and inhaled corticosteroids or systemic corticosteroids at physiological doses, which are not to exceed 10 mg/day of prednisone, or an equivalent corticosteroid. Steroid premedication given as prophylaxis for imaging contrast allergy should not be counted for this criterion
Active or prior documented autoimmune or inflammatory disorders (including inflammatory bowel disease, diverticulitis with the exception of diverticulosis, celiac disease, irritable bowel disease;Wegner syndrome) within the past 2 years. Subjects with vitiligo, alopecia, Grave's disease, or psoriasis not requiring systemic treatment (within the past 3 years) are not excluded
History of primary immunodeficiency
History of allogeneic organ transplant
Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, symptomatic congestive heart failure, uncontrolled hypertension, unstable angina pectoris, cardiac arrhythmia, active peptic ulcer disease or gastritis, active bleeding diatheses including any subject known to have psychiatric illness/social situations that would limit compliance with study requirements or compromise the ability of the subject to give written informed consent
Active infection including tuberculosis (clinical evaluation including: physical examination findings, radiographic findings, positive PPD test, etc.), hepatitis B (known positive HBV surface antigen [HBsAg] result), hepatitis C, or human immunodeficiency virus (positive HIV 1/2 antibodies as defined by a positive ELISA test). Patients with a past or resolved HBV infection (defined as the presence of hepatitis B core antibody [anti-HBc] and absence of HBsAg) are eligible. Patients positive for hepatitis C (HCV) antibody are eligible only if polymerase chain reaction is negative for HCV RNA. HIV testing is not required in the absence of clinical suspicion
Pregnant or lactating women
Live attenuated vaccination within 30 days prior to study entry or within 30 days of receiving PD-1/PD-L1 inhibitor
Any condition that, in the opinion of the investigator, would interfere with the evaluation of study treatment or interpretation of patient safety or study results
History of allergy or hypersensitivity to any of the active substances or excipients in the study drug
Involvement in the planning and/or conduct of the study (investigator staff and/or staff at the study site)
Judgment by the investigator that the subject should not participate in the study if the subject is unlikely to comply with study procedures, restrictions and requirements