Phase II Randomized Study of Neoadjuvant Chemotherapy and Nivolumab Versus Chemotherapy Alone in Locally Advanced Resectable Non-Small Cell Lung Cancer

Trial ID: 2024-513731-24-00
Sponsor: Fundacion GECP

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Diseases & Conditions

Non-small cell lung cancer

Objectives

The primary objective of this study is to evaluate the **pathological Complete Response (pCR)**, defined as the absence of residual tumor in the lung and lymph nodes, in patients with locally advanced and potentially resectable non-small cell lung cancer (NSCLC) treated with a combination of chemo-immunotherapy versus chemotherapy alone. This objective is clinically relevant as achieving a pCR is associated with improved long-term outcomes and survival rates in cancer patients.

Secondary objectives include:

Overall survival
Progression-free survival
Major pathological response rate
Downstaging
Portion of delayed/canceled surgeries, length of hospital stays, surgical approach, incidence of adverse events (AE) and serious adverse events (SAE) related to surgery
Mortality at 90 days after surgery
Safety and tolerability, with adverse events graded according to CTCAE v5.0
Biomarker endpoints
Association between major pathological response and histology
Association of histology with progression-free survival at 18 months

Participants

The clinical trial involves participants diagnosed with **non-small cell lung cancer (NSCLC)**, specifically those with stage IIIA disease or potentially resectable locally advanced stage IIIB with T3N2 disease. The study population includes both male and female subjects over the age of 18, with an Eastern Cooperative Oncology Group (ECOG) performance status of 0-1, indicating they are fully active or restricted in physically strenuous activity but ambulatory. Participants are required to have correct hematological, hepatic, and renal function. The trial does not include a vulnerable population. All participants must have measurable or evaluable disease according to RECIST 1.1 criteria and must be capable of proper therapeutic compliance and accessible for correct follow-up. The sponsor has not provided the total number of participants involved in the study. Lifestyle considerations such as diet, physical activity, or habits are not specified. Key inclusion criteria include the requirement for a negative pregnancy test for women of childbearing potential and the use of effective contraceptive methods for all sexually active participants during the study and for at least 12 months following the last administration of trial drugs.

Plans and Procedures

The clinical trial is designed as a **randomized**, phase II study to evaluate the efficacy of neo-adjuvant chemo/immunotherapy versus chemotherapy alone in patients with locally advanced and potentially resectable **non-small cell lung cancer (NSCLC)**. The primary objective is to assess the pathological Complete Response (pCR), defined as the absence of residual tumor in the lung and lymph nodes. The trial will also evaluate secondary endpoints such as overall survival, progression-free survival, and major pathological response rate. The study is expected to commence recruitment on June 3, 2024, and conclude by January 1, 2027.

Participants will be randomly assigned to receive either the combination of chemotherapy and **nivolumab** or chemotherapy alone. The trial is double-blind and controlled to ensure unbiased results. The investigational product, OPDIVO 10 mg/mL concentrate for solution for infusion, will be administered via intravenous infusion. The maximum treatment period is 12 months, with a maximum daily dose of 360 mg and a total dose of 480 mg.

The sequence of study visits includes an initial screening visit to confirm eligibility based on criteria such as histologically- or cytologically-documented NSCLC, stage IIIA or IIIB disease, and resectability. Follow-up visits will be scheduled to monitor treatment response and adverse events, graded according to CTCAE v5.0. The end-of-study visit will assess the primary and secondary endpoints, including safety and tolerability.

Participant involvement is expected to last up to 12 months, with conditions for early termination including non-compliance with the study protocol, withdrawal of consent, or adverse events that compromise safety. The trial will adhere to ethical guidelines, ensuring informed consent is obtained from all participants. The study aims to provide valuable insights into the potential benefits of combining immunotherapy with chemotherapy in treating NSCLC.

Treatment

The clinical trial involves the administration of **OPDIVO** (nivolumab), a **concentrate for solution for infusion**. This experimental medication is provided in a concentration of 10 mg/mL and is intended for intravenous infusion. The maximum daily dose is 360 mg, with a total maximum dose of 480 mg over the course of the treatment. The treatment period is set for a maximum of 12 months. Nivolumab is a protein-based therapeutic agent, specifically classified under the ATC code L01FF01, and is produced by Bristol-Myers Squibb Pharma EEIG. The administration of nivolumab is conducted via intravenous infusion, ensuring precise delivery of the medication directly into the bloodstream.

In addition to the experimental treatment, the study includes a comparator treatment consisting of standard chemotherapy. This non-experimental treatment serves as a control to evaluate the efficacy of the chemo-immunotherapy regimen against chemotherapy alone. The chemotherapy regimen is administered according to standard-of-care protocols for patients with locally advanced and potentially resectable non-small cell lung cancer (NSCLC). The study aims to compare the pathological complete response (pCR) between the two treatment groups, with pCR defined as the absence of residual tumor in the lung and lymph nodes.

Efficacy

Efficacy in this clinical trial will be assessed primarily through the evaluation of **Pathological Complete Response (pCR)**, which is defined as the absence of residual tumor in the lung and lymph nodes. This primary endpoint will compare patients treated with chemo-immunotherapy versus chemotherapy alone. Secondary endpoints include overall survival, progression-free survival, major pathological response rate, downstaging, and various surgical outcomes such as the portion of delayed or canceled surgeries, length of hospital stays, surgical approach, and incidence of adverse events related to surgery. Additional secondary endpoints involve mortality at 90 days post-surgery, safety and tolerability assessed by adverse events graded according to CTCAE v5.0, biomarker endpoints, and the association between major pathological response and histology, as well as the association of histology with progression-free survival at 18 months.

Inclusion and Exclusion Criteria

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Inclusion Criteria

Previously untreated patients with histologically- or cytologically- documented NSCLC who present stage IIIA disease (according to 8th version of the International Association for the Study of Lung Cancer Staging Manual in Thoracic Oncology) and also, potentially resectable locally advanced NSCLC patients’ stage IIIB with T3N2 disease according to 8th edition can be included
Tumor should be considered resectable before study entry by a multidisciplinary team
ECOG (Performance status) 0-1
Correct hematological, hepatic and renal function
All patients are notified of the investigational nature of this study and signed a written informed consent in accordance with institutional and national guidelines, including the Declaration of Helsinki prior to any
Patients aged > 18 years
Women of childbearing potential, including women who had their last menstrual period in the last 2 years, must have a negative serum or urine pregnancy test within 7 days before beginning of chemotherapy
All sexually active men and women of childbearing potential must use an effective contraceptive method during the study treatment and for a period of at least 12 months following the last administration of trial drugs
Patient capable of proper therapeutic compliance and accessible for correct follow-up
Measurable or evaluable disease (according to RECIST 1.1 criteria)

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Exclusion Criteria

All patients carrying activating mutations in the TK domain of EGFR or any variety of alterations in the ALK gene
Patients with active, known or suspected autoimmune disease. Subjects with vitiligo, type I diabetes mellitus, residual hypothyroidism due to autoimmune thyroiditis only requiring hormone replacement or unexpected conditions of recurrence in the absence of an external trigger are allowed to be included
Patients with a condition requiring systemic treatment with either corticosteroids or other immunosuppressive medications within 14 days of enrollment. Inhaled or topical steroids, and adrenal replacement steroid doses > 10 mg daily prednisone equivalent, are permitted in the absence of active autoimmune disease
Patients with a history of interstitial lung disease cannot be included if they have sympthomatic ILD (Grade 3-4) and/or poor lung function.
Patients with other active malignancy requiring concurrent intervention and/or concurrent treatment with other investigational drugs or anticancer therapy
Patients with previous malignancies (except non-melanoma skin cancers, and the following in situ cancers: bladder, gastric, colon, endometrial, cervical/dysplasia, melanoma, or breast) are excluded unless a complete remission was achieved at least 2 years prior to study entry and no additional therapy is required during the study period.
Any medical, mental or psychological condition which in the opinion of the investigator would not permit the patient to complete the study or understand the patient information
Patients who have had prior treatment with an anti-PD-1, anti-PD-L1, anti-PD-L2, anti-CTLA-4 antibody, or any other antibody or drug specifically targeting T-cell costimulation or immune checkpoint pathways
Patients with positive test for hepatitis B virus surface antigen (HBV sAg) or hepatitis C virus ribonucleic acid (HCV antibody) indicating acute or chronic infection
Patients with known history of testing positive for human immunodeficiency virus (HIV) or known acquired immunodeficiency syndrome (AIDS)
Patients with history of allergy to study drug components excipients
Women who are pregnant or in the period of breastfeeding
Sexually active men and women of childbearing potential who are not willing to use an effective contraceptive method during the study