Phase II Study of Neoadjuvant Chemotherapy and Nivolumab Followed by Adjuvant Therapy in Resectable Non-Small Cell Lung Cancer Pancoast Tumor

Trial ID: 2024-512359-19-00
Sponsor: Fundacion GECP

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Diseases & Conditions

Non-small cell lung cancer Pancoast's tumour

Objectives

The primary objective of this Phase II clinical trial is to estimate **progression-free survival (PFS)** at 24 months from diagnosis in patients with resectable non-small cell lung cancer (NSCLC) specifically diagnosed with a Pancoast tumor. PFS is defined as the time from diagnosis to relapse, progression, or death, whichever occurs first. This measure is clinically relevant as it provides insight into the efficacy of the treatment regimen in delaying disease progression, which is crucial for improving patient outcomes in this aggressive cancer type.

Secondary objectives include:

Overall survival (OS) at 24 months, which assesses the long-term efficacy of the treatment.
Complete resection (R0) after induction treatment with chemotherapy plus **nivolumab**, indicating the potential for curative surgery.
Objective treatment response rate (ORR), disease control rate (DCR), and duration of response (DOR), which evaluate the immediate effectiveness of the treatment.
Pathological response, including pathological complete response (pCR), major pathological response (MPR), and percentage of residual tumor viable (RTV%) in the primary tumor, providing insights into the biological impact of the treatment.
Treatment safety and tolerability, ensuring the regimen is manageable for patients.
Study of the prognostic value of basal circulating tumor DNA (ctDNA), examining the association of basal levels with PFS and OS, which could offer predictive insights for patient stratification and personalized treatment approaches.

Participants

The clinical trial involves participants diagnosed with **resectable non-small cell lung cancer Pancoast tumor**. The study population includes both male and female subjects, aged between 18 and 75 years, who are in generally good health as indicated by an ECOG performance status of 0-2. The trial does not include a vulnerable population. Participants were selected based on specific inclusion criteria, such as having previously untreated NSCLC diagnosed with a Pancoast tumor, measurable or evaluable disease according to RECIST 1.1 criteria, and a life expectancy of at least 12 weeks. All participants are required to have correct lung function, defined by a forced expiratory volume in 1 second (FEV1) greater than 40% of the predicted normal volume. The sponsor has not provided information regarding the total number of participants. Lifestyle considerations such as diet and physical activity are not specified in the available data. Key inclusion criteria include the requirement for women of childbearing potential to have a negative pregnancy test and for all sexually active participants to use effective contraception during the study and for a specified period afterward. The trial aims to estimate progression-free survival at 24 months from diagnosis.

Plans and Procedures

The clinical trial is designed as a **Phase II** study to evaluate the efficacy of a neo-adjuvant chemo/immunotherapy regimen followed by adjuvant treatment based on resection status in patients with resectable **non-small cell lung cancer** (NSCLC) diagnosed with a Pancoast tumor. The trial employs a randomized, double-blind, controlled methodology to ensure the reliability and validity of the results. The primary objective is to estimate progression-free survival (PFS) at 24 months from diagnosis, with secondary endpoints including overall survival rate, complete resection rate, and safety and tolerability assessments. The trial is expected to run until March 2029, with recruitment having commenced in May 2023.

Participants will undergo a series of study visits, beginning with an inclusion (screening) visit to confirm eligibility based on criteria such as histological or cytological documentation of NSCLC, measurable disease according to RECIST 1.1 criteria, and adequate organ function. Baseline assessments will include PET/CT scans and brain imaging to rule out distant disease. Following enrollment, participants will receive the investigational treatment, with follow-up visits scheduled to monitor treatment response, adverse events, and overall health status. The end-of-study visit will occur at the conclusion of the treatment period or upon early termination.

The expected length of participant involvement is approximately 12 months, corresponding to the maximum treatment period. Conditions that may lead to early termination from the study include disease progression, unacceptable toxicity, withdrawal of consent, or any other reason deemed appropriate by the investigator. Throughout the trial, participants will receive **nivolumab** as part of the treatment regimen, administered intravenously as a solution for infusion. The trial is conducted in accordance with ethical guidelines, including obtaining informed consent from all participants prior to any trial-related interventions.

Treatment

The clinical trial involves the administration of **OPDIVO**, a **concentrate for solution for infusion**. The active substance in OPDIVO is **nivolumab**, a protein-based therapeutic agent. Nivolumab is administered intravenously, with a maximum daily dose of 360 mg and a total maximum dose of 480 mg. The treatment period is capped at 12 months. The pharmaceutical form of OPDIVO is a solution for infusion, and it is provided by Bristol-Myers Squibb Pharma EEIG. The product is not a pediatric formulation and is not classified as an orphan drug. The administration schedule and participant compliance are monitored to ensure adherence to the dosing regimen.

Efficacy

Efficacy in this clinical trial will be assessed primarily through the estimation of **progression-free survival (PFS)** at 24 months from diagnosis. PFS is defined as the time from diagnosis to relapse, progression, or death, whichever occurs first. Secondary endpoints include the overall survival rate (OS) at 24 months, complete resection (R0) after induction treatment with chemotherapy plus nivolumab, objective treatment response rate (ORR), disease control rate (DCR), and duration of response (DOR). Systemic ORR will be determined by the investigator according to RECIST v1.1 criteria. Additionally, pathological response and percentage of residual tumor viable (RTV%) in the primary tumor will be evaluated, with pathological complete response (pCR) defined as the absence of residual tumor and major pathological response rate (MPR) defined as the number of randomized participants with less than 10% residual tumor.

Safety and tolerability will also be assessed by measuring the incidence of adverse events (AE), serious adverse events (SAE), immune-related AEs, deaths, and laboratory abnormalities. The association between treatment adverse events and PFS and OS will be determined, with adverse events graded according to CTCAE v5.0. Biomarker endpoints will include the study of the prognostic value of basal circulating tumor DNA (ctDNA) and its association with PFS and OS. These efficacy parameters will be collected and analyzed at specified timepoints throughout the trial to ensure comprehensive evaluation of the treatment's impact on patients with non-small cell lung cancer (NSCLC) diagnosed with Pancoast tumor.

Inclusion and Exclusion Criteria

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Inclusion Criteria

Previously untreated patients with histologically or cytologicallydocumented NSCLC diagnosed with Pancoast tumor according to 8th edition of the TNM (stages IIB, IIIA and T3N2 (IIIB) patients)
PET/CT including IV contrast (CT of diagnostic quality) will be performed at baseline (28 days +10 before enrollment) to rule out the presence of distant disease. Also, a brain CT-SCAN or brain MRI will be done at baseline
Positive mediastinal lymph nodes by PET-CT must be confirmed histologically. Mediastinal involvement may be considered without the need for histological confirmation when there is a mass of lymph nodes in which the margins cannot be distinguished
Measurable or evaluable disease (according to RECIST 1.1 criteria)
ECOG (Performance status) 0-2
Patients with a life expectancy of at least more than 12 weeks
Patients aged > 18 years and ≤ 75 years
Screening laboratory values must meet the following criteria and should be obtained within 14 days prior to enrollment i. Neutrophils ≥ 1500×109/L ii. Platelets ≥ 100 ×109/L iii. Hemoglobin > 10.0 g/dL iv. Serum creatinine ≤ 1.5 x ULN or creatinine clearance (CrCl) ≥ 40 mL/min (if using the Cockcroft-Gault formula below): a. Female CrCl = (140 - age in years) x weight in kg x 0.85/ 72 x serum creatinine in mg/dL b. Male CrCl = (140 - age in years) x weight in kg x 1.00/ 72 x serum creatinine in mg/dL v. AST/ALT ≤ 2.5 x ULN vi. Total Bilirubin ≤ 1.5 x ULN (except subjects with Gilbert Syndrome, who can have total bilirubin < 3.0 mg/dL) vii. The patients need to have a forced expiratory volume (FEV1) ≥ 1.2 liters or >40% predicted value viii. INR/APTT within normal limits
Correct lung function without bronchodilators, defined by forced expiratory volume in 1 second (FEV1) >40% of the predicted normal volume, and a pulmonary diffusing capacity for carbon monoxide (DLCO) >40% of the predicted normal value
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 trial-related intervention
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 enrollment.
All sexually active men and women of childbearing potential must use an effective contracep-tive method (two barrier methods or a barrier method plus a hormonal 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.

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Exclusion Criteria

Patients that receive previous treatment with antineoplastic drugs, chest radiotherapy, or previous surgery for lung cancer or for another reason
Pleural or pericardial effusion: Both will be considered indicative of metastatic disease unless proven otherwise. Those that, even being cytologically negative for malignancy, are exudates, will also be excluded. Patients with pleural effusion not visible on chest X-ray or too small to perform diagnostic puncture safely may be included.
Patients with a weight loss >10% in the 3 months prior to the study entry
All patients carrying activating mutations in the TK domain of EGFR or any variety of altera-tions in the ALK gene or ROS1 mutations.
Patients with active, known or suspected autoimmune disease. Subjects with vitiligo, type I diabetes mellitus, residual hypothyroidism due to autoimmune thyroiditis only requiring hor-mone replacement or unexpected conditions of recurrence in the absence of an external trigger are allowed to be included.
Patients with symptomatic neuropathy > grade 1 according to the CTCAE v5.0 and that were not related to the tumor
Patients with a condition requiring systemic treatment with either corticosteroids (>10 mg daily prednisone equivalent) 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. In case of doubt please contact trial team.case of doubt please contact trial team.
Patients with other active malignancy requiring concurrent intervention and/or concurrent treatment with other investigational drugs or anti-cancer therapy
Patients with uncontrolled comorbidities that may affect the clinical trial compliance
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 5 years prior to study entry AND no additional therapy is required during the study period.
Any medical, mental, neurological or psychological condition which in the opinion of the in-vestigator would not permit the patient to complete the study or understand the patient information sheet.
Patients in any psychological, familiar, sociological or geographical situation that may hinder compliance with the study protocol and/or the follow up
Patients who have had prior treatment with an anti-PD-1, anti-PDL1, 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 know hypersensitivity to drugs with a structure similar to the study drug and/or 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 ef-fective contraceptive method during the study