Neoadjuvant Durvalumab and Adaptive Low-Dose Radiotherapy for Tumor Microenvironment Modification in Early-Stage Non-Small Cell Lung Cancer

Trial ID: 2024-516580-87-00
Sponsor: Amsterdam UMC Stichting

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Diseases & Conditions

Non-small cell lung cancer

Objectives

The primary objective of the study is to assess the **safety** of neoadjuvant single fixed-dose 1500mg intravenous **durvalumab** combined with an adaptive low dose radiotherapy schedule in patients with early-stage non-small cell lung cancer (NSCLC). Evaluating the safety profile is clinically relevant as it determines the feasibility and potential risks associated with this treatment regimen, which is crucial for patient management and treatment planning.

Secondary objectives include:

Exploring tumor immune infiltration following the neoadjuvant treatment, which may provide insights into the immunomodulatory effects of the therapy and its potential to enhance anti-tumor immune responses.
Investigating the radiological and metabolic response to the treatment, which could offer valuable information on the efficacy of the regimen in reducing tumor burden and altering tumor metabolism.

Participants

The clinical trial involves participants diagnosed with **early stage non-small cell lung cancer (NSCLC)**. The study population includes both male and female subjects, aged 18 years and older, who are in generally good health as indicated by an Eastern Cooperative Oncology Group (ECOG) performance status of 0-1. Participants must have a life expectancy of at least 12 weeks and demonstrate adequate organ function. The trial does not include vulnerable populations. The selection criteria require participants to have histologically confirmed NSCLC and measurable disease based on RECIST 1.1. The sponsor has not provided information regarding the total number of participants. Lifestyle considerations such as diet and physical activity are not specified. The trial population was selected based on specific inclusion criteria, including the ability to provide informed consent and adequate lung function for surgical resection. The study does not focus on any particular lifestyle habits or conditions beyond the medical criteria outlined.

Plans and Procedures

The clinical trial is designed to evaluate the safety and pathological response of **durvalumab** in combination with an adaptive low-dose radiotherapy schedule in patients with early-stage non-small cell lung cancer (NSCLC). This trial is structured as a randomized, double-blind, controlled study, with an estimated duration from August 2021 to August 2025. Participants will receive a single fixed-dose of 1500 mg intravenous durvalumab, followed by radiotherapy, and subsequently undergo surgical resection. The primary endpoints include assessing the safety, defined by the percentage of patients experiencing adverse events, and evaluating the major pathological response (MPR) and pathological complete response (pCR) rates in resected tumor specimens. Secondary endpoints focus on tumor immune infiltration and radiological response using RECIST v1.1 criteria, as well as metabolic response based on 18F-FDG PET.

The sequence of study visits begins with an inclusion (screening) visit, where eligibility is confirmed based on criteria such as histologically confirmed NSCLC, measurable disease, and adequate organ function. Participants must be above 18 years of age, have a body weight over 30 kg, and a life expectancy of at least 12 weeks. Follow-up visits will be scheduled to monitor the safety and efficacy of the treatment, with assessments including pulmonary function tests and imaging studies. The end-of-study visit will conclude the trial, evaluating the final outcomes and any long-term effects of the treatment. Participant involvement is expected to last until the end of the trial, unless early termination is warranted due to adverse events, withdrawal of consent, or any condition that compromises the participant's safety or the integrity of the study.

Treatment

The clinical trial involves the administration of **IMFINZI** (durvalumab), a **concentrate for solution for infusion**. The pharmaceutical form is a solution for infusion, and the active substance is durvalumab, a protein-based therapeutic agent. The medication is provided at a concentration of 50 mg/mL and is administered intravenously. Participants receive a single fixed dose of 1500 mg of durvalumab. The administration is conducted as part of a neoadjuvant treatment regimen, which is designed to assess safety and explore the pathological response in early-stage non-small cell lung cancer (NSCLC). The product is manufactured by AstraZeneca AB and is authorized for use in the European Union under the marketing authorization number EU/1/18/1322/001.

In addition to the experimental treatment with durvalumab, the study protocol includes an adaptive low-dose radiotherapy schedule. This non-experimental treatment is integrated into the trial to evaluate its combined effect with durvalumab on the tumor microenvironment. The radiotherapy is administered as a short-course, medium-dose regimen, complementing the immunotherapy approach. The trial does not include a placebo or comparator treatment, as the focus is on the dual-immunotherapy and radiotherapy combination. Participant compliance with the dosing schedule is monitored throughout the study to ensure adherence to the treatment protocol.

Efficacy

Efficacy in the clinical trial titled "Dual-immunotherapy and short-course medium-dose radiotherapy, followed by surgery for tumor microenvironment modification in early-stage NSCLC: the DIRECT-trial" will be assessed using several primary and secondary endpoints. The primary endpoints include the evaluation of safety, defined as the percentage of patients experiencing adverse events, and the assessment of **major pathological response (MPR)** and pathological complete response (pCR) rates in resected tumor specimens. These endpoints will provide insights into the pathological changes induced by the treatment regimen.

Secondary endpoints focus on the tumor's immune response and radiological changes. Tumor immune infiltration will be categorized into four distinct groups following treatment with durvalumab and radiotherapy. Additionally, the radiological response will be measured using the RECIST v1.1 criteria, and metabolic response will be evaluated based on 18F-FDG PET scans. These assessments will help determine the treatment's impact on tumor characteristics and patient outcomes.

Inclusion and Exclusion Criteria

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Inclusion Criteria

Histologically confirmed NSCLC
T1c-3N0-2, here T3 tumors are based on size, but not based in invasion into the thoracic wall, mediastinum, vertebra or diaphragm or ipsilateral lung nodules
Willing and able to provide written informed consent for the trial
Above 18 years of age on day of signing informed consent
Have measurable disease based on RECIST 1.1
Have a ECOG performance status of 0-1, and are considered operable based on pulmonary function test and/or exercise testing
Demonstrate adequate organ function, as deemed acceptable by the treating physician in the context of immunotherapy: a. Leukocytes ≥ 3,000/mm3 b. Absolute neutrophil count (ANC) ≥ 1000/mm3 c. Platelet count ≥ 75,000/mm3 d. Hemoglobin ≥ 6 mmol/L (9.7 g/dL) e. Creatinine ≤ 1.5 x ULN or creatinine clearance (CrCl) ≥40 mL/min (if using the Cockcroft-Gault formula below): i. Female CrCl = [(140 - age) x weight x 0.85]/(0.85 x creat in mmol/L) ii. Male CrCl = [(140 - age) x weight x 1.00]/(0.81 x creat in mmol/L) f. Total Bilirubin ≤ 1.5 x ULN (except subjects with Gilbert Syndrome) g. AST and ALT ≤ 2.5 times the upper limit of normal h. Subjects must have adequate lung function to permit surgical resection determined by preenrollment pulmonary function tests to include DLCO
Body weight >30 kg
Must have a life expectancy of at least 12 weeks

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Exclusion Criteria

Prior surgery and/or radiotherapy on the ipsilateral thorax
Patients deemed inoperable
Subjects with a condition requiring systemic treatment with either corticosteroids (> 10 mg daily prednisone equivalent) or other immunosuppressive medications within 14 days of day 0. Inhaled or topical steroids, and adrenal replacement steroid >10 mg daily prednisone equivalent, are permitted in the absence of active autoimmune disease.
Additional malignancy that is progressing or requires active treatment. Exceptions include basal cell carcinoma of the skin, squamous cell carcinoma of the skin, or in situ cervical cancer that has undergone potentially curative therapy.
Active or prior documented autoimmune or inflammatory disorders (including inflammatory bowel disease [e.g., colitis or Crohn's disease], diverticulitis [with the exception of diverticulosis], systemic lupus erythematosus, Sarcoidosis syndrome, or Wegener syndrome [granulomatosis with polyangiitis, Graves' disease, rheumatoid arthritis, hypophysitis, uveitis, etc.]). The following are exceptions to this criterion:  Patients with vitiligo or alopecia  Patients with hypothyroidism (e.g., following Hashimoto syndrome) stable on hormone replacement  Any chronic skin condition that does not require systemic therapy  Patients without active disease in the last 5 years may be included but only after consultation with the study physician  Patients with celiac disease controlled by diet alone
Uncontrolled intercurrent illness, including but not limited to symptomatic congestive heart failure, uncontrolled hypertension, unstable angina pectoris, cardiac arrhythmia, interstitial lung disease, serious chronic gastrointestinal conditions associated with diarrhea, or psychiatric illness/social situations that would limit compliance with study requirement, substantially increase risk of incurring AEs or compromise the ability of the patient to give written informed consent
Active infection requiring systemic therapy.
A history of Human Immunodeficiency Virus (HIV) (HIV 1/2 antibodies).
Active infection including tuberculosis (clinical evaluation that includes clinical history, physical examination and radiographic findings, and TB testing in line with local practice), hepatitis B (known positive HBV surface antigen (HBsAg) result), hepatitis C, 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.
Psychiatric or substance abuse disorders that would interfere with cooperation with the requirements of the trial.
Has received prior therapy with an anti-PD-1, anti-PD-L1 including durvalumab, anti-PD-L2, anti-CTLA-4 antibody, or any other antibody or drug specifically targeting T-cell co-stimulation or immune checkpoint pathways.
Patient is pregnant or breastfeeding or expecting to conceive within the projected duration of the trial, starting with the pre-screening or screening visit through 23 weeks after the last dose of trial treatment.