FDG-PET-Based Accelerated Chemoradiotherapy Followed by Durvalumab in Locally Advanced Unresectable NSCLC with PD-L1 ≥ 1%

Trial ID: 2023-510506-41-00
Protocol: ESR-21-21536
Sponsor: TheraOp gGmbH

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Diseases & Conditions

Non-small cell lung cancer stage III

Objectives

The primary objective of this study is to assess the **feasibility** of an FDG-PET-based small volume accelerated chemoradiotherapy followed by immunotherapy with **durvalumab** in comparison to the standard FDG-PET-based chemoradiotherapy followed by immunotherapy with durvalumab. This is clinically relevant as it aims to determine whether a more targeted and accelerated treatment approach can be effectively implemented in patients with locally advanced, unresectable non-small-cell lung cancer (NSCLC) with a PD-L1 expression of ≥ 1%.

Secondary objectives include:

To assess the **safety** and tolerability of the FDG-PET-based small volume accelerated chemoradiotherapy followed by immunotherapy with durvalumab.
To evaluate the **efficacy** of this treatment approach compared to the standard method in terms of time to locoregional progression, time to locoregional in- and out-of-RT-field progression, time to distant progression, progression-free survival, overall survival, objective response rate, and disease control rate.
To assess symptoms and patient-reported health-related **quality of life** (QoL) in patients receiving the accelerated treatment compared to those receiving the standard treatment.

Participants

The clinical trial involves a total of **10 participants** diagnosed with **locally advanced, unresectable non-small-cell lung cancer (NSCLC)**, specifically Stage III with a PD-L1-expression of ≥ 1%. The study population includes both male and female subjects aged **18 years or older**, with no vulnerable populations selected. Participants were chosen based on their ability to comply with the study's requirements, including scheduled visits and treatment protocols. All participants 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. The trial does not specify any particular lifestyle considerations such as diet or physical activity. Participants are required to have adequate bone marrow and organ function, as well as pulmonary function test results, to ensure they are fit for simultaneous chemoradiotherapy and consolidation immunotherapy. The selection criteria also include histologically proven PD-L1-expression of ≥ 1% in tumor samples and tumor assessment by FDG-PET CT within 21 days prior to the start of chemoradiotherapy.

Plans and Procedures

The clinical trial is designed to evaluate the feasibility of an FDG-PET-based small volume accelerated chemoradiotherapy followed by immunotherapy with **durvalumab** in patients with locally advanced, unresectable non-small-cell lung cancer (NSCLC) with a PD-L1 expression of ≥ 1%. This is a Phase II, randomized, double-blind, controlled trial. The trial is expected to commence recruitment on August 1, 2024, and conclude by March 31, 2029. Participants will be randomly assigned to receive either the investigational treatment or the standard treatment, both followed by immunotherapy with durvalumab.

The study will include several key visits: an initial screening visit, regular follow-up visits, and an end-of-study visit. During the **screening visit**, eligibility will be assessed based on criteria such as adequate bone marrow and organ function, ECOG performance status of 0 or 1, and histologically proven PD-L1 expression of ≥ 1%. Participants must also provide written informed consent. Follow-up visits will occur at regular intervals to monitor treatment response, adverse events, and overall health status. The **end-of-study visit** will evaluate the primary and secondary endpoints, including completion rate, safety, efficacy, and quality of life.

Participant involvement is expected to last up to 12 months, with the possibility of early termination if criteria such as severe adverse events or non-compliance with the study protocol are met. The primary endpoint is the completion rate, defined by the receipt of the prescribed radiotherapy dose, simultaneous platinum-based chemotherapy, and at least three doses of durvalumab, unless discontinued due to extrathoracic immune-related toxicity. Secondary endpoints include safety, time to progression, progression-free survival, overall survival, and quality of life assessments. The trial will adhere to rigorous standards to ensure the integrity and reliability of the data collected.

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 it is administered via the **intracavernous route**. The active substance, durvalumab, is a protein of other origin, specifically classified under the ATC code L01FF03. The maximum daily dose is 1500 mg, with a total maximum dose of 1500 mg over the treatment period. The treatment duration is set for a maximum of 12 months. The product is not a pediatric formulation and is not classified as an orphan drug. The concentrate is provided by AstraZeneca AB and is identified by the marketing authorization number EU/1/18/1322/001.

In this study, durvalumab is used as an immunotherapy following chemoradiotherapy in patients with locally advanced non-small cell lung cancer (NSCLC). The trial aims to assess the feasibility of an FDG-PET-based small volume accelerated chemoradiotherapy followed by immunotherapy with durvalumab, compared to the standard FDG-PET-based chemoradiotherapy followed by immunotherapy with durvalumab. No additional non-experimental treatments, such as standard-of-care therapy, placebo, or comparator treatments, are specified in the trial data. Participant compliance with the dosing schedule will be monitored throughout the study to ensure adherence to the treatment protocol.

Efficacy

Efficacy in the clinical trial titled "PACCELIO - FDG-PET based small volume accelerated immuno chemoradio-therapy in locally advanced NSCLC" will be assessed using several endpoints. The primary efficacy endpoint is the completion rate, defined as the rate of patients who have received the prescribed radiotherapy dose within ±2 fractions, simultaneous platinum-based chemotherapy, and immunotherapy consolidation with **durvalumab** starting within 42 days after the last dose of chemoradiotherapy. This includes either at least three doses of durvalumab or fewer if immunotherapy was permanently discontinued due to documented extrathoracic immune-related toxicity.

Secondary efficacy endpoints include time to locoregional progression, time to locoregional in-RT-field progression, time to locoregional out-of-RT-field progression, time to distant progression, progression-free survival (PFS), overall survival (OS), objective response rate (ORR), and disease control rate (DCR). Additionally, quality of life will be evaluated using the EORTC QLQ-C30 and QLQ-LC13 questionnaires, assessing changes in symptoms, functioning, and global health status/quality of life. Radiotherapy quality will also be assessed by the percentage of patients without major protocol deviations regarding radiotherapy quality.

Inclusion and Exclusion Criteria

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Inclusion Criteria

Written informed consent
Patients irrespective of sex and gender, aged 18 years or older at the time of signing the ICF
Patients must be willing and able to comply with scheduled visits, treatment schedule, laboratory testing, and other requirements of the study as determined by the investigator
Patients with histologically or cytologically documented NSCLC who present with locally advanced, unresectable (Stage III) disease (according to version 8 of the International Association for the Study of Lung Cancer Staging Manual in Thoracic Oncology (IASLC Staging Manual in Thoracic Oncology 2016))
Patients fit for simultaneous chemoradiotherapy and consolidation immunotherapy according to interdisciplinary consensus
Histologically proven PD-L1-expression of ≥ 1% (tumor proportion score; TPS) in tumor sample as assessed in routine staging using a validated test such as Ventana SP236 assay
Eastern Cooperative Oncology Group (ECOG) performance status (PS) of 0 or 1 at enrolment
Tumor assessment by FDG-PET CT within 21 days prior to start of chemoradiotherapy.
Adequate pulmonary function test results a. Pre- or post-bronchodilator forced expiratory volume 1 of 1.0 L or >40% of predicted AND b. Diffusing capacity of the lung for carbon monoxide (DLCO) >30% of predicted
Adequate bone marrow and organ function at enrolment a) Hemoglobin ≥9.0 g/dL b) Absolute neutrophil count >1.5 × 109/L c) Platelet count >100 × 109/L d) Serum bilirubin ≤1.5 × upper limit of normal (ULN) e) Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) ≤2.5 × ULN f) Measured creatinine clearance (CrCl) >40 mL/min or calculated CL >40 mL/min as determined by Cockcroft-Gault (using actual body weight)
Body weight of >30 kg at enrolment
Evidence of post-menopausal status, or negative urinary or serum pregnancy test for female pre-menopausal patients. Women will be considered post-menopausal if they are amenorrhoic for 12 months or more without an alternative medical cause. The following age-specific requirements apply: a. Women <50 years old would be considered post-menopausal if they have been amenorrhoic for 12 months or more following cessation of exogenous hormonal treatments with luteinizing hormone and folliclestimulating hormone levels in the post-menopausal range for the institution b. Women ≥50 years old would be considered post-menopausal if they have been amenorrhoic for 12 months or more following cessation of all exogenous hormonal treatments, radiation-induced oophorectomy with last menses >1 year ago, chemotherapy-induced menopause with >1 year interval since last menses, or surgical sterilization (bilateral oophorectomy or hysterectomy)
Women of childbearing potential (WOCBP) and male patients with partners of childbearing potential must agree to always use a highly effective form of contraception according to the Clinical Trials Facilitation and Coordination Group during the treatment phase of this study and for at least 90 days after the last dose durvalumab or 6 months after the last dose of chemotherapy, whichever occurs last

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Exclusion Criteria

Mixed small cell and NSCLC histology
Neuroendocrine tumour, except of large cell neuroendocrine carcinoma of the lung
Distant metastases
Malignant pleural effusion or pericardial effusion
Acute superior vena cava obstruction
Receipt of prior or current cancer treatment for NSCLC, including but not limited to, surgical resection, radiation therapy, investigational agents, hemotherapy, and mAbs. Exception: Prior surgical resection of limited metachronous NSCLC (i.e., stage I or II) is permitted.
Receipt of live attenuated vaccine within 30 days prior to the start of therapy. Note: Patients, if enrolled, should not receive live vaccine during treatment phase and up to 30 days end of treatment
Major surgical procedure (as defined by the Investigator) within 28 days prior start of treatment.
Prior exposure to immune-mediated therapy, including but not limited to, other anti-CTLA-4, anti-PD-1, anti-PD-L1 (including durvalumab), and anti-PD-L2 antibodies, including therapeutic anticancer vaccines
Current use of ongoing long-term immunosuppressive medication. The following are exceptions to this criterion a. Intranasal, inhaled, topical steroids, or local steroid injections (e.g., intra articular injection) b. Systemic corticosteroids at physiologic doses not to exceed 10 mg/day of pred-nisone or its equivalent c. Steroids as premedication for hypersensitivity reactions (e.g., CT scan premedication)
History of allogeneic organ transplantation
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, Wegener syndrome [granulomatosis with polyangiitis, Graves' disease, rheumatoid arthritis, hypophysitis, uveitis, etc.]). The following are exceptions to this criterion: a. Patients with vitiligo or alopecia b. Patients with hypothyroidism (e.g., following Hashimoto syndrome) stable on hormone replacement c. Any chronic skin condition that does not require systemic therapy d. Patients without active disease in the last 5 years at randomization may be included but only after consultation with the local study physician e. Patients with celiac disease controlled by diet alone
Uncontrolled intercurrent illness, including but not limited to, ongoing or active infection, symptomatic congestive heart failure, uncontrolled hypertension, unstable angina pectoris, cardiac arrhythmia, ILD, 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
Patients with oxygen dependence
Acute inflammation of mediastinal lymph nodes/mediastinal lymphadenopathy in the context of active pneumoconiosis, sarcoidosis or tuberculosis
History of another primary malignancy except for a) Basal cell carcinoma of the Skin b) Second malignancy diagnosed > 2 years prior to NSCLC diagnosis if after curative treatment without persistence or progression at baseline. Patients with a previous history of radiation therapy are eligible provided field overlap is minimal and the risk of toxicity to tissues in the overlapping region(s) is deemed to be acceptable by treating radiation oncologist. c) Adequately treated non-melanoma skin cancer or lentigo maligna without evi-dence of disease d) Adequately treated carcinoma in situ without evidence of disease
History of leptomeningeal carcinomatosis
Positive diagnostic test for hepatitis B (hepatitis B surface antigen) or hepatitis C (hepatitis C antibody or hepatitis C RNA)
Known active infection of tuberculosis or human immunodeficiency virus
Known allergy or hypersensitivity to concomitant chemotherapy and durvalumab or any of the excipients
Any medical contraindication to treatment with platinum-based doublet chemotherapy as listed in the applying SmPCs
Patients who have disease considered for surgical treatment as part of their care plan, such as Pancoast or superior sulcus tumors.
Concurrent enrolment in another clinical study, unless it is an observational (noninterventional) clinical study or the follow-up period of an interventional study
Participation in another clinical study with an investigational product during the 4 weeks prior to enrolment
Pregnancy or breast-feeding