PACCELIO - FDG-PET Based Small Volume Accelerated Immuno Chemoradiotherapy in Locally Advanced NSCLC

Study Overview
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Brief Summary
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Multinational, randomized, controlled, open-label, multicenter phase II trial. Eligible patients will be randomized in a ratio of 1:1 to Experimental Arm (FDG-PET-based small volume accelerated radiotherapy with concurrent standard of care chemotherapy) or Conventional Arm (standard FDG-PET-based radiotherapy with concurrent standard of care chemotherapy). Patients showing complete response, partial response, or stable disease following chemoradiotherapy will receive standard of care consolidation therapy with durvalumab (fixed dose of 1500 mg q4w) for up to 12 months or until progression of disease, unacceptable toxicity, patient´s wish, or investigator´s decision, whichever comes first. After end of durvalumab therapy, patients will undergo safety follow up for 90 (+7) days followed by survival follow up until overall end of study. Overall end of study will be reached 24 months after the last patient has started durvalumab therapy. Patients showing PD following chemoradiotherapy will be treated according to investigator´s decision but will be followed up until overall end of study.

Official Title
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PACCELIO - FDG-PET Based Small Volume Accelerated Immuno Chemoradiotherapy in Locally Advanced NSCLC

Conditions
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Stage III Non-small Cell Lung Cancer, Locally Advanced, Unresectable

Intervention / Treatment
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* Radiation: standard Radiotherapy
* Drug: Chemotherapy
* Drug: Immunotherapy
* Radiation: Experimental Radiotherapy


Participation Criteria
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Eligibility 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 Pre- or post-bronchodilator forced expiratory volume 1 of 1.0 L or >40% of predicted AND Diffusing capacity of the lung for carbon monoxide (DLCO) >30% of predicted Adequate bone marrow and organ function at enrolment Hemoglobin ≥9.0 g/dL Absolute neutrophil count >1.5 × 109/L Platelet count >100 × 109/L Serum bilirubin ≤1.5 × upper limit of normal (ULN) Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) ≤2.5 × ULN 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: 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 follicle-stimulating hormone levels in the post-menopausal range for the institution 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, chemotherapyinduced 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 Exclusion Criteria: Mixed small cell and NSCLC histology Neuroendocrine tumor 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, chemotherapy, and monoclonal antibodies (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 Intranasal, inhaled, topical steroids, or local steroid injections (e.g., intra articular injection) Systemic corticosteroids at physiologic doses not to exceed 10 mg/day of prednisone or its equivalent 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: 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 at randomization may be included but only after consultation with the local study physician 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 o Diagnosis of second malignancy (except basal cell carcinoma) < 2 years prior to NSCLC diagnosis, or persistence or progression of previously diagnosed malignancy. 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. Adequately treated non-melanoma skin cancer or lentigo maligna without evidence of disease 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

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: Experimental Arm (FDG-PET-based small volume accelerated radiotherapy with concurrent standard of care chemotherapy) Conventional Arm (standard FDG-PET-based radiotherapy with concurrent standard of care chemotherapy)
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Conventional Arm<br>standard FDG-PET-based radiotherapy with concurrent standard of care chemotherapy | Radiation: standard Radiotherapy<br>* standard FDG-PET-based radiotherapy<br>* Other names: standard;Drug: Chemotherapy<br>* concurrent standard of care chemotherapy<br>* Other names: standard;Drug: Immunotherapy<br>* standard of care consolidation therapy with durvalumab (fixed dose of 1500 mg q4w) for up to 12 months or until progression of disease, unacceptable toxicity, patient´s wish, or investigator´s decision, whichever comes first.<br>* Other names: standard;|
| Experimental: Experimental Arm<br>FDG-PET-based small volume accelerated radiotherapy with concurrent standard of care chemotherapy | Drug: Chemotherapy<br>* concurrent standard of care chemotherapy<br>* Other names: standard;Drug: Immunotherapy<br>* standard of care consolidation therapy with durvalumab (fixed dose of 1500 mg q4w) for up to 12 months or until progression of disease, unacceptable toxicity, patient´s wish, or investigator´s decision, whichever comes first.<br>* Other names: standard;Radiation: Experimental Radiotherapy<br>* FDG-PET-based small volume accelerated radiotherapy<br>* Other names: Experimental;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Comparison of the Completion rate of Experimental Arm to Conventional Arm | To assess the feasibility of an FDG-PET-based small volume accelerated chemoradiotherapy followed by immunotherapy with durvalumab compared to standard FDG-PET-based chemoradiotherapy followed by immunotherapy with durvalumab Completion rate defined as rate of patients having received: the prescribed radiotherapy dose ± 2 fractions and simultaneous platinum-based chemotherapy and · immunotherapy consolidation with durvalumab starting within 42 days after the last dose of chemoradiotherapy and either at least 3 doses of durvalumab or less than 3 doses of durvalumab in case immunotherapy was permanently discontinued due to documented extrathoracic immune-related toxicity. | approximately 22 weeks after start of radio-chemotherapy | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Comparison of the Occurrence of adverse events and serious events of Experimental Arm to Conventional Arm | To assess the safety and tolerability of an FDGPET- based small volume accelerated chemoradiotherapy followed by immunotherapy with durvalumab compared to standard FDG-PET-based chemoradiotherapy followed by immunotherapy with durvalumab Occurrence of adverse events and serious events: adverse events grade ≥ 3 (according to NCI CTCAE v5.0) SAEs Unexpected AEs | up to 78 weeks | 
| Comparison of the Time to locoregional progression of Experimental Arm to Conventional Arm | Assess efficacy of FDG-PET-based smallvolumeaccelerated CRT followed by immunotherapy compared to standard FDG-PET-based CRT followed by immunotherapy in terms of time to locoreg. progression, time to locoreg. in- and out-of-RTfield progress - Time to locoregional progression | time from randomization to progression in the primary tumor or any of mediastinal lymph nodes, up to 143,5 weeks | 
| Comparison of the Time to locoregional in-RT-field progression of Experimental Arm to Conventional Arm | Assess efficacy of FDG-PET-based smallvolumeaccelerated CRT followed by immunotherapy compared to standard FDG-PET-based CRT followed by immunotherapy in terms of time to locoreg. progression, time to locoreg. in- and out-of-RTfield progress · Time to locoregional in-RT-field progression | time from rando to progression in primary tumor or mediastinal lymph nodes within the target volume, up to 143,5 weeks | 
| Comparison of the Time to locoregional out-of-RT-field progression of Experimental Arm to Conventional Arm | Assess efficacy of FDG-PET-based smallvolumeaccelerated CRT followed by immunotherapy compared to standard FDG-PET-based CRT followed by immunotherapy in terms of time to locoreg. progression, time to locoreg. in- and out-of-RTfield progress · Time to locoregional out-of-RT-field progression | time from rando to progression in mediastinal lymph nodes outside the target volume, up to 143,5 weeks | 
| Comparison of the Time to distant progression time from rando to appearance of metastases elsewhere of Experimental Arm to Conventional Arm | Assess efficacy of FDG-PET-based smallvolumeaccelerated CRT followed by immunotherapy compared to standard FDG-PET-based CRT followed by immunotherapy in terms of time to locoreg. progression, time to locoreg. in- and out-of-RTfield progress · Time to distant progression time from rando to appearance of metastases elsewhere | time from rando to appearance of metastases elsewhere, up to 143,5 weeks | 
| Comparison of the PFS of Experimental Arm to Conventional Arm | Assess efficacy of FDG-PET-based smallvolumeaccelerated CRT followed by immunotherapy compared to standard FDG-PET-based CRT followed by immunotherapy in terms of time to locoreg. progression, time to locoreg. in- and out-of-RTfield progress · PFS | time from rando to disease progression or death by any cause, up to 143,5 weeks | 
| Comparison of the OS of Experimental Arm to Conventional Arm | Assess efficacy of FDG-PET-based smallvolumeaccelerated CRT followed by immunotherapy compared to standard FDG-PET-based CRT followed by immunotherapy in terms of time to locoreg. progression, time to locoreg. in- and out-of-RTfield progress · OS | time from rando to death by any cause, up to 143,5 weeks | 
| Comparison of the ORR of Experimental Arm to Conventional Arm | Assess efficacy of FDG-PET-based smallvolumeaccelerated CRT followed by immunotherapy compared to standard FDG-PET-based CRT followed by immunotherapy in terms of time to locoreg. progression, time to locoreg. in- and out-of-RTfield progress · ORR | Objective response rate defined as the proportion of randomized patients with best response of complete or partial response, up to 143,5 weeks | 
| Comparison of the DCR of Experimental Arm to Conventional Arm | Assess efficacy of FDG-PET-based smallvolumeaccelerated CRT followed by immunotherapy compared to standard FDG-PET-based CRT followed by immunotherapy in terms of time to locoreg. progression, time to locoreg. in- and out-of-RTfield progress · DCR | Disease control rate defined as the proportion of rando patients with best response of complete response, partial response, or stable disease, up to 143,5 weeks | 
| Comparison of the Change in symptoms of Experimental Arm to Conventional Arm | Assess symptoms and patient-reported QoL in patients receiving an FDG-PET-based smallvolumeaccelerated CRT followed by immunotherapy compared to patients receiving standard FDG-PET-based CRT followed by immunotherapy Change in symptoms assessed with the EORTC QLQ-C30 Change in symptoms assessed with the EORTC QLQ-LC13 The results of the questionnaire are usually presented as scale scores, ranging from 0 to 100. Higher scores on the symptom scales indicate a worse quality of life. | up to 143,5 weeks | 
| Comparison of the Change in functioning of Experimental Arm to Conventional Arm | Assess symptoms and patient-reported QoL in patients receiving an FDG-PET-based smallvolumeaccelerated CRT followed by immunotherapy compared to patients receiving standard FDG-PET-based CRT followed by immunotherapy Change in functioning assessed with the EORTC QLQ-C30 Change in functioning assessed with the EORTC QLQ-LC13 The results of the questionnaire are usually presented as scale scores, ranging from 0 to 100. Higher scores on the functional scales indicate a better quality of life. | up to 143,5 weeks | 
| Comparison of the Change in global health-status/QoL of Experimental Arm to Conventional Arm | Assess symptoms and patient-reported QoL in patients receiving an FDG-PET-based smallvolumeaccelerated CRT followed by immunotherapy compared to patients receiving standard FDG-PET-based CRT followed by immunotherapy Change in global health-status/QoL assessed with the EORTC QLQ-C30 Change in global health-status/QoL assessed with the EORTC QLQ-LC13 The results of the questionnaire are usually presented as scale scores, ranging from 0 to 100. Higher scores on the global health and quality of life scale indicate a better quality of life. | up to 143,5 weeks | 
| To assure radiotherapy quality in terms of percentage of patients without major protocol deviations of ≥85% | Percentage of patients without major protocol deviations regarding radiotherapy quality | up to 55 months | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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chemoradiotherapy, immunotherapy, small volume accelerated chemoradiotherapy