Multimodality Treatment in Stage III Non-small Cell Lung Cancer (NSCLC)

NCT04245514 | Active Not Recruiting Phase 2 DMC

• 1 other identifier: SAKK 16/18
• Study Type: interventional
• Target: 90
• Locations: 2 countries
• Sites: 13

Brief Summary

Resectable, locally advanced NSCLC with involvement of mediastinal lymph nodes (N2) is associated with a high risk of (systemic) recurrence despite neo-adjuvant chemotherapy. Neo-adjuvant immunotherapy is a promising additional treatment modality aiming at increasing local control and better tackling micrometastases at the time of radical local treatment. Radiotherapy is thought to act synergistically with immunotherapy through release of tumor antigens and modulation of the local immune microenvironment in favor of a better antigen-presentation and (systemic) anti-tumor immune response (abscopal effect). The aim of the proposed SAKK 16/18 trial is to evaluate the efficacy and safety of adding immune-modulatory radiotherapy to the SAKK 16/14 treatment regimen by combining neo-adjuvant radio-immunotherapy. Due to the lack of evidence for an optimal radiotherapy regimen for an "in-situ vaccination" effect three different radiotherapy regimens will be tested.

Conditions

Non-small Cell Lung Cancer; NSCLC

Keywords

Immune-modulatory radiotherapy; neoadjuvant PD-L1 blockade; neoadjuvant chemotherapy; non-small cell lung cancer (NSCLC); NSCLC; Surgery; abscopal effect

Outcome Measures

Primary Outcomes (1)

• Event-free survival (EFS) at 12 months

  EFS is defined as time from registration to one of the following events, whichever occurs first: * Relapse or progression according to RECIST 1.1 criteria. * Second tumor * Death due to any cause Patients not experiencing an event will be censored at the date of last tumor assessment before starting a subsequent treatment, if any. As a sensitivity analysis, the primary endpoint will also be calculated according to the following definition of an event: * Progression during neoadjuvant treatment leading to inoperability * Recurrence of loco-regional disease after surgery * Appearance of metastases at any localization * Second tumor * Death due to any cause

  at 12 months

Secondary Outcomes (10)

• Event-free survival (EFS)

  From the date of registration until the date of progressive disease, relapse, second tumor or death, whichever occurs first, assessed up to 20 years after registration

• Recurrence-free survival (RFS) after R0 resection

  From the date of surgery until the date of recurrence of loco-regional disease, appearance of metastases, or death, whichever occurs first, assessed up to 20 years after registration

• Overall survival (OS)

  From the date of registration until the date of death from any cause, assessed up to 20 years after registration

• Objective response (OR) after neoadjuvant chemotherapy

  At the date of tumor assessment after neoadjuvant chemotherapy, estimated at approximately 9 weeks post-baseline

• OR after neoadjuvant immuno-radiotherapy

  At the date of tumor assessment after neoadjuvant immune-radiotherapy, estimated at approximately 13 weeks post-baseline

Study Arms (1)

Durvalumab with 3 RT cohorts

EXPERIMENTAL

Patients will be allocated in a 1:1:1 ratio to the three radiotherapy regimens (Arm A: 20 x 2 Gy weekdaily, Arm B: 5 x 5 Gy weekdaily, and Arm C: 3 x 8 Gy q2d) using the minimization method with a random component (80% allocation probability) to reduce predictability of allocation according to the following stratification factor: T classification (T1-2 vs T3-4).

Drug: Durvalumab; Radiation: Radiotherapy

Interventions

Durvalumab DRUG

Immunotherapy

Durvalumab with 3 RT cohorts

Radiotherapy RADIATION

Immune-modulatory radiotherapy to the primary tumor, with either Cohort A: 20 x 2 Gy weekdaily Cohort B: 5 x 5 Gy weekdaily Cohort C: 3 x 8 Gy q2d

Durvalumab with 3 RT cohorts

Eligibility Criteria

• Age: 18 Years - 75 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Written informed consent according to ICH-GCP regulations before registration and prior to any trial specific procedures.
• Histologically (cytology is accepted if histology is not possible) confirmed NSCLC (adeno-, squamous-, large cell carcinoma, or NSCLC not otherwise specified (NOS)) irrespective of genomic aberrations or PD-L1 expression status.
• Tumor stage T1-4\>7 N2 M0 (i.e. T1-3 N2 or T4 N2 but T4 only allowed if due to size \> 7cm, not allowed if due to invasion or nodule in different ipsilateral lobe), according to the TNM classification, 8th edition, December 2016 (see Appendix 2). Mediastinal lymph node staging has to follow the process chart.
• Tumor is considered resectable based on a multidisciplinary tumor board decision made before neoadjuvant treatment. Resectable is when a complete resection can be achieved according to Rami-Porta
• Patients with a prior malignancy (except NSCLC) and treated with curative intention are eligible if all treatment of that malignancy was completed at least 2 years before registration and the patient has no evidence of disease at registration. Less than 2 years is acceptable for malignancies with low risk of recurrence and/or no late recurrence, after consultation with CI.
• Measurable disease per RECIST v1.1 criteria by PET/CT with contrast enhanced CT-scan.
• Tumor tissue is available for the mandatory translational research (formalin-fixed; preferably histology, cytology allowed if histology is not possible)
• Age 18-75 years at time of registration
• WHO performance status 0-1
• Adequate bone marrow function: absolute neutrophil count ≥ 1.5 x 109/L, platelet count ≥ 100 x 109/L, hemoglobin ≥ 90 g/L (transfusion allowed)
• Adequate hepatic function: total bilirubin ≤ 1.5 x ULN (except for patients with Gilbert's disease ≤ 3.0 x ULN), AST and ALT ≤ 1.5 x ULN, AP ≤ 2.5 x ULN.
• Adequate renal function: calculated creatinine clearance ≥ 60 mL/min, according to the formula of Cockcroft-Gault
• Appropriate lung function based on the ESTS guidelines:
• For pneumonectomy: FEV1 and DLCO ≥80%. If one of both \<80%, an exercise test peak VO2 \>75% or 20ml/kg/min is needed
• For resection less than pneumonectomy (resection up to the calculated extent): exercise test peak VO2 ≥35% or ≥10ml/kg/min, with predicted postoperative FEV1 and DLCO ≥ 30%.

You may not qualify if:

• Presence of any distant metastasis or N3 disease. Brain metastases have to be excluded by CT or MRI.
• Sulcus superior tumors (Pancoast tumors) or T4 for any other reason than size \>7cm.
• Any previous treatment for NSCLC
• Any previous treatment with immune checkpoint inhibitors, including durvalumab
• Previous radiotherapy to the chest (with the exception of tangential breast irradiation with minimal dose to lung and mediastinum, and superficial orthovoltage or electron irradiation of localized skin lesions)
• Concomitant or recent (within 30 days of registration) treatment with any other experimental drug and/or enrollment in another clinical trial.
• Concomitant use of other anti-cancer drugs or radiotherapy.
• Severe or uncontrolled cardiovascular disease (congestive heart failure NYHA III or IV) unstable angina pectoris, history of myocardial infarction within the last three months, serious arrhythmias requiring medication (with exception of atrial fibrillation or paroxysmal supraventricular tachycardia), uncontrolled hypertension.
• Preexisting peripheral neuropathy (\> Grade 1)
• Body weight less than 30 kg
• Known history of human immunodeficiency virus (HIV) or active chronic Hepatitis C or Hepatitis B virus infection or any uncontrolled active systemic infection requiring intravenous (iv) antimicrobial treatment.
• Known history of allogeneic organ transplant
• Active autoimmune disease or a syndrome requiring systemic treatment within the past 3 months or a documented history of clinically severe autoimmune disease. Exceptions: vitiligo, resolved childhood asthma/atopy, hypothyroidism stable on hormone replacement, Sjögren's syndrome
• Active or prior documented inflammatory bowel disease (e.g. Crohn's disease, ulcerative colitis)
• Concomitant or prior use of immunosuppressive medication within 28 days before registration, with the exceptions of intranasal and inhaled corticosteroids, or systemic corticosteroids which must not exceed 10 mg/day of prednisone or a dose equivalent corticosteroid, and the premedication for chemotherapy

Sponsors & Collaborators

• Swiss Cancer Institute: lead

Study Sites (13)

Universitätsklinikum Tübingen

Tübingen, 72076, Germany

Location

Kantonsspital Aarau

Aarau, CH-5001, Switzerland

Location

Kantonsspital Baden

Baden, 5404, Switzerland

Location

St. Claraspital Basel

Basel, 4016, Switzerland

Location

Universitaetsspital Basel

Basel, 4031, Switzerland

Location

IOSI Ospedale Regionale di Bellinzona e Valli

Bellinzona, 6500, Switzerland

Location

Inselspital

Bern, 3010, Switzerland

Location

Kantonsspital Graubuenden

Chur, CH-7000, Switzerland

Location

Hôpitaux Universitaires de Genève

Geneva, 1211, Switzerland

Location

Kantonsspital - St. Gallen

Sankt Gallen, CH-9007, Switzerland

Location

Regionalspital Thun

Thun, 3600, Switzerland

Location

Stadtspital Triemli

Zurich, 8063, Switzerland

Location

Universitätsspital Zuerich

Zurich, 8091, Switzerland

Location

Related Publications (1)

• Bahce I, Dickhoff C, Schneiders FL, Veltman J, Heineman DJ, Hashemi SMS, Vrijmoet A, Houda I, Ulas EB, Bakker J, van de Ven P, Bouwhuis N, Meijboom LJ, Oprea-Lager DE, van Maldegem F, Fransen MF, de Gruijl TD, Radonic T, Senan S. Single-arm trial of neoadjuvant ipilimumab plus nivolumab with chemoradiotherapy in patients with resectable and borderline resectable lung cancer: the INCREASE study. J Immunother Cancer. 2024 Sep 30;12(9):e009799. doi: 10.1136/jitc-2024-009799.

  PMID: 39349061 DERIVED

MeSH Terms

Conditions

Carcinoma, Non-Small-Cell Lung

Interventions

durvalumab; Radiotherapy

Condition Hierarchy (Ancestors)

Carcinoma, Bronchogenic; Bronchial Neoplasms; Lung Neoplasms; Respiratory Tract Neoplasms; Thoracic Neoplasms; Neoplasms by Site; Neoplasms; Lung Diseases; Respiratory Tract Diseases

Intervention Hierarchy (Ancestors)

Therapeutics

Study Officials

• Sacha Rothschild, MD

  Universitätsspital Basel

  STUDY CHAIR

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: NA
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Model Details: Prospective, multicenter, phase II trial with 1 single arm with 3 radiotherapy cohorts

Study Record Dates

• First Submitted: January 16, 2020
• First Posted: January 29, 2020
• Study Start: July 15, 2020
• Primary Completion: July 16, 2026
• Study Completion (Estimated): December 1, 2031
• Last Updated: April 2, 2026

Record last verified: 2026-03

Locations

DE (1); CH (12)