Prospective randomized Phase II trial on Induction Immunochemotherapy followed by surgery or definitive chemoradiation and consolidation Durvalumab (MEDI4736) in resectable and borderline resectable stage IIIA/B NSCLC (InDuRanS)

Overview

Sponsor-declared trial summary

Key facts

Sponsor

Rheinische Friedrich-Wilhelms-Universitaet Bonn

Participant type

Patients

Age range

18-64 years, 65+ years

Gender

Male and Female

Therapeutic area

Diseases [C] - Neoplasms [C04]

Trial duration

24 Apr 2025 → ongoing

Decision date (initial)

2025-02-10

Transition trial

No

Low-intervention

No

Rare-disease indication

No

Vulnerable population

No

Funding sources

AstraZeneca

Trial design

CTIS Part I — objectives, methods, condition coding

Main objective

Scope: Therapy, Safety

To assess the efficacy of a multimodality treatment in resectable stage III A/B (N2) NSCLC patients including induction immunochemotherapy followed by chemoradiation or surgical resection and immunotherapy consolidation for 12 months measured as event-free survival (EFS) rate within 2 years after randomization.

Secondary objectives 9

1. To analyze the health-related Quality of Life (QoL) using EORTC QLQ-C30 and QLQ-LC13 questionnaires
2. To assess the safety and tolerability of a multimodality treatment in resectable stage III NSCLC participants including induction immunochemotherapy followed by a chemoradiation or definitive surgical resection and immunotherapy consolidation for 12 months according to arm
3. To assess the efficacy of a multimodality treatment in resectable and borderline resectable stage IIIA/B (N2) NSCLC participants consisting of induction immunochemotherapy followed by either chemoradiation or definitive surgical resection and subsequent consolidation immunotherapy for up to 12 months according to arm
4. To assess the outcome of surgery in resected participants.
5. To assess response of participants after induction therapy
6. To assess quantity of PD-L1 positive tumor cells per participant (enrolled population)
7. To assess the rate of participants with <1%, 1-49% and ≥50 % PD-L1 positive tumor cells in the group of stage IIIA/B (N2) NSCLC participants (enrolled population)
8. To assess compliance and treatment toxicity effects according to arm
9. To assess toxicity of ICT and any causes (i.e. progression) that prevent randomization or surgery or completion of surgery

Conditions and MedDRA coding

resectable and borderline resectable stage IIIA/B NSCLC

Eligibility criteria

Principal inclusion / exclusion criteria as submitted by sponsor

Inclusion criteria 18

1. Patient is capable of giving signed informed consent which includes compliance with the requirements and restrictions listed in the informed consent form (ICF) and in this protocol. Written informed consent and any locally required authorization (e.g., Health Insurance Portability and Accountability Act in the US, European Union [EU] Data Privacy Directive in the EU) obtained from the patient /legal representative prior to performing any protocol-related procedures, including screening evaluations
2. Patient is willing and able to comply with the protocol for the duration of the study including undergoing treatment and scheduled visits and examinations including follow-up
3. Age ≥18 years and <75 years at the time of study entry
4. All sex and gender
5. Female patients of childbearing potential as well as 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 (CTFG) during the course of this study and for at least 90 days after the last dose of durvalumab or 6 months after the last dose of chemotherapy, whichever occurs last. Female patients of childbearing potential must conduct a urine pregnancy test at least monthly during the course of this study.
6. Evidence of post-menopausal status or negative serum pregnancy test for female pre-menopausal patients. Women will be considered post-menopausal if they have been amenorrhoeic for 12 months without an alternative medical cause.
7. Histologically and / or cytologically proven NSCLC (EGFRm-, ALK-)
8. Selected patients with NSCLC stage IIIA/B: a. IIIA: one or more lymph node levels involved at EBUS/mediastinoscopy T1/T2 N2. b. IIIB: one or more lymph node levels involved at EBUS/mediastinoscopy T3/T4 N2.
9. Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1
10. Given technical/oncologic complete resectability (R0) at the time of inclusion
11. Sufficient functional reserves for the planned surgery
12. Fulfilment of adequate criteria for functional and medical resectability as described in the European Respiratory Society (ERS)/ European Society of Thoracic Surgeons (ESTS) guidelines (Brunelli et al. 2009) and acceptable general clinical condition for multimodality treatment (interdisciplinary committee)
13. Life expectancy of > 12 weeks
14. Body weight > 30 kg
15. Adequate normal organ and bone marrow function as defined below: 1. Haemoglobin ≥ 9.0 g/dL, 2. Absolute neutrophil count (ANC) ≥ 1.5 × 109 /L, 3. Platelet count ≥ 100 × 109/L, 4. Serum bilirubin ≤ 1.5 x institutional upper limit of normal (ULN). (This will not apply to patients with confirmed Gilbert’s syndrome (persistent or recurrent hyperbilirubinemia that is predominantly unconjugated in the absence of hemolysis or hepatic pathology), who will be allowed only in consultation with their physician.), 5. AST (SGOT)/ALT (SGPT) ≤2.5 x institutional upper limit of normal, 6. Measured creatinine clearance (CL) ≥ 60 mL/min or Calculated creatinine CL ≥ 60 mL/min by the Cockcroft-Gault formula (Cockcroft and Gault 1976) or by 24- hour urine collection for determination of creatinine clearance
16. Stable cardiac function (no myocardial infarction (MI) within 6 months, no heart failure NYHA III-IV)
17. Discussion in a multidisciplinary tumor board which supports participation in this clinical trial, indicating that both chemoradiotherapy and surgery are possible local treatments
18. Participants should only be randomized if all of the following inclusion criteria are fulfilled at the time of randomization: 1. Given technical/oncologic complete resectability (R0) at the time of randomization. 2. Sufficient functional reserves for the planned surgery 3. Adequate normal organ and bone marrow function as defined before

Exclusion criteria 35

1. Unresectable disease
2. Mixed histology with areas of small cell carcinoma (neuroendocrine markers)
3. ALK+/ EGFRm disease
4. Clinically symptomatic vena cava superior syndrome
5. Diffuse mediastinal involvement
6. Patients with N3 tumors (IASLC/UICC 8)
7. Invasion of the thoracic aorta (T4 – aorta) or the heart (except left atrium – T4 – heart) or the esophagus (T4 – esophagus), or invasion of spine (T4 – spine) NOTE: T4 with invasion of diaphragm are eligible
8. Pancoast-syndrome in tumors of the superior sulcus (T3-4 Nx)
9. Metastatic disease (M1)
10. Endobronchial tumor extension to the contralateral main stem bronchus
11. Lung or heart function not allowing the intended surgical procedure at the time of inclusion
12. Prior treatments including prior mediastinal irradiation
13. Insufficient patients’ compliance (e.g., symptomatic psychiatric disorder) or missing written informed consent or definitive refusal for participation
14. Prior randomization of treatment in a previous durvalumab clinical study regardless of treatment arm assignment
15. Patients who have received prior anti-PD-1, anti-PD-L1, or anti-CTLA-4: a) Must not have experienced a toxicity that led to permanent discontinuation of prior immunotherapy. b) All AEs while receiving prior immunotherapy must have completely resolved or resolved to baseline prior to screening for this study. c) Must not have experienced a ≥Grade 3 immune related AE or an immune related neurologic or ocular AE of any grade while receiving prior immunotherapy. NOTE: Patients with endocrine AE of ≤Grade 2 are permitted to be enrolled if they are stably maintained on appropriate replacement therapy and are asymptomatic. d) Must not have required the use of additional immunosuppression other than corticosteroids for the management of an AE, not have experienced recurrence of an AE if re-challenged, and not currently require maintenance doses of >10 mg prednisone or equivalent per day.
16. Participation in another clinical study with an investigational product during the last 12 months
17. Concurrent enrolment in another clinical study, unless it is an observational (non-interventional) clinical study or during the follow-up period of an interventional study
18. History of idiopathic pulmonary fibrosis, pneumonitis (including drug induced), organizing pneumonia (i.e., bronchiolitis obliterans, cryptogenic organizing pneumonia, etc.), or evidence of active pneumonitis on screening chest CT scan
19. Any concurrent chemotherapy (other than study therapy), Investigational Product, biologic, or hormonal therapy for cancer treatment. Concurrent use of hormonal therapy for non-cancer-related conditions (e.g., hormone replacement therapy) is acceptable.
20. Major surgical procedure (as defined by the Investigator) within 28 days prior to the first dose of durvalumab
21. History of allogenic organ transplantation or a stem cell transplantation
22. 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: a. Vitiligo or alopecia b. Hypothyroidism (e.g., following Hashimoto syndrome) stable on hormone replacement c. Any chronic skin condition that does not require systemic therapy d. Celiac disease controlled by diet alone e. Patients without active disease in the last 5 years may be included but only after consultation with the study physician
23. Uncontrolled intercurrent illness, including but not limited to, ongoing or active infection, 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
24. History of another primary malignancy except for a. Malignancy treated with curative intent and with no known active disease ≥5 years before the first dose of Durvalumab and of low potential risk for recurrence b. Adequately treated non-melanoma skin cancer or lentigo maligna without evidence of disease c. Adequately treated carcinoma in situ without evidence of disease
25. History of active primary immunodeficiency
26. History of leptomeningeal carcinomatosis
27. Known 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, hepatitis C, or human immunodeficiency virus (positive HIV-1 or HIV-2). 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.
28. Current or prior use of immunosuppressive medication within 14 days before the first dose of durvalumab. 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 prednisone or its equivalent c. Steroids as premedication for hypersensitivity reactions (e.g., CT scan premedication)
29. Current or prior use of immunostimulatory agents within 14 days before the first dose of Durvalumab
30. Receipt of live attenuated vaccine within 30 days prior to the first dose of Durvalumab. Note: Patients, if enrolled, should not receive live vaccine whilst receiving study treatment and up to 90 days after the last dose of study treatment.
31. Female patients who are pregnant or breastfeeding or male or female patients of reproductive potential who are not willing to employ effective birth control from screening to 90 days after the last dose of durvalumab monotherapy or 6 months after the last dose of chemotherapy, whichever occurs last.
32. Known allergy or hypersensitivity to any of the study drugs or any of the study drug excipients
33. Any medical contraindication to treatment with platin-based doublet chemotherapy as listed in the applying SmPCs
34. Judgment by the investigator that the patient is unsuitable to participate in the study and the patient is unlikely to comply with study procedures, restrictions and requirements
35. Participants should not be randomized if any of the following exclusion criteria are fulfilled at the time of randomization: 1. Complete remission after induction immunochemotherapy. 2. Any unresolved toxicity NCI CTCAE Grade ≥ 2 from previous immunochemotherapy with the exception of alopecia, vitiligo, and the laboratory values defined in the inclusion criteria: a. Participants with Grade ≥ 2 neuropathy will be evaluated on a case-by-case basis after consultation between the Sponsor Representative and the Study Physician. b. Participants with irreversible toxicity not reasonably expected to be exacerbated by treatment with durvalumab may be included only after consultation between the Sponsor Representative and the Study Physician (exception: alopecia). 3. Allergy or hypersensitivity to durvalumab or concurrent chemotherapeutic drugs or any excipient appearing for the first time during previous immunochemotherapy

Endpoints

Primary and secondary outcome measures (English text)

Primary endpoints 1

1. 2-year EFS rate is defined as percentage of participants without an event specified as relapse or progression according to RECIST 1.1 criteria, secondary tumor, or death of any cause, whichever occurs first, within 2 years after date of randomization.

Secondary endpoints 15

1. Changes in QLQ-C30 / QLQ-LC13 symptom scales from date of randomization
2. Changes in QLQ-C30 functional scales and global health status from date of randomization
3. Occurrence of adverse events according to CTCAE (V5.0): adverse events grade ≥ 3 (according to NCI CTCAE v5.0)
4. Occurrence of adverse events according to CTCAE (V5.0): SAEs
5. Occurrence of adverse events according to CTCAE (V5.0): Unexpected AEs
6. Efficacy will be assessed in terms of: Overall survival (OS) defined as time from randomization until death due to any cause
7. Efficacy will be assessed in terms of: Progression free survival (PFS) defined as time from randomization to objective disease progression or death by any cause, whichever occurs first
8. Rate of pathological complete response (pCR), major pathological response (mPR) and R0 in resected participants
9. Functional response (FDG-PET-CT-scan) to induction therapy prior to thoracotomy / chemoradiation according to RECIST and PERCIST in the whole population and in both arms according to CR, PR, SD and PD
10. Analysis of the SUVmax response and MTV response on the planning FDG-PET-CT in comparison to the pretreatment FDG-PET-CT
11. Number of PD-L1 positive tumor cells at screening visit
12. Rate of participants with <1%, 1-49%, ≥50 % PD-L1 positive tumor cells in the group of stage III NSCLC patients (screened population)
13. Rate of randomized participants who completed the planned treatment
14. Rate of participants who discontinued study treatment due to adverse event
15. Rate of participants with events / PD that prevent fulfillment of criteria for randomization / surgery

Investigational products

Investigational medicinal products (IMPs), comparators, placebo, auxiliary

Test 2

Auxiliary 7

Sponsors and contacts

Sponsor organisations, regulatory contacts, third parties

Rheinische Friedrich-Wilhelms-Universitaet Bonn

Sponsor organisation

Rheinische Friedrich-Wilhelms-Universitaet Bonn

Address

Venusberg-Campus 1, Venusberg Venusberg

City

Bonn

Postcode

53127

Country

Germany

Scientific contact point

Organisation

Rheinische Friedrich-Wilhelms-Universitaet Bonn

Contact name

Prof. Dr. Eleni Gkika

Public contact point

Organisation

Rheinische Friedrich-Wilhelms-Universitaet Bonn

Contact name

Studienbüro Strahlentherapie (Frau Katja Klever)

Third parties 1

Locations

1 EU/EEA country · 7 investigational sites

By country

Investigational sites

Country notifications

Trial-start, recruitment-start, end and early-termination notifications submitted per Member State

Results and documents

Annex IV summary of results, Annex V layperson summary, and all documents registered in CTIS for this trial

Documents 12 files

Public protocol annexes, IB summaries, regulatory submissions and post-authorisation documents registered in CTIS.

Application history

4 submissions — initial application plus substantial / non-substantial modifications