Phase II Randomized Trial of Induction Immunochemotherapy with Durvalumab, Cisplatin, Paclitaxel, and Vinorelbine in Resectable Stage IIIA/B NSCLC
- Trial ID
- 2024-516367-80-00
Trial statistics
Objectives
The primary objective of this study is to assess the **efficacy** of a multimodality treatment in patients with resectable stage IIIA/B (N2) non-small cell lung cancer (NSCLC). This treatment includes induction immunochemotherapy followed by either chemoradiation or surgical resection, and subsequent immunotherapy consolidation for 12 months. The efficacy will be measured as the event-free survival (EFS) rate within 2 years after randomization. This is clinically relevant as it aims to improve long-term outcomes and survival rates in this patient population.
Secondary objectives include:
- Analyzing the health-related Quality of Life (QoL) using EORTC QLQ-C30 and QLQ-LC13 questionnaires.
- Assessing the safety and tolerability of the multimodality treatment, including induction immunochemotherapy followed by chemoradiation or surgical resection and immunotherapy consolidation for 12 months.
- Evaluating the efficacy of the treatment in resectable and borderline resectable stage IIIA/B (N2) NSCLC patients.
- Assessing the outcome of surgery in resected patients.
- Evaluating the response of patients after induction therapy.
- Assessing the quantity of PD-L1 positive tumor cells per patient.
- Determining the rate of patients with varying percentages of PD-L1 positive tumor cells in stage IIIA/B (N2) NSCLC patients.
- Evaluating compliance and treatment toxicity effects according to treatment arm.
- Assessing the toxicity of induction chemotherapy and any causes that prevent randomization, surgery, or completion of surgery.
Participants
The clinical trial involves participants diagnosed with **resectable and borderline resectable stage IIIA/B non-small cell lung cancer (NSCLC)**. The study population includes both male and female subjects aged between 18 and 74 years. Participants are required to have a stable general health status, with adequate organ and bone marrow function, and a life expectancy of more than 12 weeks. The trial does not include a vulnerable population. The selection criteria ensure that participants have sufficient functional reserves for planned surgery and meet the technical and oncologic resectability requirements. Lifestyle considerations such as diet and physical activity are not specified. The sponsor has not provided information regarding the total number of participants in the trial.
Plans and Procedures
The clinical trial is designed as a **randomized**, **double-blind**, controlled study to evaluate the efficacy of a multimodality treatment in patients with resectable and borderline resectable stage IIIA/B non-small cell lung cancer (**NSCLC**). The trial aims to assess the event-free survival (EFS) rate within two years after randomization. The study involves induction immunochemotherapy followed by either surgical resection or definitive chemoradiation, with consolidation therapy using **durvalumab** for 12 months. The trial is expected to conclude by December 31, 2029, with recruitment starting on December 31, 2024.
Participants will undergo a series of study visits, beginning with an inclusion (screening) visit to confirm eligibility based on specific criteria, such as adequate organ function and a life expectancy of more than 12 weeks. Following randomization, participants will receive treatment according to the assigned study arm. Follow-up visits will be scheduled to monitor treatment response, adverse events, and overall health status. The end-of-study visit will occur after the completion of the treatment regimen and follow-up period, assessing the primary and secondary endpoints, including overall survival and progression-free survival.
The expected duration of participant involvement in the study is approximately 12 months, with additional follow-up for up to two years post-randomization. Conditions that may lead to early termination from the study include the occurrence of severe adverse events, disease progression, or withdrawal of consent. Participants must comply with the study protocol, including scheduled visits and examinations, to remain in the trial. The study will adhere to ethical guidelines, ensuring informed consent and data privacy for all participants.
Treatment
The clinical trial involves the administration of several **experimental medications** and **non-experimental treatments**. The primary experimental medication is **Durvalumab**, a concentrate for solution for infusion, with an active substance origin classified as a protein. Durvalumab is administered via infusion at a maximum daily dose of 1500 mg, with a total dose not exceeding 1500 mg over a treatment period of up to 9 months. This medication is designated as an orphan drug and plays a central role in the trial as a test product.
**Cisplatin Teva®** is another experimental medication used in the trial. It is a solution for infusion with the active substance **Cisplatin**, a chemical compound. The dosage is calculated based on body surface area, with a maximum daily dose of 50 mg/m² and a total dose of 500 mg/m² over a treatment period of 105 days. Cisplatin is administered via infusion and is not designated as an orphan drug.
**Paclitaxel Onkovis** is also included in the trial as a solution for infusion. The active substance, **Paclitaxel**, is a chemical compound. The maximum daily dose is 175 mg/m², with a total dose of 525 mg/m² over a treatment period of 63 days. Paclitaxel is administered via infusion and is not designated as an orphan drug.
**Vinorelbin NC** is administered as a solution for infusion or intravenous injection. The active substance, **Vinorelbine**, is a chemical compound. The maximum daily dose is 20 mg/m², with a total dose of 80 mg/m² over a treatment period of 63 days. Vinorelbin is not designated as an orphan drug.
**Carboplat Onkovis** is another solution for infusion used in the trial. The active substance, **Carboplatin**, is a chemical compound. The maximum daily dose is 50 mg/m², with a total dose of 500 mg/m² over a treatment period of 105 days. Carboplatin is administered via infusion and is not designated as an orphan drug.
Participant compliance with the dosing schedules is monitored throughout the trial to ensure adherence to the treatment protocols. The trial aims to assess the efficacy of these treatments in patients with resectable and borderline resectable stage IIIA/B non-small cell lung cancer (NSCLC), focusing on event-free survival rates within two years post-randomization.
Efficacy
The efficacy of the clinical trial will be assessed primarily through the measurement of the 2-year **event-free survival (EFS)** rate. This is defined as the percentage of patients who do not experience an event such as relapse, progression according to RECIST 1.1 criteria, secondary tumor, or death from any cause within two years after randomization. Secondary endpoints include changes in quality of life as measured by QLQ-C30 and QLQ-LC13 symptom scales, functional scales, and global health status from the date of randomization. Additionally, changes in FACT-L well-being scales will be evaluated. The occurrence of adverse events will be monitored according to CTCAE (V5.0), focusing on adverse events of grade ≥ 3, serious adverse events (SAEs), and unexpected adverse events.
Further efficacy assessments will include overall survival (OS), defined as the time from randomization until death from any cause, and progression-free survival (PFS), defined as the time from randomization to objective disease progression or death by any cause. The rate of pathological complete response (pCR), major pathological response (mPR), and R0 resection in patients will also be evaluated. Functional response to induction therapy will be assessed using FDG-PET-CT scans according to RECIST and PERCIST criteria. The analysis will include SUVmax and MTV responses on planning FDG-PET-CT compared to pretreatment scans. The number of PD-L1 positive tumor cells at the screening visit will be recorded, and the rate of patients with varying percentages of PD-L1 positive tumor cells will be analyzed. The trial will also track the rate of randomized patients who complete the planned treatment, those who discontinue due to adverse events, and those with events or disease progression that prevent fulfillment of criteria for randomization or surgery.
Inclusion and Exclusion Criteria
Inclusion Criteria
- 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
- 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
- Age ≥18 years and <75 years at the time of study entry
- All sex and gender
- 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.
- 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.
- Histologically and / or cytologically proven NSCLC (EGFRm-, ALK-)
- 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.
- Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1
- Given technical/oncologic complete resectability (R0) at the time of inclusion
- Sufficient functional reserves for the planned surgery
- 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)
- Life expectancy of > 12 weeks
- Body weight > 30 kg
- 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
- Stable cardiac function (no myocardial infarction (MI) within 6 months, no heart failure NYHA III-IV)
- Discussion in a multidisciplinary tumor board which supports participation in this clinical trial, indicating that both chemoradiotherapy and surgery are possible local treatments
- 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
- Unresectable disease
- Mixed histology with areas of small cell carcinoma (neuroendocrine markers)
- ALK+/ EGFRm disease
- Clinically symptomatic vena cava superior syndrome
- Diffuse mediastinal involvement
- Patients with N3 tumors (IASLC/UICC 8)
- 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
- Pancoast-syndrome in tumors of the superior sulcus (T3-4 Nx)
- Metastatic disease (M1)
- Endobronchial tumor extension to the contralateral main stem bronchus
- Lung or heart function not allowing the intended surgical procedure at the time of inclusion
- Prior treatments including prior mediastinal irradiation
- Insufficient patients’ compliance (e.g., symptomatic psychiatric disorder) or missing written informed consent or definitive refusal for participation
- Prior randomization of treatment in a previous durvalumab clinical study regardless of treatment arm assignment
- 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.
- Participation in another clinical study with an investigational product during the last 12 months
- 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
- 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
- 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.
- Major surgical procedure (as defined by the Investigator) within 28 days prior to the first dose of durvalumab
- History of allogenic organ transplantation or a stem cell 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, 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
- 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
- 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
- History of active primary immunodeficiency
- History of leptomeningeal carcinomatosis
- 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.
- 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)
- Current or prior use of immunostimulatory agents within 14 days before the first dose of Durvalumab
- 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.
- 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.
- Known allergy or hypersensitivity to any of the study drugs or any of the study drug excipients
- Any medical contraindication to treatment with platin-based doublet chemotherapy as listed in the applying SmPCs
- 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
- 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
Trial Status by Country
| Country | Status | Start of Recruitment | Planned Patients |
|---|---|---|---|
 Germany | Recruiting | 31 Dec 2024 | 176 |
Sites & Investigators
Investigational Products
Details about the medicinal products being studied in this clinical trial.
| Product Name | Role in Trial | Formulation | Administration | Max Daily Dose | Treatment Duration | EU MP Number |
|---|---|---|---|---|---|---|
DURVALUMAB | Test | — | INFUSION | 1500 | 9 | SUB176342 |
Paclitaxel onkovis, 6 mg/ml, Konzentrat zur Herstellung einer Infusionslösung | Other | KONZENTRAT ZUR HERSTELLUNG EINER INFUSIONSLÖSUNG | INFUSION | 175 | 63 | PRD803002 |
Cisplatin Teva® 1 mg/ml Konzentrat zur Herstellung einer Infusionslösung | Other | KONZENTRAT ZUR HERSTELLUNG EINER INFUSIONSLÖSUNG | INFUSION | 50 | 105 | PRD11884225 |
DURVALUMAB | Test | — | INFUSION | 1500 | 12 | SUB176342 |
Cisplatin Teva® 1 mg/ml Konzentrat zur Herstellung einer Infusionslösung | Other | KONZENTRAT ZUR HERSTELLUNG EINER INFUSIONSLÖSUNG | INFUSION | 50 | 105 | PRD11884224 |
Paclitaxel onkovis, 6 mg/ml, Konzentrat zur Herstellung einer Infusionslösung | Other | KONZENTRAT ZUR HERSTELLUNG EINER INFUSIONSLÖSUNG | INFUSION | 175 | 63 | PRD11963868 |
Vinorelbin NC 10 mg/ml - Konzentrat zur Herstellung einer Infusionslösung | Other | KONZENTRAT ZUR HERSTELLUNG EINER INFUSIONSLÖSUNG | IV INJECTION, IV INFUSION | 20 | 63 | PRD753835 |
Paclitaxel onkovis, 6 mg/ml, Konzentrat zur Herstellung einer Infusionslösung | Other | KONZENTRAT ZUR HERSTELLUNG EINER INFUSIONSLÖSUNG | INFUSION | 175 | 63 | PRD11963869 |
Carboplat onkovis 10 mg/ml Konzentrat zur Herstellung einer Infusionslösung | Other | KONZENTRAT ZUR HERSTELLUNG EINER INFUSIONSLÖSUNG | INFUSION | 50 | 105 | PRD1808013 |