Phase II Study on Durvalumab, Etoposide, and Platinum in First-Line Treatment of Advanced Large-Cell Neuroendocrine Carcinoma of the Lung
- Trial ID
- 2023-506590-35-00
- Protocol
- ET23-132
- Sponsor
- Centre Leon Berard
Trial statistics
Diseases & Conditions
Objectives
The primary objective of this study is to determine the **efficacy** of the combination of durvalumab with etoposide and platinum (either cisplatin or carboplatin) as a first-line treatment for patients with advanced large-cell neuroendocrine carcinoma (LCNEC) of the lung. This is clinically relevant as LCNEC is a rare and aggressive form of lung cancer, and effective first-line treatments are crucial for improving patient outcomes.
Secondary objectives include evaluating the 12-week Objective Response Rate, the 12-week Disease Control Rate, Progression-Free Survival, Overall Survival, and the safety profile of the treatment regimen. These secondary objectives are important for understanding the broader impact of the treatment on disease progression and patient safety.
Participants
The clinical trial involves participants diagnosed with **Large-Cell Neuroendocrine Carcinoma of the lung**, specifically those with locally advanced (Stage III) not eligible for loco-regional therapy or metastatic (Stage IV) in first-line treatment. The study population includes both male and female subjects aged 18 years and older. Participants are required to have a performance status of 0 or 1 according to the Eastern Cooperative Oncology Group (ECOG) scale, a body weight greater than 30 kg, and a life expectancy of at least 12 weeks. The trial does not include a vulnerable population. Participants must have adequate normal organ and marrow function, and women of childbearing potential must have evidence of post-menopausal status or a negative pregnancy test. The sponsor has not provided information regarding the total number of participants. Selection criteria include the ability to comply with the study protocol, including treatment, scheduled visits, and examinations. Participants must also be affiliated with a social security system and capable of providing informed consent. Lifestyle considerations such as diet and physical activity are not specified in the available data.
Plans and Procedures
The clinical trial is designed to evaluate the efficacy and safety of a combination treatment involving **durvalumab**, **etoposide**, and platinum-based agents (**cisplatin** or **carboplatin**) as a first-line treatment for patients with advanced Large-Cell Neuroendocrine Carcinoma (LCNEC) of the lung. This is a multicenter, phase II study employing a randomized, double-blind, controlled trial design. The trial is expected to commence recruitment in February 2024 and is estimated to conclude by December 2029, with a maximum treatment period of 27 weeks for each participant.
Participants will undergo a series of study visits, beginning with an inclusion (screening) visit to assess eligibility based on criteria such as age, performance status, and histological confirmation of LCNEC. Following successful screening, participants will be randomized to receive the investigational treatment. The study includes regular follow-up visits to monitor treatment response and safety, with assessments conducted according to the RECIST 1.1 criteria. The primary endpoint is the progression-free rate at 12 months, with secondary endpoints focusing on additional efficacy and safety measures.
The expected duration of participant involvement is approximately 27 weeks, with conditions for early termination including disease progression, unacceptable toxicity, or withdrawal of consent. Participants must comply with protocol requirements, including the use of effective contraception and adherence to scheduled visits and examinations. The trial aims to provide valuable insights into the potential benefits of combining **durvalumab** with chemotherapeutic agents in treating LCNEC, contributing to the advancement of therapeutic strategies for this challenging condition.
Treatment
The clinical trial involves the administration of **durvalumab**, marketed as IMFINZI, which is a **concentrate for solution for infusion**. The pharmaceutical form is a solution for infusion, and it is administered via **intravenous use**. The dosage is 50 mg/mL, with a maximum daily dose of 1500 mg and a total maximum dose of 12000 mg over a treatment period of 27 weeks. Durvalumab is an anti-PD-L1 monoclonal antibody produced by AstraZeneca AB, and it is not a pediatric formulation. Participant compliance will be monitored through regular assessments of infusion administration and adherence to the dosing schedule.
**Carboplatin** is another treatment used in the study, classified as an antineoplastic agent. It is administered in the form of PHF00230MIG, with a dosage unit of mg/m². The maximum daily dose is 80 mg/m², and the total maximum dose is 640 mg/m² over the same 27-week period. Carboplatin is administered intravenously and is a chemical substance. Compliance will be monitored through infusion records and dose adjustments as necessary.
**Cisplatin** is also included in the trial as a chemotherapeutic agent. It is provided as a concentrate for solution for infusion, with administration via intravenous route. The dosage is measured in mg/m², with a maximum daily dose of 80 mg/m² and a total maximum dose of 640 mg/m² over 27 weeks. Cisplatin is a chemical substance, and participant adherence will be tracked through infusion logs and clinical evaluations.
**Etoposide** is the final treatment in the study, categorized as a chemotherapeutic agent. It is administered in the form of PHF675, with a dosage unit of mg/m². The maximum daily dose is 100 mg/m², and the total maximum dose is 800 mg/m² over the 27-week treatment period. Etoposide is administered intravenously and is a chemical substance. Compliance will be ensured through monitoring of infusion schedules and participant follow-up visits.
Efficacy
The efficacy of the combination treatment of **durvalumab** with etoposide and platinum (either cisplatin or carboplatin) in patients with large-cell neuroendocrine carcinomas (LCNECs) of the lung will be assessed primarily through the measurement of the Progression-Free Rate at 12 months. This endpoint will provide insight into the duration patients remain free from disease progression following the initiation of the treatment regimen. The trial is designed as a multicenter phase II study, ensuring a comprehensive evaluation across diverse patient populations.
Inclusion and Exclusion Criteria
Inclusion Criteria
- Age ≥ 18 years at the time of study entry
- Locally documented histological diagnosis of Large-Cell NeuroEndocrine Carcinoma of the lung (LCNEC)
- Patient must have sufficient material to achieve central histological confirmation and exploratory analyses (IHC and HES diagnostic slides must be sent with 1 representative FFPE block or at least 10 unstained slides); Nota Bene: Cytological diagnosis is not accepted (EBUS, brush biopsy…)
- Setting of the disease: locally advanced (Stage III) not eligible for locoregional therapy or metastatic (Stage IV) in first line treatment (8th TNM classification). Nota Bene: patients with recurrence of local or locally advanced LCNEC are eligible to the trial provided that recurrence occurs beyond 3 months after the last chemotherapy administration. For relapsing patients, tumor material collected at diagnosis can be used for the FIRST-NEC trial if relapse occurs within two years of initial management and if initial histologic tumor material is available
- Measurable disease as per the RECIST 1.1
- Performance Status (PS) of the Eastern Cooperative Oncology Group (ECOG): 0 or 1
- Body weight > 30Kg
- Must have a life expectancy of at least 12 weeks
- Adequate normal organ and marrow function as defined below: • Haemoglobin ≥8.0 g/dL (with or without transfusion) • Absolute neutrophil count (ANC) ≥1.5 × 109 /L • Platelet count ≥100 × 109 /L • Serum bilirubin ≤1.5 x institutional upper limit of normal (ULN), or ≤3.0xULN in case of liver metastases. Note: 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. • AST (SGOT)/ALT (SGPT) ≤2.5 x institutional upper limit of normal unless liver metastases are present, in which case it must be ≤5x ULN • For patients undergoing a treatment by cisplatin: measured creatinine clearance (CrCl) ≥60 mL/min or Calculated creatinine CrCl ≥60 mL/min by the CKD-EPI equation or by 24-hour urine collection for determination of creatinine clearance (CrCl). Nota Bene: if creatinine clearance ≥60 mL/min, patients can be treated either by carboplatin or by cisplatin (as per investigator’s decision); if creatinine clearance is <60 ml/min, patients must be treated with carboplatin rather than cisplatin
- Evidence of post-menopausal status or negative urinary or serum pregnancy test for female pre-menopausal patients. Women will be considered postmenopausal if they have been amenorrheic for 12 months without an alternative medical cause. The following age-specific requirements apply: • Women <50 years of age would be considered post-menopausal if they have been amenorrheic for 12 months or more following cessation of exogenous hormonal treatments and if they have luteinizing hormone and follicle-stimulating hormone levels in the post-menopausal range for the institution or underwent surgical sterilization (bilateral oophorectomy or hysterectomy). • Women ≥50 years of age would be considered post-menopausal if they have been amenorrheic for 12 months or more following cessation of all exogenous hormonal treatments, had radiation-induced menopause with last menses >1 year ago, had chemotherapy-induced menopause with last menses >1 year ago, or underwent surgical sterilization (bilateral oophorectomy, bilateral salpingectomy or hysterectomy)
- Patient (male or female) using a highly effective contraception as defined in (Appendix 6) during the treatment period and at least up to 6 months after the last administration of chemotherapy or 90 days after the last administration of durvalumab, whichever is longer. Prior to dispensing study drugs, the investigator must confirm and document the patient’s (and his/her partner) use of highly effective contraceptive methods, dates of negative pregnancy tests, and confirm the patient’s understanding of the teratogenic potential of study drugs
- 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
- Affiliation to a social security system
- 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 obtained from the patient/legal representative prior to performing any protocol-related procedures, including screening evaluations
Exclusion Criteria
- 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 (wash-out period of 28 days)
- Patient previously treated for a LCNEC in a metastatic setting
- Any previous treatment with a PD1 or PD-L1 inhibitor, including durvalumab
- Any concurrent chemotherapy, 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 21 days prior to the first dose of study drugs. Note: Local surgery or radiotherapy of isolated lesions for palliative intent is acceptable
- History of allogenic 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, or 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 may be included but only after consultation with the 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, unstable cardiac arrhythmia, interstitial lung disease, peripheral neuropathy > grade II, 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: FIRST-NEC – Clinical trial protocol – Version 1.0 dated October 10th 2023 Page 14 / 128 • Malignancy treated with curative intent and with no known active disease ≥5 years before the first dose of IP and of low potential risk for recurrence • Adequately treated non-melanoma skin cancer or lentigo maligna without evidence of disease • Adequately treated carcinoma in situ without evidence of disease, or Gleason ≤ 6 prostate cancer
- Central Nervous System metastases, unless asymptomatic (including patients treated with anticonvulsants) or previously treated (surgery or radiation therapy combined with corticosteroids ≤10 mg per day) and stable and asymptomatic at the time of the first dose of study drugs for at least 15 days
- Carcinomatous meningitis
- Mean QT interval corrected for heart rate using Fridericia's formula (QTcF) ≥470 ms
- History of active primary immunodeficiency
- Active hepatitis infection, positive hepatitis C virus (HCV) antibody, hepatitis B virus (HBV) surface antigen (HBsAg) or HBV core antibody (anti-HBc), at screening. Participants with a past or resolved HBV infection (defined as the presence of anti HBc and absence of HBsAg) are eligible. Participants positive for HCV antibody are eligible only if polymerase chain reaction is negative for HCV RNA
- Known to have tested positive for human immunodeficiency virus (HIV) (positive HIV 1/2 antibodies) or active tuberculosis infection
- Current or prior use of immunosuppressive medication within 14 days before the first dose of durvalumab. 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)
- Receipt of live attenuated vaccine within 30 days prior to the first dose of IP. Note: Patients, if enrolled, should not receive live vaccine whilst receiving durvalumab and up to 30 days after the last dose of durvalumab
- Known allergy or hypersensitivity to any of the study drugs or any of the study drug excipients
- Pregnant or breast-feeding woman
Trial Status by Country
| Country | Status | Start of Recruitment | Planned Patients |
|---|---|---|---|
 France | Recruiting | 01 Feb 2024 | 80 |
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 |
|---|---|---|---|---|---|---|
CARBOPLATIN | Test | PHF00230MIG | INTRAVENOUS | 80 | 27 | SCP10337134 |
ETOPOSIDE | Test | PHF675 | INTRAVENOUS | 100 | 27 | SCP138959 |
IMFINZI 50 mg/mL concentrate for solution for infusion. | Test | CONCENTRATE FOR SOLUTION FOR INFUSION | INTRAVENOUS USE | 1500 | 27 | PRD6651398 |
CISPLATIN | Test | — | INTRAVENOUS | 80 | 27 | SUB07483MIG |