Phase II Study of Durvalumab, Carboplatin, and Etoposide in Metastatic Pulmonary Large-Cell Neuroendocrine Carcinoma
- Trial ID
- 2024-516157-41-00
- Protocol
- GOIRC-05-2020
Trial statistics
Diseases & Conditions
Objectives
The primary objective of this study is to explore the **efficacy** of the combination of carboplatin, etoposide, and durvalumab in treatment-naïve patients with metastatic pulmonary large-cell neuroendocrine carcinoma (LCNEC). This is clinically relevant as it aims to determine the potential of this combination therapy to improve outcomes in a patient population with limited treatment options.
Secondary objectives include:
- Evaluating the activity of the combination of carboplatin, etoposide, and durvalumab as a first-line treatment for patients with metastatic pulmonary LCNEC.
- Assessing the safety and tolerability profile of this combination therapy in the same patient population.
Participants
The clinical trial involves participants diagnosed with **metastatic pulmonary large-cell neuroendocrine carcinoma (LCNEC)**. The study population includes both male and female subjects, aged 18 years and older, with a focus on those who have not previously received chemotherapy or other systemic anti-cancer treatments. Participants are required to have a life expectancy of at least 12 weeks and must demonstrate adequate hematologic, hepatic, and renal functions. The trial does not specify the total number of participants, as this information was not provided by the sponsor. The selection process for the trial population emphasizes the ability to comply with the study protocol and the provision of informed consent. Lifestyle considerations such as diet and physical activity are not explicitly mentioned, but participants must have an Eastern Cooperative Oncology Group (ECOG) performance status of 0-1, indicating they are fully active or restricted in physically strenuous activity but ambulatory. The trial includes a vulnerable population, although specific details regarding this aspect are not disclosed.
Plans and Procedures
The clinical trial is a multicenter, phase II, single-arm study designed to evaluate the efficacy of a combination therapy involving **durvalumab**, **carboplatin**, and **etoposide** in patients with metastatic pulmonary large-cell neuroendocrine carcinoma (LCNEC). The trial aims to explore the therapeutic potential of this regimen in treatment-naïve patients. The study is structured to include an initial treatment phase consisting of four cycles of the combination therapy, followed by a maintenance phase with durvalumab alone. The trial is expected to span from December 2021 to June 2026, with the primary endpoint being overall survival measured at one year.
Participants will undergo a series of study visits, beginning with a screening visit to assess eligibility based on specific inclusion criteria, such as adequate hematologic, hepatic, and renal function, and a life expectancy of at least 12 weeks. The inclusion visit will also confirm the histological or cytological diagnosis of LCNEC and ensure compliance with the study protocol. Following the screening, participants will receive the combination therapy intravenously, with follow-up visits scheduled to monitor treatment response and adverse events. The end-of-study visit will evaluate the overall outcomes and any long-term effects of the treatment.
The expected duration of participant involvement is up to 24 months, depending on individual response and tolerance to the treatment. Conditions that may lead to early termination from the study include disease progression, unacceptable toxicity, or withdrawal of consent. The study will adhere to rigorous methodological standards, including the use of RECIST 1.1 criteria for assessing disease progression and response. Secondary endpoints will include progression-free survival, objective response rate, and median duration of response, with toxicity assessed according to NCI CTCAE version 5.0.
Treatment
The clinical trial involves the administration of **ETOPOSIDE**, a **concentrate for solution for infusion**. This experimental medication is a chemical substance classified as an inhibitor of the enzyme topoisomerase II. The pharmaceutical form is designed for **intravenous use**. The maximum daily dose is 100 mg/m², with a total dose not exceeding 100 mg/m² over a treatment period of up to 12 weeks. Participant compliance will be monitored through regular assessments to ensure adherence to the dosing schedule.
**IMFINZI** (durvalumab) is another experimental medication used in this trial. It is a **50 mg/mL concentrate for solution for infusion** and is a monoclonal antibody with potential anti-cancer properties. The administration route is **intravenous**, with a maximum daily dose of 1500 mg. The total dose should not exceed 1500 mg over a treatment period of up to 24 weeks. Compliance will be monitored through scheduled infusions and follow-up visits to ensure proper administration and adherence to the protocol.
**CARBOPLATIN** is also included in the trial as a **concentrate for solution for infusion**. This neoplastic chemotherapeutic agent is administered via **intravenous use**. The maximum daily dose is 750 mg, with a total dose not exceeding 750 mg over a treatment period of up to 12 weeks. Participant adherence to the dosing regimen will be closely monitored through infusion records and regular clinical evaluations.
All medications are administered in a controlled clinical setting to ensure safety and efficacy. The trial aims to explore the efficacy of the combination of carboplatin, etoposide, and durvalumab in treatment-naïve patients with metastatic pulmonary large-cell neuroendocrine carcinoma (LCNEC). The study protocol includes detailed instructions for dosing schedules and participant monitoring to ensure compliance and accurate assessment of treatment outcomes.
Efficacy
The efficacy of the treatment regimen in the clinical trial will be assessed using several primary and secondary endpoints. The primary endpoint is **Overall Survival (OS)**, which will be measured from the date of registration to the date of death by any cause and analyzed as the survival rate at 1 year. Secondary endpoints include Median OS, Progression Free Survival (PFS), Objective Response Rate (ORR), Median Duration of Response (DoR), Disease Control Rate (DCR), and Toxicity.
Progression Free Survival (PFS) will be measured from the date of registration to the date of disease progression or death, based on the Investigator’s assessment according to standard RECIST 1.1 criteria, and reported as median PFS and 6-month and 12-month PFS rates. The Objective Response Rate (ORR) will be defined as the sum of complete response (CR) and partial response (PR), based on the Investigator’s assessment according to standard RECIST 1.1 criteria. Median Duration of Response (DoR) will be measured from the date of first radiological evidence of PR or CR to the date of first evidence of progressive disease (PD), both based on the Investigator’s assessment according to standard RECIST 1.1 criteria. Disease Control Rate (DCR) will be considered as the sum of complete responses (CRs), partial responses (PRs), and stable disease (SD), according to standard RECIST 1.1 criteria. Patients with no tumor assessment after baseline will be classified as non-responders.
Toxicity will be assessed based on the frequency and severity of adverse events, with severity measured according to the NCI Common Terminology Criteria for Adverse Events (CTCAE), version 5.0. The worst severity grade adverse event will be considered for each patient. These efficacy parameters will be collected and analyzed at specified timepoints throughout the trial to determine the overall effectiveness of the treatment regimen in patients with metastatic pulmonary large-cell neuroendocrine carcinoma (LCNEC).
Inclusion and Exclusion Criteria
Inclusion Criteria
- 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 obtained from the patient/legal representative prior to performing any protocol-related procedures, including screening evaluations
- Age ≥18 years at the time of study entry
- Histologically or cytologically (cell blocks only; smears are not acceptable) documented pulmonary large-cell neuroendocrine carcinoma (LCNEC)
- Stage IV disease or unresectable stage IIIB, which cannot be safely encompassed in a single RT field (e.g. supraclavicular N3, T4 by infiltration of vertebral body), according to the AJCC 8th edition Cancer Staging Manual
- Body weight >30 kg
- No prior chemotherapy or treatment with another systemic anti-cancer agent. Patients who have received prior chemoradiotherapy for locally advanced pulmonary LCNEC must have been treated with curative intent and experienced a treatment-free interval of at least 6 months from last chemotherapy, radiotherapy or chemoradiotherapy cycle to disease relapse, progression, or diagnosis of metastatic LCNEC. In this case, all toxicity from previous treatments should be resolved and no cumulative toxicity of Grade >1 should be present (see also Section 4.2 “Exclusion criteria”)
- No need for concomitant chest irradiation
- ECOG performance status 0-1
- Life expectancy ≥ 12 weeks
- At least one lesion measurable according to RECIST v 1.1 outside of the CNS, not previously irradiated, that can be accurately measured at baseline as ≥ 10 mm in the longest diameter (except lymph nodes which must have short axis ≥ 15 mm) with computed tomography (CT) or magnetic resonance imaging (MRI) and which is suitable for accurate repeated measurements
- Adequate hematologic function, as evidenced by an absolute neutrophil count (ANC) ≥1500/μL, hemoglobin ≥9 g/dL (5.58 mmol/L), and platelets ≥100,000/μL.
- Adequate hepatic and renal functions: - Total bilirubin < 1.5 times the upper limits of normal [ULN] - 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 - Serum creatinine ≤1.5 times the ULN or creatinine clearance, calculated according to the formula of Cockcroft and Gault > 60 ml/min
- The patient has adequate coagulation function as defined by International Normalized Ratio (INR) ≤1.5 and a partial thromboplastin time (PTT) (PTT/aPTT) < 1.5 x ULN.). Patients on full-dose anticoagulation must be on a stable dose (minimum duration 14 days) of oral anticoagulant or low molecular weight heparin (LMWH). If receiving warfarin, the patient must have an INR ≤3.0.
- Female patients must have a negative pregnancy test and not be breast-feeding prior to start of dosing if of child-bearing potential or must have evidence of non-child-bearing potential by fulfilling one of the following criteria at screening: - Post-menopausal defined as aged more than 50 years and amenorrhoeic for at least 12 months following cessation of all exogenous hormonal treatments - Women under 50 years old would be considered postmenopausal if they have been amenorrhoeic for 12 months or more following cessation of exogenous hormonal treatments and with LH and FSH levels in the post-menopausal range for the institution - Documentation of irreversible surgical sterilization by hysterectomy, bilateral oophorectomy or bilateral salpingectomy but not tubal ligation
- For female patients of childbearing potential, agreement (by patient and/or partner) to use a highly effective form of contraception that results in a low failure rate (< 1% per year) when used consistently and correctly, and to continue its use for 6 months after the last dose of chemotherapy or 90 days after the last dose of durvalumab, whichever occurs last. Such methods include: combined (estrogen and progestogen containing) hormonal contraception, progestogen-only hormonal contraception associated with inhibition of ovulation together with another additional barrier method always containing a spermicide, intrauterine device (IUD), intrauterine hormone-releasing system (IUS), bilateral tubal occlusion, and vasectomized partner (on the understanding that this is the only one partner during the whole study duration)
- Male patients who are sexually active must be willing to use barrier contraceptives (i.e., by use of condoms) during sex with all partners during treatment with chemotherapy and for at least 6 months after the final dose of chemotherapy or 90 days after the last dose of durvalumab, whichever occurs last, to avoid exposing the embryo. Men must refrain from donating sperm during this same period
- Ability to comply with the study protocol, in the investigator's judgment
Exclusion Criteria
- Symptomatic brain metastases or spinal cord compression (CT or MRI of the head is required within 4 weeks prior to randomization) requiring immediate radiotherapy for palliation. Patients with asymptomatic CNS lesions are eligible, provided that all of the following criteria are met: - The patient has no history of intracranial hemorrhage, spinal cord hemorrhage or hemorrhagic intracranial lesions - At least 14 days between the end of stereotactic radiotherapy or whole brain radiotherapy and initiation of study treatment, or at least 28 days between neurosurgical resection and initiation of study treatment - The patient is on a dose of corticosteroids ≤ 10 mg of oral prednisone or equivalent; anticonvulsant therapy at a stable dose is permitted - Metastases are limited to the cerebellum or the supratentorial region (i.e., no metastases to the midbrain, pons, medulla or spinal cord) - There is no evidence of interim progression between completion of CNS directed therapy (if administered) and initiation of study treatment
- History of leptomeningeal disease
- Uncontrolled pleural effusion, pericardial effusion, or ascites requiring recurrent drainage procedures: - Patients with indwelling catheters (e.g., Pleura-Cath) are allowed
- Uncontrolled or symptomatic hypercalcemia (ionized calcium > 1.5 mmol/L, calcium > 12 mg/dL or corrected calcium > ULN)
- 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 (known positive HBV surface antigen (HBsAg) result), hepatitis C: - 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 if polymerase chain reaction is negative for HCV RNA
- Significant traumatic injury or radiotherapy involving an extensive field within the last 4 weeks prior to first dose of study treatment or anticipation of the need for major surgery during study treatment. Palliative radiotherapy to a limited field is allowed if concluded at least 2 weeks prior enrolment
- Other malignancies (previous or current), except for adequately treated in situ carcinoma of the uterine cervix, basal or squamous cell carcinoma of the skin, localized prostate cancer surgically treated with curative intent or ductal carcinoma in situ treated surgically treated with curative intent or if previous malignancy was more than 5 years prior and there are no signs or symptoms of recurrence
- Major surgery (including open biopsy) within 28 days prior to first dose of protocol therapy, or minor surgery/subcutaneous venous access device placement within 7 days prior to the first dose of protocol therapy. The patient has elective or planned major surgery to be performed during the course of the clinical trial
- Prior allogeneic stem cell or solid organ transplantation
- Patients with any underlying medical condition that might be aggravated by treatment or which cannot be controlled i.e. patients with active serious infection, uncontrolled diabetes mellitus, pericardial effusion
- Any concurrent chemotherapy, IP, biologic, or hormonal therapy for cancer treatment other than those in the present study. Concurrent use of hormonal therapy for non-cancerrelated conditions (e.g., hormone replacement therapy) is acceptable
- Treatment with any other investigational agent within 30 days prior to starting study treatment, or 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
- Evidence of any other disease, metabolic dysfunction, physical examination finding or laboratory finding giving reasonable suspicion of a disease or condition that contraindicates the use of an investigational drug or puts the patient at high risk for treatmentrelated complications
- 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
- History or active autoimmune neurologic paraneoplastic syndrome (e.g. non-infectious encephalitis, Lambert-Eaton syndrome etc.) or any other immune-mediated paraneoplastic syndrome: - Patients with SIADH or ectopic ATCH production are allowed on the study
- Patient has received a live-virus vaccination within 30 days of planned treatment start. Seasonal flu vaccines that do not contain live virus are permitted. Note: Patients, if enrolled, should not receive live vaccine whilst receiving IP and up to 30 days after the last dose of IP
- History of idiopathic pulmonary fibrosis, including pneumonitis, drug-induced pneumonitis, organizing pneumonia (i.e., bronchiolitis obliterans, cryptogenic organizing pneumonia), or evidence of active pneumonitis on screening chest computed tomography (CT) scan. History of radiation pneumonitis in the radiation field (fibrosis) is permitted
- Prior therapy with any anti-PD-1, anti-PD-L1, or anti-PD-L2 agent and anti-CTL-A4 agent
- Treatment with systemic immunostimulatory agents (including, but not limited to, interferon and interleukin 2 [IL-2]) within 4 weeks or 5 drug elimination half-lives (whichever is longer) prior to initiation of study treatment
- Any condition requiring systemic treatment with either corticosteroids or other immunosuppressive medications within 14 days of randomization. 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 or current evidence of any condition, therapy, or laboratory abnormality that might confound the results of the study, interfere with the subject’s participation for the full duration of the study, or is not in the best interest of the subject to participate, in the opinion of the treating Investigator
- History of allergies or hypersensitivity to any study drugs or study drug components or CHO derived products
- The patient is pregnant or breast-feeding
- Any unresolved toxicity NCI CTCAE Grade ≥2 from previous anticancer therapy with the exception of alopecia, vitiligo, and the laboratory values defined in the inclusion criteria - Patients with Grade ≥2 neuropathy will be evaluated on a case-by-case basis after consultation with the Study Physician. - Patients with irreversible toxicity not reasonably expected to be exacerbated by treatment with carboplatin, etoposide or durvalumab may be included only after consultation with the Study Physician
- 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
- Patients should not donate blood whilst on this study
Trial Status by Country
| Country | Status | Start of Recruitment | Planned Patients |
|---|---|---|---|
 Italy | Not Recruiting | 01 Dec 2021 | 49 |
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 |
|---|---|---|---|---|---|---|
ETOPOSIDE | Test | — | INTRAVENOUS USE | 100 | 12 | SUB07337MIG |
IMFINZI 50 mg/mL concentrate for solution for infusion. | Test | CONCENTRATE FOR SOLUTION FOR INFUSION | INTRAVENOUS USE | 1500 | 24 | PRD6651406 |
CARBOPLATIN | Test | — | INTRAVENOUS USE | 750 | 12 | SUB06614MIG |