A multicenter phase II, single arm study of Durvalumab (MEDI 4736) with Carboplatin plus Etoposide for 4 cycles followed by Durvalumab maintenance in patients with metastatic pulmonary large-cell neuroendocrine carcinoma (LCNEC) - DUPLE trial
- Conditions
- treatment-naïve patients with metastatic pulmonary large-cell neuroendocrine carcinoma (LCNEC)MedDRA version: 20.0Level: PTClassification code 10071542Term: Neuroendocrine carcinoma metastaticSystem Organ Class: 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps)Therapeutic area: Diseases [C] - Cancer [C04]
- Registration Number
- EUCTR2020-005942-41-IT
- Lead Sponsor
- GRUPPO ONCOLOGICO ITALIANO DI RICERCA CLINICA (GOIRC)
- Brief Summary
Not available
- Detailed Description
Not available
Recruitment & Eligibility
- Status
- Authorised-recruitment may be ongoing or finished
- Sex
- All
- Target Recruitment
- 49
•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
Are the trial subjects under 18? no
Number of subjects for this age range:
F.1.2 Adults (18-64
•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-cancer-related conditions (e.g., hormone replacement therapy) is acceptable.
Study & Design
- Study Type
- Interventional clinical trial of medicinal product
- Study Design
- Not specified
- Primary Outcome Measures
Name Time Method Main Objective: To assess the efficacy of the combination of carboplatin + etoposide + durvalumab in treatment-naïve patients with metastatic pulmonary LCNEC;Secondary Objective: To assess activity of the combination of carboplatin + etoposide + durvalumab as first-line treatment for patients with metastatic pulmonary LCNEC<br><br>To assess the safety and tolerability profile of the combination of carboplatin + etoposide + durvalumab as first-line treatment for patients with metastatic pulmonary LCNEC;Primary end point(s): The primary endpoint is Overall Survival (OS) that will be measured from the date of registration to the date of death by any cause and will be analyzed as survival rate at 1 year.;Timepoint(s) of evaluation of this end point: 1 year
- Secondary Outcome Measures
Name Time Method