Pulmonary Large-cell Neuroendocrine Carcinoma
Conditions
Brief summary
A prospective multicenter, single-arm phase II study enrolling treatment-naïve patients with metastatic pulmonary large-cell neuroendocrine carcinoma (LCNEC)
Detailed description
This is a prospective multicenter, single-arm phase II study enrolling treatment-naïve patients with metastatic pulmonary large-cell neuroendocrine carcinoma (LCNEC). Enrolled subjects will receive a combination of intravenous carboplatin (AUC 5 on day 1), etoposide (100 mg/sqm on days 1-3), and durvalumab (1500 mg on day 1) administered every three weeks for a total of 4 courses (induction phase) or until progression of disease, unacceptable toxicity, patient refusal or loss of clinical benefit. Treatment with intravenous durvalumab (1500 mg on day 1) every 4 weeks (maintenance phase) will continue until completion of 24 courses (for a total of 28 courses, including the 4 courses of induction phase) or 2 years of treatment whichever occurs first, disease progression, unacceptable toxicity, patient refusal or loss of clinical benefit.
Interventions
DRUGDurvalumab 50 MG/1 ML Intravenous Solution [IMFINZI]
Intravenous infusion of durvalumab 1500 mg on day 1 (induction phase) with carboplatin (AUC 5 on day 1), etoposide (100 mg/sqm on days 1-3) every 3 weeks, and durvalumab (1500 mg on day 1) administered every three weeks for up to 4 cycles (induction phase) or until progression of disease, unacceptable toxicity, patient refusal or loss of clinical benefit (for durvalumab). Treatment with intravenous durvalumab (1500 mg on day 1) every 4 weeks ± 3 days (maintenance phase) will continue until completion of 24 courses (for a total of 28 courses, including the 4 courses of induction phase) or 2 years of treatment whichever occurs first, disease progression, unacceptable toxicity, patient refusal or loss of clinical benefit.
Sponsors
Gruppo Oncologico Italiano di Ricerca Clinica
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Efficacy of the combination of carboplatin + etoposide + durvalumab in treatment-naïve patients, as first line treatment, with metastatic pulmonary LCNEC | 1 year | Efficacy of the combination of carboplatin + etoposide Overall Survival rate at 1 year |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Activity of the combination of carboplatin + etoposide + durvalumab as first-line treatment for patients with metastatic pulmonary LCNEC | 1 year | Activity of the combination of carboplatin + etoposide + durvalumab as first-line treatment for patients with metastatic pulmonary LCNEC Median OS PFS ORR DCR and DoR at 1 year |
| Number of Participants with treatment-related Adverse Events as assessed by CTCAE v. 5.0 - The safety and tolerability profile of the combination of carboplatin + etoposide + durvalumab as first-line treatment for patients with metastatic pulmonary LCNEC | 1 year | Safety and tolerability profile of the combination of carboplatin + etoposide + durvalumab as first-line treatment for patients with metastatic pulmonary LCNEC |
Countries
Italy
Contacts
Primary ContactDavide Campana
Backup ContactMichele Tognetto
Outcome results
None listed