FIRST-NEC - A multicenter phase II study evaluating the efficacy and safety of the combination of durvalumab (MEDI 4736) with etoposide and platinum as first line treatment in patients with large-cell neuroendocrine carcinomas (LCNECs) of the lung.

Overview

Sponsor-declared trial summary

Key facts

Sponsor

Centre Leon Berard

Participant type

Patients

Age range

18-64 years, 65+ years

Gender

Male and Female

Therapeutic area

Diseases [C] - Neoplasms [C04], Diseases [C] - Respiratory Tract Diseases [C08]

Trial duration

13 Jun 2024 → ongoing

Decision date (initial)

2024-03-14

Transition trial

No

Low-intervention

No

Rare-disease indication

Yes

Vulnerable population

No

Trial design

CTIS Part I — objectives, methods, condition coding

Main objective

Scope: Efficacy, Safety

Determine the efficacy of durvalumab combined with etoposide and platinum (either cisplatin or carboplatin) for the 1st-line treatment of patients with advanced LCNEC
confirmed by centralized expert-pathologist review.

Secondary objectives 5

1. The 12-week Objective Response Rate
2. The 12-week Disease Control Rate
3. The Progression-Free Survival
4. The Overall Survival
5. The safety profile

Conditions and MedDRA coding

Large-Cell NeuroEndocrine Carcinoma of the lung

Eligibility criteria

Principal inclusion / exclusion criteria as submitted by sponsor

Inclusion criteria 14

1. Age ≥ 18 years at the time of study entry
2. Locally documented histological diagnosis of Large-Cell NeuroEndocrine Carcinoma of the lung (LCNEC)
3. 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…)
4. 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
5. Measurable disease as per the RECIST 1.1
6. Performance Status (PS) of the Eastern Cooperative Oncology Group (ECOG): 0 or 1
7. Body weight > 30Kg
8. Must have a life expectancy of at least 12 weeks
9. 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
10. 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)
11. 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
12. 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
13. Affiliation to a social security system
14. 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 19

1. 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)
2. Patient previously treated for a LCNEC in a metastatic setting
3. Any previous treatment with a PD1 or PD-L1 inhibitor, including durvalumab
4. 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
5. 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
6. History of allogenic organ transplantation
7. 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
8. 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
9. 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
10. 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
11. Carcinomatous meningitis
12. Mean QT interval corrected for heart rate using Fridericia's formula (QTcF) ≥470 ms
13. History of active primary immunodeficiency
14. 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
15. Known to have tested positive for human immunodeficiency virus (HIV) (positive HIV 1/2 antibodies) or active tuberculosis infection
16. 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)
17. 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
18. Known allergy or hypersensitivity to any of the study drugs or any of the study drug excipients
19. Pregnant or breast-feeding woman

Endpoints

Primary and secondary outcome measures (English text)

Primary endpoints 1

1. Progression-Free Rate at 12 months

Investigational products

Investigational medicinal products (IMPs), comparators, placebo, auxiliary

Test 4

Sponsors and contacts

Sponsor organisations, regulatory contacts, third parties

Centre Leon Berard

Sponsor organisation

Centre Leon Berard

Address

28 Rue Laennec

City

Lyon

Postcode

69008

Country

France

Scientific contact point

Organisation

Centre Leon Berard

Contact name

Oncology doctor

Public contact point

Organisation

Centre Leon Berard

Contact name

Clinical Project Manager

Locations

1 EU/EEA country · 25 investigational sites

By country

Investigational sites

Country notifications

Trial-start, recruitment-start, end and early-termination notifications submitted per Member State

Results and documents

Annex IV summary of results, Annex V layperson summary, and all documents registered in CTIS for this trial

Documents 11 files

Public protocol annexes, IB summaries, regulatory submissions and post-authorisation documents registered in CTIS.

Application history

6 submissions — initial application plus substantial / non-substantial modifications