Early Switch Maintenance vs Delayed Second-line Nivolumab in Advanced Stage Squamous Non-small Cell Lung Cancer (NSCLC) Patients (EDEN Trial)

Sponsor

Gruppo Oncologico Italiano di Ricerca Clinica (Other)

Overall Status

Active, not recruiting

CT.gov ID

NCT03542461

Collaborator

Mipharm S.p.A. (Other), Bioikos Ambiente Srl (Other), Istituto Toscano Tumori (Other), Temas srl (Other), Bristol Myers Squibb Srl Italia (Other)

125

Enrollment

Locations

Arms

60.2

Anticipated Duration (Months)

Patients Per Site

0.1

Patients Per Site Per Month

Study Details

Study Description

Brief Summary

The study's hypothesis is that using Nivolumab as early switch maintenance, after 4-6 cycles of standard first-line chemotherapy, might improve survival in patients with advanced stage squamous NSCLC.

Condition or Disease	Intervention/Treatment	Phase
Squamous Non-small Cell Lung Cancer	Drug: Nivolumab 10 MG/ML Intravenous Solution Other: Best Supportive Care	Phase 3

Study Design

Study Type:

Interventional

Actual Enrollment :

125 participants

Allocation:

Randomized

Intervention Model:

Parallel Assignment

Intervention Model Description:

Open-label, randomized in a 1:1 ratio to 2 treatment arms and stratified by centre and response to first-line induction therapy (minimization method)Open-label, randomized in a 1:1 ratio to 2 treatment arms and stratified by centre and response to first-line induction therapy (minimization method)

Masking:

None (Open Label)

Primary Purpose:

Treatment

Official Title:

An Open-label, Randomized Phase III Study of Early Switch Maintenance vs DElayed Second-line Nivolumab in Advanced Stage Squamous Non Small-cell Lung Cancer (NSCLC) Patients After Standard First-line Platinum-based Chemotherapy - EDEN Trial

Actual Study Start Date :

Sep 25, 2017

Anticipated Primary Completion Date :

Sep 30, 2022

Anticipated Study Completion Date :

Sep 30, 2022

Arms and Interventions

Arm	Intervention/Treatment
Experimental: A_Nivolumab Nivolumab 240 mg IV every 2 weeks until disease progression, unacceptable toxicity, patient refusal or Investigator's decision	Drug: Nivolumab 10 MG/ML Intravenous Solution 240 mg as a 30 minutes IV infusion on Day 1 of each treatment cycle every 2 weeks, until intolerable toxicity or patient refusal or investigator's decision. In case of disease progression the treatment should be discontinued unless documented clinical benefits in the Investigator's judgement (no rapid progression, tolerance of trial drug, stable performance status, treatment maintenance does not delay an imminent intervention to prevent serious complication of PD) and no evidence of further progression at a radiographic assessment performed within 6 weeks. No dose escalations or reduction allowed. Administration delay until 6 weeks as well as resuming dose are allowed according to protocol defined criteria.
Other: B_Best Supportive Care Best Supportive Care until disease progression followed by Nivolumab at a dose of 240 mg IV until further disease progression, unacceptable toxicity, patient refusal or Investigator's decision.	Drug: Nivolumab 10 MG/ML Intravenous Solution 240 mg as a 30 minutes IV infusion on Day 1 of each treatment cycle every 2 weeks, until intolerable toxicity or patient refusal or investigator's decision. In case of disease progression the treatment should be discontinued unless documented clinical benefits in the Investigator's judgement (no rapid progression, tolerance of trial drug, stable performance status, treatment maintenance does not delay an imminent intervention to prevent serious complication of PD) and no evidence of further progression at a radiographic assessment performed within 6 weeks. No dose escalations or reduction allowed. Administration delay until 6 weeks as well as resuming dose are allowed according to protocol defined criteria. Other: Best Supportive Care Care that aims to optimize the comfort, function and social support of the patients and their family at all stages of the illness. Best Supportive Care (BSC)includes the use of analgesics, antibiotics, blood tranfusions, blood products, radiotherapy, corticosteroids, antiemetics, antidiarrheals, vitamins and any intervention aiming the improvement of patient's discomfort. Any chemotherapy, immunotherapy and targeted therapy are not considered as part of BSC.

Arm

Intervention/Treatment

Experimental: A_Nivolumab

Nivolumab 240 mg IV every 2 weeks until disease progression, unacceptable toxicity, patient refusal or Investigator's decision

Drug: Nivolumab 10 MG/ML Intravenous Solution

240 mg as a 30 minutes IV infusion on Day 1 of each treatment cycle every 2 weeks, until intolerable toxicity or patient refusal or investigator's decision. In case of disease progression the treatment should be discontinued unless documented clinical benefits in the Investigator's judgement (no rapid progression, tolerance of trial drug, stable performance status, treatment maintenance does not delay an imminent intervention to prevent serious complication of PD) and no evidence of further progression at a radiographic assessment performed within 6 weeks. No dose escalations or reduction allowed. Administration delay until 6 weeks as well as resuming dose are allowed according to protocol defined criteria.

Other: B_Best Supportive Care

Best Supportive Care until disease progression followed by Nivolumab at a dose of 240 mg IV until further disease progression, unacceptable toxicity, patient refusal or Investigator's decision.

Drug: Nivolumab 10 MG/ML Intravenous Solution

Other: Best Supportive Care

Care that aims to optimize the comfort, function and social support of the patients and their family at all stages of the illness. Best Supportive Care (BSC)includes the use of analgesics, antibiotics, blood tranfusions, blood products, radiotherapy, corticosteroids, antiemetics, antidiarrheals, vitamins and any intervention aiming the improvement of patient's discomfort. Any chemotherapy, immunotherapy and targeted therapy are not considered as part of BSC.

Outcome Measures

Primary Outcome Measures

Overall survival (OS) [From date of randomization until the date of death by any cause or study discontinuation due to lost to follow up/withdrawal of consent assessed up to 14 months .]
Time from randomization to death date. Please note: a subject who has not died will be censored at the last known date alive.

Secondary Outcome Measures

Progression-Free Survival (PFS) [From date of randomization until the date of the first documented tumor progression or death by any cause, whichever occurs first, assessed up to 6 months in the arm B and 10 months in arm A.]
Time from randomization to the date of the first documented tumor progression (RECIST 1.1) or death due to any cause. Please note: clinical deterioration not radiologically confirmed is not considered progression for the purpose of this measure. Subjects who did not have any study tumor assessments and did not die will be censored on the date they were randomized. Subjects who started any subsequent anti-cancer therapy without a prior reported progression will be censored at the last evaluable tumor assessment prior to the initiation od the subsequent anti-cancer therapy.
Progression-Free Survival from induction (PFSind) [From date of first chemotherapy cycle until the date of the first documented tumor progression or death for any cause, whichever occurs first, assessed up to 10 months in the arm B and 14 months in arm A.]
Time from first chemotherapy cycle until documented tumor progression or death by any cause.
Time to Treatment Failure (TTF) [From date of randomization until the date of treatment discontinuation, assessed up to 9 months in the arm B and 14 months in arm A.]
Time from randomization to treatment discontinuation for any reason, including disease progression, treatment toxicity, patients preference, Investigator's decision or death.
Overall Survival from Induction (OSind) [From date of first chemotherapy cycle until the date of death, assessed assessed up to 14 months in the arm B and 18 months in arm A..]
Time from first chemotherapy cycle until death by any cause

Eligibility Criteria

Criteria

Ages Eligible for Study:

18 Years and Older

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

Inclusion Criteria:

pathologically (histology or cytology) confirmed diagnosis of squamous non-small cell lung cancer (NSCLC)
histologically or cytologically confirmed stage IIIB-IV or recurrent squamous NSCLC with partial response (PR), complete response (CR) or stable disease (SD) according RECIST 1.1 after 4-6 courses of standard platinum-based chemotherapy (i.e. cisplatin or carboplatin combined with either paclitaxel, docetaxel, nab-paclitaxel, gemcitabine or vinorelbine)
life expectancy ≥ 12 weeks
Eastern Cooperative Oncology Group (ECOG) performance status (PF) of 0-2
last chemotherapy course completed within 8 weeks before randomization and radiological assessment for tumor evaluation after first-line chemotherapy within 4 weeks before randomization
in case of presence of treated brain metastases, lesions should be stable for at least 4 weeks, steroids should be off or on stable dose (≤ 10 mg of prednisone or equivalent), radiotherapy should have been completed at least 14 days before randomization and any Adverse Event (AE) related to radiotherapy recovered to grade < 1 (except alopecia)
in case of females: postmenopausal status (at least 12 months after last menstrual period should have been passed) before the screening visit or surgical sterilization. Women of childbearing potential (WOCBP) must use 2 effective methods of contraception (from the time of informed consent signature trough 30 days after last trial drug dose) or agree to practice true abstinence, when this is in line with the preferred and usual lifestyle of the subject. Pregnancy should be avoided for 23 weeks after the last trial drug dose. WOCBP must have negative serum or urine pregnancy test within 24 hours prior to the start of trial drug treatment.
in case of males: even if surgically sterilized, effective barrier contraception (method with failure rate < 1%/year) during the entire study treatment period and for a period of 31 weeks after the last dose of trial drug, or practice true abstinence when this is in line with the preferred and usual lifestyle of the subject.
laboratory parameters measured within 14 days prior randomization as follows: absolute neutrophil count ≥ 1000/mmc platelet count ≥ 75000/mmc haemoglobin ≥ 9g/dL total bilirubin ≤ 1.5x the Upper Normal Limit (local laboratory range) except in case of Gilbert Syndrome where total bilirubin value < 3.0 mg/dL is allowed serum alanine aminotransferase or aspartate aminotransferase or aspartate aminotransferase ≤ 3x the Upper Normal Limit (local laboratory range) creatinine ≤ 1.5x the Upper Normal Limit or estimated creatinine clearance using Cockcroft-Gault formula ≥ 30 mL/minute for patients with creatinine levels above institutional limits
stable medical conditions, including the absence of acute exacerbations of chronic illnesses, serious infections or major surgery within 4 weeks before randomization and otherwise noted in other eligibility criteria
ability to comply with protocol requirements
ability to provide written informed consent

Exclusion Criteria:

prior treatment with nivolumab or any other immunotherapy agent (e.g. anti-PD-1, anti-PD-L1, etc.)
progressive disease after 4-6 cycles of first line platinum-based chemotherapy
non-platinum-based first-line chemotherapy
active, known or suspected autoimmune disease; please note: diabetes mellitus, hypothyroidism requiring only hormone replacement, skin disorders, such as vitiligo, psoriasis or alopecia, not requiring systemic treatment, or conditions not expected to recur without external trigger are not excluded.
condition requiring systemic treatment with either corticosteroids or other immunosuppressive medications within 14 days prior randomization; please note: topical, ocular, intranasal and inhalational corticosteroids with minimal systemic absorption, adrenal replacement steroid doses > 10 mg/day prednisone equivalent without concurrent autoimmune disease, brief course of corticosteroids treatment or prophylaxis or treatment of non-autoimmune conditions are allowed.
patients with symptomatic and/or progressive brain metastases or with carcinomatous meningitis.
previous malignancies unless complete remission has achieved at least 2 years prior to the study entry and no additional therapy is required or anticipated during the study period
any medical condition, within 6 months before receiving the first dose of trial drug, considered relevant in the investigator's opinion. Please note: chronic stable atrial fibrillation on stable anticoagulant therapy are not excluded. Pacemaker may represent an exclusion criterion and should be discussed with the project clinician. Attention should be paid to the conditions requiring treatment with potentially hepatotoxic drugs considering the hepatotoxic potential of the trial drug.
infection requiring an antibiotic therapy or other serious infection within 14 days before the first dose of trial drug
positive serum pregnancy test, pregnancy or breast feeding condition (only for females)
major surgery within 4 weeks (or 2 weeks for minor surgery) before study enrollment and not fully recovered to baseline or to a stable clinical status; lease note: insertion of vascular device is not excluded.
interstitial lung disease that is symptomatic or may interfere with the detection or management of suspected drug-related pulmonary toxicity known history of testing positive for Human Immunodeficiency Virus (HIV) or known acquired Immunodeficiency Syndrome (AIDS)
any positive test for hepatitis B virus or hepatitis C virus indicating acute or chronic infection
comorbidity or unresolved toxicities that would preclude administration of nivolumab.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	UOC Oncologia - Azienda USL di Imola - Ospedale Santa Maria della Scaletta	Imola	Bologna	Italy
2	Oncologia Medica - IRST - IRCCS di Meldola	Meldola	Forlì	Italy
3	AUSL 12 Viareggio, Ospedale Versilia, Lido di Camaiore (LU) - Oncologia Medica	Lido Di Camaiore	Lucca	Italy
4	UO Medicina Oncologica - Ospedale di Carpi (MO) - Azienda USL di Modena	Carpi	Modena	Italy
5	UOC di Oncologia Medica - ASST Valle Olona - Presidio Ospedaliero di Saronno	Saronno	Varese	Italy
6	SC Oncologia - ASO "SS Antonio e Biagio e Cesare Arrigo"	Alessandria		Italy
7	UO Oncologia Medica - A.S.S.T. Papa Giovanni XXIII di Bergamo	Bergamo		Italy
8	UO di Oncologia Medica - Azienda Ospedaliero-Universitaria S. Orsola Malpighi	Bologna		Italy
9	Divisione di Oncologia Medica - Ospedale di Bolzano	Bolzano		Italy
10	UOC Oncologia Medica - PO A.Perino ASL di Brindisi	Brindisi		Italy
11	SC di Oncologia - Istituti Ospitalieri di Cremona	Cremona		Italy
12	Dipartimento di Oncologia Medica - Azienda Ospedaliera S.Croce e Carle Cuneo - Ospedale Carle	Cuneo		Italy
13	UO di Oncologia Ematologia - Azienda Ospedaliero Universitaria di Ferrara	Ferrara		Italy
14	S.C. Oncologia Medica 1 - Azienda Ospedaliero Universitaria Careggi	Firenze		Italy
15	UOS Tumori Polmonari - IRCCS AOU San Martino -IST- Istituto Nazionale per la Ricerca sul Cancro	Genova		Italy
16	Azienda USL Toscana nord ovest - Ospedale San Luca di Lucca - Dipartimento Oncologico	Lucca		Italy
17	Azienda Ospedaliero-Universitaria di Modena - Policlinico - Dipartimento di Scienze Mediche e Chirurgiche, Materno Infantili e dell'adulto	Modena		Italy
18	SC di Oncologia Medica - A.O. San Gerardo	Monza		Italy
19	U.O.C Pneumologia ad Indirizzo Oncologico - AORN Ospedali dei Colli Monaldi	Napoli		Italy
20	IOV Istituto Oncologico Veneto - UOC di Oncologia Medica 2	Padova		Italy
21	UOC di Oncologia Medica - Azienda Ospedaliero Universitaria di Parma	Parma		Italy
22	S.C. di Oncologia Medica - Ospedale S.Maria della Misericordia	Perugia		Italy
23	AUSL - Piacenza - Ospedale "Guglielmo da Saliceto"-Dip.Oncologia e Ematologia- UO di Oncologia Medica Azienda	Piacenza		Italy
24	Azienda Ospedaliera Universitaria Pisana - Dipartimento Medico in Oncologia	Pisa		Italy
25	IRCCS CRO Aviano - SOC Oncologia medica e dei tumori Immunocorrelati - Dipartimento di Oncologia Pordenone S. Vito	Pordenone		Italy	33170
26	Pneumologia ad Indirizzo Oncologico 1 - A.O. San Camillo Forlanini	Roma		Italy
27	Università la Sapienza - Policlinico Umberto I - Dipartimento di scienze radiologiche, oncologiche e anatomo-patologiche - UOC Oncologia B	Roma		Italy
28	UO Oncologia Medica - ASL N.1 di Sassari - Ospedale Civile di Sassari	Sassari		Italy
29	U.O. Oncologia Medica - Ospedale Santa Chiara	Trento		Italy
30	Reparto di Oncologia - Azienda Sanitaria Universitaria Integrata di Udine - Presidio Ospedaliero Santa Maria della Misericordia	Udine		Italy
31	U.S.O. GIVOP (Gruppo Interdisciplinare Veronese Oncologia Polmonare) Oncologia - Azienda Ospedaliera Integrata Verona	Verona		Italy

Sponsors and Collaborators

Gruppo Oncologico Italiano di Ricerca Clinica
Mipharm S.p.A.
Bioikos Ambiente Srl
Istituto Toscano Tumori
Temas srl
Bristol Myers Squibb Srl Italia

Investigators

Principal Investigator: Andrea Ardizzoni, Dr, Medical Oncology Unit - S.Orsola Malpighi University Hospital of Bologna
Study Chair: Marcello Tiseo, Dr, Medical Oncology Unit - University Hospital of Parma