Double Immune Checkpoint Inhibitors in PD-L1-positive Stage IV Non-small Lung CancEr

Non-Small Cell Lung Cancer Metastatic Clinical Trial

— DICIPLE  

Official title:

A Randomized Phase 3 Trial Comparing Continuation Nivolumab-Ipilimumab Doublet Immunotherapy Until Progression Versus Observation in Treatment-naive Patients With PDL1-positive Stage IV Non-Small Cell Lung Cancer (NSCLC) After Nivolumab-Ipilimumab Induction Treatment

Clinical Trial Details — Status: Active, not recruiting

Administrative data

• NCT number: NCT03469960
• Other study ID #: IFCT-1701
• Secondary ID: 2017-002540-33
• Status: Active, not recruiting
• Phase: Phase 3
• Start date: May 2, 2018
• Est. completion date: December 2024

Study information

• Verified date: March 2024
• Source: Intergroupe Francophone de Cancerologie Thoracique
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

Non Small Cell lung cancer (NSCLC) remains the first cause of death by cancer in the World. For the patients presenting a NSCLC stage IV, the median of survival is about 15 months today. The chemotherapy with platinum is the standard treatment for these patients but immunotherapy showed these efficacy in 1st line for patients PD-L1 positive. On the other hand, the duration of treatment by immunotherapy is not clear. Indeed, prolonged responses and long survivals have been described in patients having interrupted the treatment. In the melanoma, a treatment of 6 months of ipilimumab demonstrated its efficacy. The objective of the study is to demonstrate that a treatment of 6 months followed by an observation (stop and go) is not less effective than a treatment given until progression or toxicity. This strategy would allow to decrease the accumulated toxicities, to improve the quality of life of the patients and to decrease the costs.

Recruitment information / eligibility

• Status: Active, not recruiting
• Enrollment: 265
• Est. completion date: December 2024
• Est. primary completion date: November 8, 2023
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years to 75 Years

Eligibility

Inclusion Criteria:

1. Signed Written Informed Consent:

Subjects must have signed and dated an IRB/IEC approved written informed consent form in accordance with regulatory and institutional guidelines. This must be obtained before the performance of any protocol related procedures that are not part of normal subject care.

Subjects must be willing and able to comply with scheduled visits, treatment schedule, and laboratory testing.

2. Histologically-proven NSCLC (squamous or non-squamous)

3. Stage IV (M1, including M1a pleural involvement) disease (8th classification TNM, UICC 2015)

4. ECOG PS < 1

5. Weight loss< 10% in previous 3 months

6. No prior systemic anticancer therapy (including EGFR or ALK inhibitors) given as primary therapy for advanced or metastatic disease.

7. Age= 18 years, <75 years

8. Life expectancy > 3 months

9. Measurable tumor disease by CT or MRI per RECIST 1.1 criteria

10. Available tumor samples for centralized PD-L1 immunohistochemistry analysis

11. PD-L1 tumor content = 1% and < 50% tumor cells as assessed locally by the investigator center

12. Adequate biological functions:

Creatinine Clearance = 50 mL/min (Cockcroft or MDRD or CKD-epi); neutrophiles = 1500/mm3 ; platelets =100 000/mm3 ; Hemoglobin = 9g/dL ; hepatic enzymes < 3x ULN, total bilirubin = 1,5 x ULN except for patients with proved, Gilbert syndrome (= 5 x ULN) or patients with hepatic metastases (= 3,0 mg/dL)

13. Women of childbearing potential (WOCBP) and sexually active should use an efficacious contraception method within the 28 days preceding the first dose and during the 6 months following the last dose of treatment. Women must have a negative serum or urine pregnancy test (minimum sensitivity 25 IU/L or equivalent units of HCG) within 24 hours prior to the start of study drug.

For Male subjects who are sexually active with WOCBP, an efficacious contraception method should be used during the treatment and during the 7 months following the last dose.

Investigators shall counsel WOCBP and male subjects who are sexually active with WOCBP on the importance of pregnancy prevention and the implications of an unexpected pregnancy. Investigators shall advise WOCBP and male subjects who are sexually active with WOCBP on the use of highly effective methods of contraception. Highly effective methods of contraception have a failure rate of < 1% when used consistently and correctly. At a minimum, subjects must agree to the use of two methods of contraception, with one method being highly effective and the other method being either highly effective or less effective.

14. Patient inclusion validated by a multidisciplinary meeting.

Exclusion Criteria:

1. Small cell lung cancer or tumors with mixt histology including a SCLC component

2. Known EGFR activating tumor mutation (deletion LREA in exon 19, L858R ou L861X mutations in exon 21, G719A/S mutation in exon 18) or HER exon 20 insertion (either tissue or plasma cfDNA mutation).

3. Known ALK or ROS1 gene rearrangement as assessed by immunohistochemistry, FISH or NGS sequencing

4. Previous or active cancer within the previous 5 years (except for treated carcinoma in situ of the cervix or basal cell skin cancer). Patients with a prostate adenocarcinoma history within the previous 5 years could be included in case of localized prostate cancer, with good prognostic factors according to d'Amico classification (= T2a and Score de Gleason = 6 and PSA (ng/ml) = 10), provided they were treated in a curative way (surgery or radiotherapy, without any chemotherapy)

5. Superior vena cava (SVC) syndrome persisting after SVC stenting

6. Thoracic radiotherapy needed at initiation of tumor treatment, except bone palliative radiotherapy on a painful or compressive metastasis, respecting 4 weeks delay between the end of radiotherapy and the beginning of induction immunotherapy treatment

7. Symptomatic untreated brain metastasis (without previous whole brain radiotherapy or stereotactic ablative brain radiotherapy or without surgical resection). At least 4 weeks delay between the end of radiotherapy and the beginning of induction immunotherapy treatment should be respected. Asymptomatic brain metastasis, not needing corticosteroids greater than 10 mg prednisone equivalent daily or mannitol infusions, with no evolution on brain MRI or CT-scan within the previous month are allowed.

8. History of previous primary immunodeficiency, organ transplantation needing an immunosuppressive treatment, any immunosuppressive drug within 28 days before randomization date, or history of severe toxicity (grade 3/4) by immune mechanism linked to another immunotherapy treatment.

9. Systemic treatment with corticosteroids with greater dose than 10 mg prednisone equivalent daily, within 14 days before initiation of the immunotherapy induction. Inhaled, nasal or topic corticosteroids are allowed.

10. History of active autoimmune disease including rheumatoid polyarthritis, Lupus, Wegener disease. Patients with type I diabetes, or hypothyroidism, or immune cutaneous disease (vitiligo, psoriasis, alopecia) not needing any immunosuppressive systemic treatment, are allowed to be included.

11. Active inflammatory intestinal disease (diverticulosis, Crohn disease, Hemorrhagic recto-colitis, coeliac disease) or any serious chronic intestinal disease with uncontrolled diarrhea

12. Active uncontrolled infection including tuberculosis, known acute viral hepatitis B and C according to serological tests. Patients with serological sequelae of cured viral hepatitis are allowed to be included.

13. HIV known infection

14. Living attenuated vaccine received within the 30 previous days

15. Previous treatment with anti-PD-1, anti-PD-L1 or Anti-CTLA4 antibody

16. Previous treatment with chemotherapy

17. General serious condition such as congestive uncontrolled cardiac failure, uncontrolled cardiac arrythmia, uncontrolled ischemic cardiac disease (unstable angina or history of myocardial infarction in the previous 6 months), history or stroke within the 6 previous months

18. Pre-existing lung interstitial disease as assessed by the diagnosis CT-scan.

Related Conditions & MeSH terms

• Carcinoma, Non-Small-Cell Lung
• Lung Neoplasms
• Non-Small Cell Lung Cancer Metastatic

Intervention

Drug:
• Ipilimumab
Ipilimumab 1 mg/kg every 6 weeks
• Nivolumab
Nivolumab 3 mg/kg every 2 weeks

Locations

Country	Name	City	State
France	Amiens - CHU	Amiens
France	Angers - CHU	Angers
France	Annecy - CH	Annecy
France	Argenteuil -CH	Argenteuil
France	Avignon - CH	Avignon
France	Bordeaux - Polyclinique Nord	Bordeaux
France	Boulogne - Ambroise Paré	Boulogne-Billancourt
France	Caen - CHU Côte de Nacre	Caen
France	Cahors - CH	Cahors
France	CH de Pontoise	Cergy Pontoise
France	CH Chambery	Chambery
France	CH de Chauny	Chauny
France	CH	Cholet
France	Clamart - Hôpital Percy	Clamart
France	Clermont Ferrand - CHU	Clermont Ferrand
France	Colmar - CH	Colmar
France	Dijon - CAC	Dijon
France	CHRU Grenoble	Grenoble
France	La Roche Sur Yon - CH	La Roche Sur Yon
France	Centre Hospitalier - Pneumologie	Le Mans
France	CHRU de Lille	Lille
France	CHU de Limoges	Limoges
France	CH Lyon Sud - Pneumologie	Lyon
France	Institut Paoli Calmette	Marseille
France	Marseille - Hôpital Européen	Marseille
France	Mont de Marsan - CH	Mont de Marsan
France	Mulhouse - CH	Mulhouse
France	Nantes - Centre René Gauducheau	Nantes
France	Centre Antoine Lacassagne	Nice
France	CHU Nîmes	Nîmes
France	Orléans - CH	Orléans
France	AP-HP Hôpital Bichat	Paris
France	AP-HP Hopital Tenon - Pneumologie	Paris
France	GH Paris Saint-Joseph	Paris
France	Hôpital Saint Louis APHP	Paris
France	Paris - Institut Curie	Paris
France	Rouen - CHU	Rouen
France	Saint Quentin - CH	Saint Quentin
France	Centre René Huguenin	Saint-Cloud
France	HIA Begin	Saint-Mandé
France	ICL Lucien Neuwirth	Saint-Priest-en-Jarez
France	Suresnes - Hopital Foch	Suresnes
France	Toulon - CHI	Toulon
France	CHU Toulouse	Toulouse
France	CHRU de Tours	Tours
France	Versailles - CH	Versailles
France	CH de Villefranche - Pneumologie	Villefranche

Sponsors (1)

Lead Sponsor	Collaborator
Intergroupe Francophone de Cancerologie Thoracique

Country where clinical trial is conducted

France, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Progression Free Survival (PFS1)	Time between the date of randomization and the first date of documented progression, as determined by BICR (Blinded Independent Central Review), or death due to any cause, whichever occurs first.	24 months after randomization of the last subject
Secondary	Progression Free Survival (PFS2)	Time between the start date of the second line and the second date of documented progression, as determined by BICR, or death due to any cause, whichever occurs first.	24 months after randomization of the last subject
Secondary	Quality of life (QoL)	Time until definitive deterioration (TUDD) from the randomization time in the experimental arm B.	24 months after randomization of the last subject
Secondary	Overall survival (OS)		6, 12 and 18 months after randomization
Secondary	Biological correlative exploratory studies (PD-L1)	PD-L1-stained % of tumor cells will be associated to the rate of disease control patients at 6 months, PFS1, PFS2 and OS	6 months
Secondary	Biological correlative exploratory studies (PD-L1 H score)	PD-L1 H-score will be associated to the rate of disease control patients at 6 months, PFS1, PFS2 and OS	6 months
Secondary	Biological correlative exploratory studies (CD3/CD8)	CD3/CD8 tumor infiltration will be associated to the rate of disease control patients at 6 months, PFS1, PFS2 and OS	6 months
Secondary	Biological correlative exploratory studies (neutrophil)	neutrophil tumor infiltration will be associated to the rate of disease control patients at 6 months, PFS1, PFS2 and OS	6 months
Secondary	Biological correlative exploratory studies (cytokines)	plasma concentration of different cytokines at baseline or at the randomization point, will be associated to the rate of disease control patients at 6 months, PFS1, PFS2 and OS	6 months
Secondary	Biological correlative exploratory studies (chemokines)	plasma concentration of different chemokines at baseline or at the randomization point, will be associated to the rate of disease control patients at 6 months, PFS1, PFS2 and OS	6 months

External Links

•   IFCT website