Clinical Trials /

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

NCT03469960

Description:

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.

Related Conditions:
  • Non-Small Cell Lung Carcinoma
Recruiting Status:

Recruiting

Phase:

Phase 3

Trial Eligibility

Document

Title

  • Brief Title: Double Immune Checkpoint Inhibitors in PD-L1-positive Stage IV Non-small Lung CancEr
  • 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 IDs

  • ORG STUDY ID: IFCT-1701
  • SECONDARY ID: 2017-002540-33
  • NCT ID: NCT03469960

Conditions

  • Non-Small Cell Lung Cancer Metastatic

Interventions

DrugSynonymsArms
IpilimumabArm A : standard treatment
NivolumabArm A : standard treatment

Purpose

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.

Trial Arms

NameTypeDescriptionInterventions
Arm A : standard treatmentActive Comparator6 months of treatment by nivolumab + ipilimumab then nivolumab + ipilimumab then in case of progression platinum-based doublet recommended
  • Ipilimumab
  • Nivolumab
Arm B : experimental armExperimental6 months of treatment by nivolumab + ipilimumab then observation the in case of progression nivolumab + ipilimumab then in case of progression platinum-based doublet recommended
  • Ipilimumab
  • Nivolumab

Eligibility Criteria

        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.
      
Maximum Eligible Age:75 Years
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Progression Free Survival (PFS1)
Time Frame:24 months after randomization of the last subject
Safety Issue:
Description: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.

Secondary Outcome Measures

Measure:Progression Free Survival (PFS2)
Time Frame:24 months after randomization of the last subject
Safety Issue:
Description: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.
Measure:Quality of life
Time Frame:24 months after randomization of the last subject
Safety Issue:
Description:Time until definitive deterioration (TUDD) from the randomization time in the experimental arm B.
Measure:Overall survival (OS)
Time Frame:6, 12 and 18 months after randomization
Safety Issue:
Description:
Measure:Biological correlative exploratory studies (PD-L1)
Time Frame:6 months
Safety Issue:
Description:PD-L1-stained % of tumor cells will be associated to the rate of disease control patients at 6 months, PFS1, PFS2 and OS
Measure:Biological correlative exploratory studies (PD-L1 H score)
Time Frame:6 months
Safety Issue:
Description:PD-L1 H-score will be associated to the rate of disease control patients at 6 months, PFS1, PFS2 and OS
Measure:Biological correlative exploratory studies (CD3/CD8)
Time Frame:6 months
Safety Issue:
Description:CD3/CD8 tumor infiltration will be associated to the rate of disease control patients at 6 months, PFS1, PFS2 and OS
Measure:Biological correlative exploratory studies (neutrophil)
Time Frame:6 months
Safety Issue:
Description:neutrophil tumor infiltration will be associated to the rate of disease control patients at 6 months, PFS1, PFS2 and OS
Measure:Biological correlative exploratory studies (cytokines)
Time Frame:6 months
Safety Issue:
Description: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
Measure:Biological correlative exploratory studies (chemokines)
Time Frame:6 months
Safety Issue:
Description: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

Details

Phase:Phase 3
Primary Purpose:Interventional
Overall Status:Recruiting
Lead Sponsor:Intergroupe Francophone de Cancerologie Thoracique

Trial Keywords

  • IFCT
  • DICIPLE
  • NSCLC

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