Trial comparing the continuation of nivolumab and ipilimumab (doublet immunotherapy) to observation after a first 6 months treatment by nivolumab - ipilimumab in patient with stage IV lung cancer

Overview

Sponsor-declared trial summary

Key facts

Sponsor

Intergroupe Francophone De Cancerologie Thoracique

Participant type

Patients

Age range

18-64 years, 65+ years

Gender

Male and Female

Therapeutic area

Diseases [C] - Neoplasms [C04]

Trial duration

2 May 2018 → 15 Oct 2025

Decision date (initial)

2025-01-21

Transition trial

Yes

Low-intervention

No

Rare-disease indication

No

Vulnerable population

Yes

External identifiers

EU CT number

2024-514586-20-01

EudraCT number

2017-002540-33

ClinicalTrials.gov

NCT03469960

Trial design

CTIS Part I — objectives, methods, condition coding

Main objective

Scope: Therapy, Efficacy, Safety

To observe not significantly different median 1st Progression-Free Survival (=PFS) from the date of randomization (thus in disease controlled patients) for the 'stop and go' arm B, as compared to the standard arm A with induction immunotherapy, followed by cisplatin-based chemotherapy at progression.

Secondary objectives 7

1. QOL by using EQ-5D and a visual analogic scale questionnaire scores and assessing Time Until Definitive Deterioration (TUDD).
2. PFS-2 from the date of second-line chemotherapy initiation or from the date of resuming double immunotherapy to 2nd progression date
3. OS from the date of randomization or from the date of inclusion to the date of death or last vital status information will be assessed in both arms
4. Centrally-assessed PD-L1 tumour expression prognostic and predictive value (with the treatment arm as interaction term)
5. Locally-assessed PD-L1 tumour expression prognostic and predictive value (with the treatment arm as interaction term)
6. Pharmaco-economics study assessing for micro-costing of the two tested therapeutic strategies
7. Safety and tolerance will be performed in all treated patients

Conditions and MedDRA coding

Non small cell lung cancer

Regulatory references

Plan to share IPD

No

Eligibility criteria

Principal inclusion / exclusion criteria as submitted by sponsor

Inclusion criteria 14

1. 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. 2. Histologically-proven NSCLC (squamous or non-squamous). A cytologically-proven NSCLC is allowed if a cytoblock has been prepared.
3. 3. Stage IV (M1, including M1a pleural involvement) disease (8th classification TNM, UICC 2015)
4. 4. ECOG PS ≤ 1
5. 5. Weight loss< 10% in previous 3 months
6. 6. No prior systemic anticancer therapy (including EGFR or ALK inhibitors) given as primary therapy for advanced or metastatic disease.
7. 7. Age≥ 18 years, <75 years
8. 8. Life expectancy > 3 months
9. 9. Measurable tumor disease by CT or MRI per RECIST 1.1 criteria
10. 10. Available tumor samples for centralized PD-L1 immunohistochemistry analysis
11. 11. PD-L1 tumor content as assessed locally by the investigator center
12. 12. Adequate biological functions: Creatinine Clearance ≥ 50 mL/min (Cockroft or MDRD or CKD-epi); neutrophiles ≥ 1500/mm3 ; platelets ≥100 000/mm3 ; Hemoglobin ≥ 9g/dL ; AST and ALT < 3x ULN, total bilirubine ≤ 1,5 x ULN except for patients with proved Gilbert syndrome or patients with hepatic metastases who must have AST and ALT ≤ 5 x ULN and a baseline total bilirubine ≤ 3,0 mg/dL.
13. 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. 14. Patient inclusion validated by a multidisciplinary meeting.

Exclusion criteria 18

1. 1. Small cell lung cancer or tumors with mixt histology including a SCLC component
2. 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. 3. Known ALK or ROS1 gene rearrangement as assessed by IH, FISH or NGS sequencing
4. 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. 5. Superior vena cava syndrome persisting after VCS stenting
6. 6. Thoracic radiotherapy needed at initiation of tumor treatment, except bone palliative radiotherapy on a painful or compressive metastasis, respecting 2 weeks delay between the end of radiotherapy and the beginning of induction immunotherapy treatment
7. 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, are allowed.
8. 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. 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. 10. History of active autoimmune disease including rheumatoid polyarthritis, Lupus, Wegener disease. Patients with type I diabetes, or hypothyroïdy, or immune cutaneous disease (vitiligo, psoriasis, alopecia) not needing any immunosuppressive systemic treatment, are allowed to be included.
11. 11. Active inflammatory intestinal disease (diverticulosis, Crohn disease, Hemorrhagic recto-colitis, coeliac disease) or any serious chronic intestinal disease with uncontrolled diarrhea
12. 12. Active uncontrolled infection including tuberculosis, known acute viral hepatitis B and C according to serological tests. Patients with serological sequellae of cured viral hepatitis are allowed to be included.
13. 13. HIV known infection
14. 14. Living attenuated vaccine received within the 30 previous days
15. 15. Previous treatment with anti-PD-1, anti-PD-L1 or Anti-CTLA4 antibody
16. 16. Previous treatment with chemotherapy
17. 17. General serious condition such as congestive uncontrolled cardiac failure, uncontrolled cardiac arythmia, 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. 18. Pre-existing lung interstitial disease as assessed by the diagnosis CT-scan.

Endpoints

Primary and secondary outcome measures (English text)

Primary endpoints 1

1. Progression Free Survival (PFS1)

Secondary endpoints 9

1. Progression Free Survival (PFS2)
2. Quality of life (QoL)
3. Overall survival (OS)
4. Biological correlative exploratory studies (PD-L1)
5. Biological correlative exploratory studies (PD-L1 H score)
6. Biological correlative exploratory studies (CD3/CD8)
7. Biological correlative exploratory studies (neutrophil)
8. Biological correlative exploratory studies (cytokines)
9. Biological correlative exploratory studies (chemokines)

Investigational products

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

Test 2

Sponsors and contacts

Sponsor organisations, regulatory contacts, third parties

Intergroupe Francophone De Cancerologie Thoracique

Sponsor organisation

Intergroupe Francophone De Cancerologie Thoracique

Address

10 Rue De La Grange Bateliere

City

Paris

Postcode

75009

Country

France

Scientific contact point

Organisation

Intergroupe Francophone De Cancerologie Thoracique

Contact name

Contact

Public contact point

Organisation

Intergroupe Francophone De Cancerologie Thoracique

Contact name

Contact

Locations

1 EU/EEA country · 60 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 10 files

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

Application history

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