Denna sida har översatts automatiskt och översättningens korrekthet kan inte garanteras. Vänligen se engelsk version för en källtext.

Evaluation of the Effect of Time of Administration on the Activity on First Line of Pembrolizumab in Association With Carboplatin-pemetrexed in Metastatic Non-squamous Lung Cancer. A Randomised Multicenter Phase III Trial (IMMUNOTIME)

28 oktober 2026 uppdaterad av: Assistance Publique - Hôpitaux de Paris

IMMUNOTIME is a French multicenter randomised phase III trial in patients with metastatic non-squamous non-small cell lung cancer starting first-line treatment with pembrolizumab, carboplatin and pemetrexed. Patients receive the standard regimen and are randomised to start their pembrolizumab infusions either in the morning (08:00-12:00) or in the afternoon (13:00-17:00). The trial aims to determine whether morning administration improves survival at one year. A total of 242 patients will be included in 33 centres.

Studieöversikt

Status

Har inte rekryterat ännu

Betingelser

Intervention / Behandling

Detaljerad beskrivning

Pembrolizumab combined with carboplatin and pemetrexed is the standard first-line treatment for metastatic non-squamous NSCLC without EGFR, or ALK activation. Several immune functions involved in the response to anti-PD-1 therapy follow a circadian rhythm, including T-cell activity, tumour infiltration by dendritic cells and PD-1 expression. Retrospective studies in more than 1,600 patients treated with immune checkpoint inhibitors have reported longer progression-free and overall survival when treatment was given earlier in the day. In a meta-analysis of 782 NSCLC patients, the hazard ratio for death was 0.53 (95% CI 0.34-0.80). More recently, a retrospective cohort of 713 NSCLC patients treated with pembrolizumab plus chemotherapy showed markedly longer overall survival with morning infusions. No randomised trial has yet addressed this question.

IMMUNOTIME is an open-label, randomised (1:1), multicentre superiority trial. Eligible patients are adults with stage IV non-squamous NSCLC, ECOG performance status 0 or 1, known PD-L1 status, at least one measurable lesion and no indication for targeted therapy. Patients previously treated with immunotherapy, receiving immunosuppressive treatment or with an autoimmune disease at risk of severe flare are not eligible.

Randomisation is stratified by centre, sex, performance status and PD-L1 expression (<1%, 1-49%, ≥50%). In both groups, treatment is given every 21 days and follows routine practice: pembrolizumab 200 mg followed by pemetrexed 500 mg/m² and carboplatin AUC 5 for 4 cycles, then pembrolizumab and pemetrexed maintenance (for up to two years, as in standart care). The only study intervention is the time of the pembrolizumab infusion, which starts between 08:00 and 12:00 in the morning group and between 13:00 and 17:00 in the afternoon group during the first year. Each patient keeps the same time slot (±1 hour) throughout treatment.

The primary endpoint is the 1-year survival rate. Secondary endpoints include: progression-free survival, overall survival, best and early tumour response (RECIST), time to treatment discontinuation, toxicity (CTCAE v5.0), quality of life (EQ-5D, EORTC QLQ-C30), sleep quality (PSQI), chronotype (Horne-Östberg questionnaire) and cost-utility. Survival will also be analysed according to the actual time of infusion, in order to model the optimal timing.

Three optional ancillary studies will explore circadian biomarkers of response and tolerance: home monitoring with a wearable sensor and nocturnal polygraphy in about 50 patients, pembrolizumab pharmacokinetics, cytokines and circulating immune cells, clock gene expression in tumour and blood samples

The 242 patients will be recruited over 18 months. Each patient takes part for up to 25 months, including one year of treatment and one year of follow-up, and the trial will last 43 months in total. The primary analysis will be performed in the intention-to-treat population. An independent Data Safety Monitoring Board will oversee the trial. The sponsor is Assistance Publique - Hôpitaux de Paris, and the trial is funded by the PHRC-K programme.

Studietyp

Interventionell

Inskrivning (Beräknad)

254

Fas

  • Fas 3

Kontakter och platser

Det här avsnittet innehåller kontaktuppgifter för dem som genomför studien och information om var denna studie genomförs.

Studiekontakt

Studieorter

  • Frankrike
    • Auvergne-Rhône-Alpes
      • Aurillac, Auvergne-Rhône-Alpes, Frankrike, 15000
        • CH Henri Mondor - Service d'oncologie
        • Kontakt:
      • Bron, Auvergne-Rhône-Alpes, Frankrike, 69500
        • Hôpital Louis Pradel [HCL] - Service de pneumologie
        • Kontakt:
    • Bouches-du-Rhône
      • Marseille, Bouches-du-Rhône, Frankrike, 13915
        • Hôpital Nord [AP-HM] - Service d'oncologie multidisciplinaire et innovations thérapeutiques
        • Kontakt:
    • Calvados
      • Bayeux, Calvados, Frankrike, 14400
        • CH Aunay-Bayeux - Service d'oncologie
        • Kontakt:
      • Caen, Calvados, Frankrike, 14076
        • Centre François Baclesse - Service de pneumologie
        • Kontakt:
    • Hauts-de-Seine
      • Suresnes, Hauts-de-Seine, Frankrike, 92150
        • Hôpital Foch - Service d'oncologie médicale
    • Ile-et-Vilaine
      • Rennes, Ile-et-Vilaine, Frankrike, 35033
        • CHU de Rennes, Hôpital Pontchaillou - Service de pneumologie
        • Kontakt:
    • Maine-et-Loire
      • Angers, Maine-et-Loire, Frankrike, 49933
    • Nord
      • Lille, Nord, Frankrike, 59037
        • CHU Lille - Service de pneumologie et d'oncologie thoracique
        • Kontakt:
    • Paris 14
      • Paris, Paris 14, Frankrike, 75014
        • Hôpital Cochin [AP-HP] - Service de pneumologie, Unité oncologie thoracique
        • Kontakt:
      • Paris, Paris 14, Frankrike, 75014
        • Hôpital Paris Saint Joseph - Service de pneumo-oncologie et d'allergologie
        • Kontakt:
    • Paris 15
      • Paris, Paris 15, Frankrike, 75015
        • Hôpital Européen Georges Pompidou [APHP] - Service d'oncologie thoracique
        • Kontakt:
    • Pyrénées-Atlantiques
      • Bayonne, Pyrénées-Atlantiques, Frankrike, 64100
        • CH de la Côte Basque - Service de pneumologie médicale
        • Kontakt:
    • Saint-Maur-des-Faussés
      • Créteil, Saint-Maur-des-Faussés, Frankrike, 94010
    • Seine-Saint-Denis
      • Bobigny, Seine-Saint-Denis, Frankrike, 93000
        • CH d'Avicenne [AP-HP] - Service d'oncologie médicale et thoracique
        • Kontakt:
      • Montfermeil, Seine-Saint-Denis, Frankrike, 93370
        • GHI Le Raincy Montfermeil - Service d'oncologie
        • Kontakt:
    • Val-de-Marne
      • Villejuif, Val-de-Marne, Frankrike, 94800
        • Hôpital Paul-Brousse [AP-HP] - Service d'oncologie digestive et médicale
        • Kontakt:
      • Villejuif, Val-de-Marne, Frankrike, 94805
        • Hôpital Gustave Roussy - Service d'oncologie médicale
        • Kontakt:
    • Var
    • Yvelines
      • Le Chesnay, Yvelines, Frankrike, 78157
        • CH de Versailles, Hôpital André Mignot - Service de pneumologie
        • Kontakt:

Deltagandekriterier

Forskare letar efter personer som passar en viss beskrivning, så kallade behörighetskriterier. Några exempel på dessa kriterier är en persons allmänna hälsotillstånd eller tidigare behandlingar.

Urvalskriterier

Åldrar som är berättigade till studier

18 år och äldre (Vuxen, Äldre vuxen)

Tar emot friska volontärer

Nej

Kön som är behöriga för studier

Allt

Beskrivning

Inclusion Criteria:

  • 1 Have a histologically-confirmed or cytologically confirmed diagnosis of stage IV (M1a or M1b- AJCC 7th edition) non-squamous NSCLC.
  • 2. Have confirmation that EGFR or ALK-directed therapy is not indicated (documentation of absence of tumor activating EGFR mutations AND absence of ALK gene rearrangements) OR presence of a K-Ras mutation.
  • 3. Have measurable disease based on RECIST 1.1 as determined by the local site investigator/radiology assessment. Target lesions situated in a previously irradiated area are considered measurable if progression has been demonstrated in such lesions.
  • 4. Have not received prior systemic treatment for their advanced/metastatic NSCLC.

Subjects who received adjuvant or neoadjuvant therapy are eligible if the adjuvant/neoadjuvant therapy was completed at least 12 months prior to the development of metastatic disease.

  • 5. Have provided tumor tissue from locations not radiated prior to biopsy; formalin fixed specimens after the subject has been diagnosed with metastatic disease will be preferred for determination of PD-L1 status prior to randomisation. Biopsies obtained prior to receipt of adjuvant/neoadjuvant chemotherapy will be permitted if recent biopsy is not feasible.

  • 6. Be ≥18 years of age on the day of signing informed consent.

  • 7. Have a life expectancy of at least 3 months.

  • 8. Have a performance status of 0 or 1 on the Eastern Cooperative Oncology Group (ECOG) Performance Status.

  • 9. Have adequate organ function as indicated by the following laboratory values :

    1. Hematological Absolute neutrophil count (ANC) ≥ 1,500 /mcL
    2. Platelets Hemoglobin (4 weeks without transfusions) ≥ 100,000 / mcL ≥ 9.0 g/dL or ≥ 5.6 mmol/L
    3. Renal calculated creatinine clearance (CrCl)a ≥ 50 mL/min
    4. Hepatic Serum total bilirubin ≥ 50 mL/min ≤ 1.5xULN Direct bilirubin ≤ ULN for subjects with total bilirubin levels > 1.5xULN
    5. AST (SGOT) and ALT (SGPT) ≤ 2.5xULN or ≤ 5xULN for subjects with liver metastases
    6. Coagulation International Normalized Ratio (INR) or Prothrombin Time (PT) / Activated Partial Thromboplastin Time (aPTT) or Partial Thromboplastin Time (PTT) ≤ 1.5xULN unless the subject is receiving anticoagulant therapy
    7. Creatinine Clearance should be calculated using the Cockcroft-Gault Method

  • 10. If female of childbearing potential*, be willing to use an adequate method of contraception, for the course of the study through 120 days after the last dose of study medication or through 180 days after last dose of chemotherapeutic agents as specified in the protocol. Note: Abstinence is acceptable if this is the usual lifestyle and preferred contraception for the subject.

  • 11. If male subject with a female partner(s) of child-bearing potential, must agree to use an adequate method of contraception. Males with pregnant partners must agree to use a condom; no additional method of contraception is required for the pregnant partner. Note: Abstinence is acceptable if this is the usual lifestyle and preferred contraception for the subject.

  • 12. Subject has voluntarily agreed to participate by giving written informed consent/assent for the trial. The subject may also provide consent/assent for exploratory studies. However, the subject may participate in the main trial without participating in exploratory studies.

  • 13. Affiliation to French social security system

    • A woman is considered of childbearing potential (WOCBP), i.e. fertile, following menarche and until becoming post-menopausal unless permanently sterile. Permanent sterilisation methods include hysterectomy, bilateral salpingectomy and bilateral oophorectomy. A postmenopausal state is defined as no menses for 12 months without an alternative medical cause. A high follicle stimulating hormone (FSH) level in the postmenopausal range may be used to confirm a post-menopausal state in women not using hormonal contraception or hormonal replacement therapy. However in the absence of 12 months of amenorrhea, a single FSH measurement is insufficient.

Exclusion Criteria:

The patient will not be included in the trial if he or she:

  • 1. Has predominantly squamous cell histology NSCLC. Mixed tumors will be categorized by the predominant cell type; if small cell elements are present, the subject is ineligible.

  • 2. Is currently participating and receiving study therapy or has participated in a study of an investigational agent and received study therapy or used an investigational device within 4 weeks prior to administration of pembrolizumab.

  • 3. Before the first dose of trial treatment:

    1. Has received prior systemic cytotoxic chemotherapy for metastatic disease
    2. Has received antineoplastic biological therapy (e.g., erlotinib, crizotinib, cetuximab)
    3. Had major surgery

  • 4. Received radiation therapy to the lung that is > 30 Gy within 6 months of the first dose of trial treatment.

  • 5. Completed palliative radiotherapy within 7 days of the first dose of trial treatment.

  • 6. Is expected to require any other form of antineoplastic therapy while on study.

  • 7. Has received a live-virus vaccination within 30 days of planned treatment start.

Seasonal flu vaccines that do not contain live virus are permitted.

  • 8. Has clinically active diverticulitis, intra-abdominal abscess, GI obstruction, abdominal carcinomatosis.
  • 9. Has a known history of prior malignancy except if the subject has undergone potentially curative therapy with no evidence of that disease recurrence for 5 years since initiation of that therapy. Note: The time requirement for no evidence of disease for 5 years does not apply to the NSCLC tumor for which a subject is enrolled in the study. The time requirement also does not apply to subjects who underwent successful definitive resection of basal cell carcinoma of the skin, superficial bladder cancer, squamous cell carcinoma of the skin, in situ cervical cancer, or other in situ cancers
  • 10. Has known active central nervous system (CNS) metastases and/or carcinomatous meningitis. Subjects with previously treated brain metastases may participate provided they are clinically stable for at least 2 weeks and, have no evidence of new or enlarging brain metastases and also are off steroids 3 days prior to dosing with study medication. Stable brain metastases by this definition should be established prior to the first dose of study medication. Subjects with asymptomatic brain metastases (i.e., no neurological symptoms, no requirements for corticosteroids, and no lesion >1.5 cm) may participate but will require regular imaging of the brain as a site of disease.
  • 11. Previously had a severe hypersensitivity reaction to treatment with another mAb.
  • 12. Has a known sensitivity to any component of carboplatin or pemetrexed
  • 13. Contraindication to investigational medicinal products or to auxiliary medicinal products
  • 14. Has active autoimmune disease that has required systemic treatment in past 2 years (i.e. with use of disease modifying agents, corticosteroids or immunosuppressive drugs). Replacement therapy (e.g., thyroxine, insulin, or physiologic corticosteroid replacement therapy for adrenal or pituitary insufficiency, etc.) is not considered a form of systemic treatment.
  • 15. Is on chronic systemic steroids. Subjects with asthma that require intermittent use of bronchodilators, inhaled steroids, or local steroid injections would not be excluded from the study.
  • 16. Is unable to interrupt aspirin or other nonsteroidal anti-inflammatory drugs (NSAIDs), other than an aspirin dose ≤ 1.3 g per day, for a 5-day period (8-day period for longacting agents, such as piroxicam).
  • 17. Is unable or unwilling to take folic acid or vitamin B12 supplementation.
  • 18. Had prior treatment with any other anti-PD-1, or PD-L1 or PD-L2 agent or an antibody targeting other immuno-regulatory receptors or mechanisms. Has participated in any other MK-3475 trial and has been treated with MK-3475. Examples of such antibodies include (but are not limited to) antibodies against IDO, PD-L1, IL-2R, GITR
  • 19. Has an active infection requiring therapy.
  • 20. Has known history of Human Immunodeficiency Virus (HIV) (known HIV 1/2 antibodies positive).
  • 21. Has known active Hepatitis B or C. Active Hepatitis B is defined as a known positive HBsAg result. Active Hepatitis C is defined by a known positive Hep C Ab result and known quantitative HCV RNA results greater than the lower limits of detection of the assay.
  • 22. Has a history or current evidence of any condition, therapy, or laboratory abnormality that might confound the results of the study, interfere with the subject's participation for the full duration of the study, or is not in the best interest of the subject to participate, in the opinion of the treating Investigator.
  • 23. Has known psychiatric or substance abuse disorder that would interfere with cooperation with the requirements of the trial.
  • 24. Has interstitial lung disease or a history of pneumonitis that required oral or intravenous glucocorticoids to assist with management. Lymphangitic spread of the NSCLC is not exclusionary.
  • 25. Is pregnant or breastfeeding, or expecting to conceive or father children with in the projected duration of the study
  • 26. Patients under AME
  • 27. Adults subject to a legal measure protection (guardianship, curatorship and safeguard of justice)
  • 28. Patients deprived of their liberty by a judicial or administrative decision
  • Secondary exclusion criterion: If female of childbearing potential, have a positive urine or serum pregnancy test within 72 hours prior to receiving the first dose of study medication. If the urine test is positive or cannot be confirmed as negative, a serum pregnancy test will be required.

Studieplan

Det här avsnittet ger detaljer om studieplanen, inklusive hur studien är utformad och vad studien mäter.

Hur är studien utformad?

Designdetaljer

  • Primärt syfte: Behandling
  • Tilldelning: Randomiserad
  • Interventionsmodell: Parallellt uppdrag
  • Maskning: Ingen (Open Label)

Vapen och interventioner

Deltagargrupp / Arm
Intervention / Behandling
Experimentell: Early time of administration

Chemoimmunotherapy in the early time of administration group (9:00-12:00)
Övrig: Randomization of chemoimmunotherapy hour administration

Main intervention. Chemoimmunitherapy used as standart care.

Övrig: Questionnaires

Questionnaires EORTC-QLQ C30, EuroQol(EQ)-5D (quality of life) and Puttsburgh (Sleep quality) are realised before 1st Cycle, and at cycle 4, 8, 12 and 16

Questionnaire Hörne-Ostberg (Chronotype) is realised before 1st Cycle, and at cycle 4, 8

Övrig: Exploratory study 1 (facultative)

Auto-Samples: Before C1 (Day 1: 3 x saliva tubes ; Day 2: 3 x saliva tubes) to determine cortisol concentration Device ( Multisense® Product - RDS) Before C1 (3 to 7 days before), after C2 (3 to 7 days after) to collect physiological parameters

Övrig: Exploratory study 2 (facultative)

Samples: C1 (4 x 10 ml blood tubes), C2 (4 x 10ml blood tubes), C3 (2 x 10 ml blood tubes) et C4 (2 x 10ml blood tubes)

Pharmacokinetics of Pembrolizumab observation Cytokines, soluble and exosomal PDL-1 serum concentrations exploration Immunomonitoring of circulating immune populations

Övrig: Exploratory study 3 (facultative)

Samples: C1 (1 x 10 ml blood tubes), C2 (1 x 10ml blood tubes)

Analysis of global transcriptomic datasets to estimate the proportions of immune cells in the sample, as a possible marker of tumour immune infiltration, Analysis of global RNAseq data from patients to estimate the composition of immune cell types.
Aktiv komparator: Late time of administration

Chemoimmunotherapy late time of administration group (13:00 - 17:00)
Övrig: Randomization of chemoimmunotherapy hour administration

Main intervention. Chemoimmunitherapy used as standart care.

Övrig: Questionnaires

Questionnaires EORTC-QLQ C30, EuroQol(EQ)-5D (quality of life) and Puttsburgh (Sleep quality) are realised before 1st Cycle, and at cycle 4, 8, 12 and 16

Questionnaire Hörne-Ostberg (Chronotype) is realised before 1st Cycle, and at cycle 4, 8

Övrig: Exploratory study 1 (facultative)

Auto-Samples: Before C1 (Day 1: 3 x saliva tubes ; Day 2: 3 x saliva tubes) to determine cortisol concentration Device ( Multisense® Product - RDS) Before C1 (3 to 7 days before), after C2 (3 to 7 days after) to collect physiological parameters

Övrig: Exploratory study 2 (facultative)

Samples: C1 (4 x 10 ml blood tubes), C2 (4 x 10ml blood tubes), C3 (2 x 10 ml blood tubes) et C4 (2 x 10ml blood tubes)

Pharmacokinetics of Pembrolizumab observation Cytokines, soluble and exosomal PDL-1 serum concentrations exploration Immunomonitoring of circulating immune populations

Övrig: Exploratory study 3 (facultative)

Samples: C1 (1 x 10 ml blood tubes), C2 (1 x 10ml blood tubes)

Analysis of global transcriptomic datasets to estimate the proportions of immune cells in the sample, as a possible marker of tumour immune infiltration, Analysis of global RNAseq data from patients to estimate the composition of immune cell types.

Vad mäter studien?

Primära resultatmått

Resultatmått
Åtgärdsbeskrivning
Tidsram
Survival rate
Tidsram: At one year (12 months)

Survival rate is defined as the survival probability at one year.
At one year (12 months)

Sekundära resultatmått

Resultatmått
Åtgärdsbeskrivning
Tidsram
Progression Free Survival (PFS)
Tidsram: Until all-cause death or tumor progression (monitored throughout the 24 months of the patient's participation)

PFS is defined as delay from randomisation until all-cause death or tumor progression whichever comes first
Until all-cause death or tumor progression (monitored throughout the 24 months of the patient's participation)
Overall Survival (OS)
Tidsram: from randomisation until all-cause death (monitored throughout the 24 months of the patient's participation)

Overall Survival (OS) defined as delay from randomisation until all-cause death.
from randomisation until all-cause death (monitored throughout the 24 months of the patient's participation)
Tumor respons
Tidsram: Over 1 year, and early response rate at 6 weeks from randomisation

Best tumor response rate and early response rate according to RECIST criteria
Over 1 year, and early response rate at 6 weeks from randomisation
Safety
Tidsram: Up to two years (28 months)

Adverse events categorized by severity and type, rated following CTCAE v.5.0
Up to two years (28 months)
Quality of Life Index 1
Tidsram: At the 16th cycle after randomization (48 weeks)

Quality of life according to the EQ-5D-5L test results
At the 16th cycle after randomization (48 weeks)
Quality of Life Index 2
Tidsram: At the 16h cycle after randomization (48 weeks)

Quality of life according to the EORTC QLQ C30 test results
At the 16h cycle after randomization (48 weeks)
Quality of sleep index
Tidsram: At the 16th cycle after randomization (48 weeks)

Quality of sleep according to the Pittsburgh test results
At the 16th cycle after randomization (48 weeks)
Chronotype assessment
Tidsram: At the 8th cycle after randomization (24 weeks)

Chronotype assesssments according to the Hörne-Ostberg test results
At the 8th cycle after randomization (24 weeks)
Cost-Utility
Tidsram: Up to two years (28 months)

Health economics analysis, in particular through associated healthcare costs, additional GP or specialist consultations, and complementary treatments.
Up to two years (28 months)
Facultative Result (Exploratory study)
Tidsram: Up to two years (28 months)

Optimal time of administration through mathematical modelling
Up to two years (28 months)

Samarbetspartners och utredare

Det är här du hittar personer och organisationer som är involverade i denna studie.

Sponsor

Assistance Publique - Hôpitaux de Paris

Utredare

  • Huvudutredare: Boris DUCHEMANN, Dr, Research unit : CCT Chronothérapie, cancers et transplantation - Hospital Avicenne, Assistance publique des hôpitaux de Paris - Université Paris Saclay

Studieavstämningsdatum

Dessa datum spårar framstegen för inlämningar av studieposter och sammanfattande resultat till ClinicalTrials.gov. Studieposter och rapporterade resultat granskas av National Library of Medicine (NLM) för att säkerställa att de uppfyller specifika kvalitetskontrollstandarder innan de publiceras på den offentliga webbplatsen.

Studera stora datum

Studiestart (Beräknad)

1 december 2026

Primärt slutförande (Beräknad)

1 juli 2028

Avslutad studie (Beräknad)

1 juli 2029

Studieregistreringsdatum

Först inskickad

16 oktober 2026

Först inskickad som uppfyllde QC-kriterierna

28 oktober 2026

Första postat (Faktisk)

4 november 2026

Uppdateringar av studier

Senaste uppdatering publicerad (Faktisk)

4 november 2026

Senaste inskickade uppdateringen som uppfyllde QC-kriterierna

28 oktober 2026

Senast verifierad

1 oktober 2026

Mer information

Termer relaterade till denna studie

Nyckelord

Ytterligare relevanta MeSH-villkor

Andra studie-ID-nummer

  • APHP241011
  • 2025 (U.S.S. NIH-anslag/kontrakt)
  • 2025-521891-78-00 (Ctis)

Plan för individuella deltagardata (IPD)

Planerar du att dela individuella deltagardata (IPD)?

OBESLUTSAM

Läkemedels- och apparatinformation, studiedokument

Studerar en amerikansk FDA-reglerad läkemedelsprodukt

Nej

Studerar en amerikansk FDA-reglerad produktprodukt

Nej

produkt tillverkad i och exporterad från U.S.A.

Nej

Denna information hämtades direkt från webbplatsen clinicaltrials.gov utan några ändringar. Om du har några önskemål om att ändra, ta bort eller uppdatera dina studieuppgifter, vänligen kontakta register@clinicaltrials.gov. Så snart en ändring har implementerats på clinicaltrials.gov, kommer denna att uppdateras automatiskt även på vår webbplats .

Prenumerera