Metastasic NSCLCPhase 3IMMUNOTIMENCT07915037
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
A Phase 3 study testing Randomization of chemoimmunotherapy hour administration, Questionnaires and Exploratory study 1 (facultative) in people with Metastasic NSCLC, run by Assistance Publique - Hôpitaux de Paris at 20 sites in France.
Trial summary
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. Read more about this study
- Who is it for?
- Ages 18 years and older
- Conditions the study is for
- Metastasic NSCLC
- What is being tested?
- Randomization of chemoimmunotherapy hour administration, Questionnaires and Exploratory study 1 (facultative)
- Could I receive a placebo?
- No, everyone receives an active treatment
- How many people
- 254 participants
- Where
- 20 sitesFrance
- Study dates
- Dec 2026to Jul 2029
- Phase
- Phase 3
- Are there results?
- Not yet: the study is under way
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 18 years and older
- All sexes
- No healthy volunteers
- Adult, Older adult
Who may be able to join
- 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.
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- 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 :
- Hematological Absolute neutrophil count (ANC) ≥ 1,500 /mcL
- Platelets Hemoglobin (4 weeks without transfusions) ≥ 100,000 / mcL ≥ 9.0 g/dL or ≥ 5.6 mmol/L
- Renal calculated creatinine clearance (CrCl)a ≥ 50 mL/min
- Hepatic Serum total bilirubin ≥ 50 mL/min ≤ 1.5xULN Direct bilirubin ≤ ULN for subjects with total bilirubin levels > 1.5xULN
- AST (SGOT) and ALT (SGPT) ≤ 2.5xULN or ≤ 5xULN for subjects with liver metastases
- 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
- 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.
Who cannot join
- 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:
- Has received prior systemic cytotoxic chemotherapy for metastatic disease
- Has received antineoplastic biological therapy (e.g., erlotinib, crizotinib, cetuximab)
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- 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.
Trial locations and contacts
20 sites in 1 country. Contact the study team or a site near you to ask about taking part.
20 sites in 1 country
France20 sites
CHU d'Angers - Service de pneumologie
Angers, Maine-et-Loire, 49933
Grégoire JUSTEAU, Dr, +33 02.41.35.58.44, Gregoire.justeau@chu-angers.fr
CH Henri Mondor - Service d'oncologie
Aurillac, Auvergne-Rhône-Alpes, 15000
Daniela BURLACU, Dr, +33 04.71.46.56.56, d.burlacu@ch-aurillac.fr
CH Aunay-Bayeux - Service d'oncologie
Bayeux, Calvados, 14400
Pierre-Emmanuel BRACHET, Dr, +33 02.31.51.54.17, pe.brachet@ch-ab.fr
CH de la Côte Basque - Service de pneumologie médicale
Bayonne, Pyrénées-Atlantiques, 64100
Sophie SCHNEIDER, Dr, +33 05.59.44.38.85, sschneider@ch-cotebasque.fr
CH d'Avicenne [AP-HP] - Service d'oncologie médicale et thoracique
Bobigny, Seine-Saint-Denis, 93000
Boris DUCHEMANN, Dr, +33 01.48.95.50.33, boris.duchemann@aphp.fr
Hôpital Louis Pradel [HCL] - Service de pneumologie
Bron, Auvergne-Rhône-Alpes, 69500
Thomas PIERRET, Dr, +33 04.27.85.77.00, thomas.pierret@chu-lyon.fr
Centre François Baclesse - Service de pneumologie
Caen, Calvados, 14076
Hubert CURCIO, Dr, +33 02.31.45.50.50, h.curcio@baclesse.unicancer.fr
CHI de Créteil - Service de pneumologie
Créteil, Saint-Maur-des-Faussés, 94010
Gaëlle ROUSSEAU-BUSSAC, Dr, +33 01.57.02.21.01, gaelle.rousseaubussac@chicreteil.fr
CH de Versailles, Hôpital André Mignot - Service de pneumologie
Le Chesnay, Yvelines, 78157
Cécile Dr DUJON, Dr, +33 01.39.63.88.88, cdujon@ght78sud.fr
CHU Lille - Service de pneumologie et d'oncologie thoracique
Lille, Nord, 59037
Arnaud SCHERPEREEL, Pr, +33 03.20.44.49.98, arnaud.scherpereel@chu-lille.fr
Hôpital Nord [AP-HM] - Service d'oncologie multidisciplinaire et innovations thérapeutiques
Marseille, Bouches-du-Rhône, 13915
Laurent GREILLIER, Pr, +33 04.91.96.59.01, laurent.greillier@ap-hm.fr
GHI Le Raincy Montfermeil - Service d'oncologie
Montfermeil, Seine-Saint-Denis, 93370
Thierry COLLON, Dr, +33 01.41.70.80.00, thierry.collon@ght-gpne.fr
Hôpital Cochin [AP-HP] - Service de pneumologie, Unité oncologie thoracique
Paris, Paris 14, 75014
Marie WISLEZ, Pr, +33 01.58.41.18.89, marie.wislez@aphp.fr
Hôpital Paris Saint Joseph - Service de pneumo-oncologie et d'allergologie
Paris, Paris 14, 75014
Charles NALTET, Dr, +33 01.44.12.37.52, cnaltet@ghpsj.fr
Hôpital Européen Georges Pompidou [APHP] - Service d'oncologie thoracique
Paris, Paris 15, 75015
Elizabeth FABRE, Dr, +33 01.56.09.53.71, elizabeth.fabre@aphp.fr
CHU de Rennes, Hôpital Pontchaillou - Service de pneumologie
Rennes, Ile-et-Vilaine, 35033
Léa HERVE, Dr, +33 02.99.28.37.38, herve.lena@chu.rennes.fr
Hôpital Foch - Service d'oncologie médicale
Suresnes, Hauts-de-Seine, 92150
CHITS Hôpital Sainte Musse
Toulon, Var, 83000
Clarisse AUDIGIER VALETTE, Dr, +33 04.94.14.56.10, Clarisse.audigier-valette@ch-toulon.fr
Hôpital Paul-Brousse [AP-HP] - Service d'oncologie digestive et médicale
Villejuif, Val-de-Marne, 94800
Pascal HAMMEL, Pr, +33 01.45.59.65.32, pascal.hammel@aphp.fr
Hôpital Gustave Roussy - Service d'oncologie médicale
Villejuif, Val-de-Marne, 94805
Benjamin BLESSE, Pr, +33 01.42.11.43.41, benjamin.besse@gustaveroussy.fr
About this study
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.
Read the detailed description
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.
- Conditions
- Metastasic NSCLC
- Being tested
- Randomization of chemoimmunotherapy hour administration, Questionnaires, Exploratory study 1 (facultative), Exploratory study 2 (facultative), Exploratory study 3 (facultative)
- Keywords
- Circadian rythm, Chronotherapy, Immunotherapy, NSCLC, Chemoimmunotherapy
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
Randomization of chemoimmunotherapy hour administrationOther
Main intervention. Chemoimmunitherapy used as standart care.
QuestionnairesOther
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
Exploratory study 1 (facultative)Other
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
Exploratory study 2 (facultative)Other
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
Exploratory study 3 (facultative)Other
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.
| Study group | Role | What they receive |
|---|---|---|
| Early time of administration | Experimental | Chemoimmunotherapy in the early time of administration group (9:00-12:00) Receives: Other: Randomization of chemoimmunotherapy hour administration; Other: Questionnaires; Other: Exploratory study 1 (facultative); Other: Exploratory study 2 (facultative); Other: Exploratory study 3 (facultative) |
| Late time of administration | Active comparator | Chemoimmunotherapy late time of administration group (13:00 - 17:00) Receives: Other: Randomization of chemoimmunotherapy hour administration; Other: Questionnaires; Other: Exploratory study 1 (facultative); Other: Exploratory study 2 (facultative); Other: Exploratory study 3 (facultative) |
What is being measured
The primary outcome is the main question the study is designed to answer.
Survival rate
Survival rate is defined as the survival probability at one year.
Measured: At one year (12 months)
Secondary outcomes (10)
Progression Free Survival (PFS)
PFS is defined as delay from randomisation until all-cause death or tumor progression whichever comes first
Measured: Until all-cause death or tumor progression (monitored throughout the 24 months of the patient's participation)
Overall Survival (OS)
Overall Survival (OS) defined as delay from randomisation until all-cause death.
Measured: from randomisation until all-cause death (monitored throughout the 24 months of the patient's participation)
Tumor respons
Best tumor response rate and early response rate according to RECIST criteria
Measured: Over 1 year, and early response rate at 6 weeks from randomisation
Safety
Adverse events categorized by severity and type, rated following CTCAE v.5.0
Measured: Up to two years (28 months)
Quality of Life Index 1
Quality of life according to the EQ-5D-5L test results
Measured: At the 16th cycle after randomization (48 weeks)
Quality of Life Index 2
Quality of life according to the EORTC QLQ C30 test results
Measured: At the 16h cycle after randomization (48 weeks)
Quality of sleep index
Quality of sleep according to the Pittsburgh test results
Measured: At the 16th cycle after randomization (48 weeks)
Chronotype assessment
Chronotype assesssments according to the Hörne-Ostberg test results
Measured: At the 8th cycle after randomization (24 weeks)
Cost-Utility
Health economics analysis, in particular through associated healthcare costs, additional GP or specialist consultations, and complementary treatments.
Measured: Up to two years (28 months)
Facultative Result (Exploratory study)
Optimal time of administration through mathematical modelling
Measured: Up to two years (28 months)
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted4 Nov 2026
- Study startDec 2026 (estimated)
- Primary completionJul 2028 (estimated)
- Study completionJul 2029 (estimated)
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Other trials for Metastasic NSCLCStudies of the same condition, open and under way.
- More trials run by Assistance Publique - Hôpitaux de ParisThe sponsor's other registered studies.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase 3
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- None (open label)
- Enrolment
- 254 participants (estimated)
Sponsor and investigators
- Lead sponsor
- Assistance Publique - Hôpitaux de Paris
- Sponsor type
- University, hospital or other
- Responsible party
- Sponsor
- Investigators
- Boris DUCHEMANN, Dr, Principal investigator, Research unit : CCT Chronothérapie, cancers et transplantation - Hospital Avicenne, Assistance publique des hôpitaux de Paris - Université Paris Saclay
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT07915037
- Sponsor's protocol ID
- APHP241011
- Other IDs
- 2025-521891-78-00, 2025
- Acronym
- IMMUNOTIME
- Status last verified
- Oct 2026
- First submitted
- 16 Oct 2026
- Last updated
- 4 Nov 2026
- Results posted
- No
- Data monitoring committee
- No
- FDA-regulated drug
- No
- FDA-regulated device
- No
- Individual data sharing
- Undecided
Study at a glance
From the registry record, last updated by the sponsor on 4 Nov 2026. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- 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
- ClinicalTrials.gov ID
- NCT07915037
- Acronym / sponsor ID
- IMMUNOTIME / APHP241011
- Conditions
- Metastasic NSCLC
- Keywords
- Circadian rythm, Chronotherapy, Immunotherapy, NSCLC, Chemoimmunotherapy
- Phase
- Phase 3
- Study type
- Interventional
- Recruitment status
- Not yet recruiting
- Enrolment
- 254 participants (estimated)
- Lead sponsor
- Assistance Publique - Hôpitaux de ParisUniversity, hospital or other
- Study start
- Dec 2026 (estimated)
- Primary completion
- Jul 2028 (estimated)
- Study completion
- Jul 2029 (estimated)
- First posted
- 4 Nov 2026 (actual)
- Results
- Not posted in the source record
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
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.
Detailed description
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.
Study design
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- None (open label)
- Number of arms
- 2
| Arm | Type | Receives |
|---|---|---|
| Early time of administration | Experimental | Other: Randomization of chemoimmunotherapy hour administration, Other: Questionnaires, Other: Exploratory study 1 (facultative), Other: Exploratory study 2 (facultative), Other: Exploratory study 3 (facultative)Chemoimmunotherapy in the early time of administration group (9:00-12:00) |
| Late time of administration | Active comparator | Other: Randomization of chemoimmunotherapy hour administration, Other: Questionnaires, Other: Exploratory study 1 (facultative), Other: Exploratory study 2 (facultative), Other: Exploratory study 3 (facultative)Chemoimmunotherapy late time of administration group (13:00 - 17:00) |
Who may qualify
- Ages
- 18 years and older
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Adult, Older adult
Key inclusion criteria (22 listed)
- 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.
Key exclusion criteria (34 listed)
- 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:
- 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.
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| Randomization of chemoimmunotherapy hour administrationMain intervention. Chemoimmunitherapy used as standart care. | Other | Early time of administration, Late time of administration |
| QuestionnairesQuestionnaires 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 | Other | Early time of administration, Late time of administration |
| 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 | Other | Early time of administration, Late time of administration |
| 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 | Other | Early time of administration, Late time of administration |
| 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. | Other | Early time of administration, Late time of administration |
Primary outcome
Survival rate
Time frame: At one year (12 months)
Survival rate is defined as the survival probability at one year.
10 secondary outcomes
Progression Free Survival (PFS)
Time frame: Until all-cause death or tumor progression (monitored throughout the 24 months of the patient's participation)
Overall Survival (OS)
Time frame: from randomisation until all-cause death (monitored throughout the 24 months of the patient's participation)
Tumor respons
Time frame: Over 1 year, and early response rate at 6 weeks from randomisation
Safety
Time frame: Up to two years (28 months)
Quality of Life Index 1
Time frame: At the 16th cycle after randomization (48 weeks)
Quality of Life Index 2
Time frame: At the 16h cycle after randomization (48 weeks)
Quality of sleep index
Time frame: At the 16th cycle after randomization (48 weeks)
Chronotype assessment
Time frame: At the 8th cycle after randomization (24 weeks)
Cost-Utility
Time frame: Up to two years (28 months)
Facultative Result (Exploratory study)
Time frame: Up to two years (28 months)
Results and safety
This study is still under way. Results are not available in the source record yet.
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 4 Nov 2026.
- Individual participant dataSharing planned: Undecided
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Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part.
Boris DUCHEMANN, Dr principal investigator
Research unit : CCT Chronothérapie, cancers et transplantation - Hospital Avicenne, Assistance publique des hôpitaux de Paris - Université Paris Saclay
20 sites in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A Phase 3 study testing Randomization of chemoimmunotherapy hour administration, Questionnaires and Exploratory study 1 (facultative) in people with Metastasic NSCLC, run by Assistance Publique - Hôpitaux de Paris at 20 sites in France.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 22 inclusion and 34 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: opening soon, as of the sponsor's last update on 4 Nov 2026. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 20 sites in France. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
What does this phase mean?
Phase 3 studies compare the treatment with the current standard treatment or a placebo in a large group, to confirm how well it works and watch for side effects.
Not every study follows the same path, and some studies (observational studies, device studies) have no phase.
Are results available for this study?
This study is still under way. Results are not available in the source record yet.
How can a doctor refer a patient or contact the research team?
Contact Boris DUCHEMANN, Dr (+33 01.48.95.50.33, boris.duchemann@aphp.fr), or a site near the patient. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
Survival rate (time frame: At one year (12 months)). It is what the study was designed to measure, not a finding.
Where can I read the original study information?
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 4 Nov 2026.