Impact of the timing of immunotherapy administration in metastatic lung cancers

Overview

Sponsor-declared trial summary

Key facts

Sponsor

Assistance Publique Hopitaux De Paris

Participant type

Patients

Age range

18-64 years, 65+ years

Gender

Male and Female

Therapeutic area

Diseases [C] - Neoplasms [C04]

Decision date (initial)

2026-05-12

Transition trial

No

Low-intervention

Yes

Rare-disease indication

No

Vulnerable population

No

Funding sources

French Ministry of Health · ARC Foundation

Trial design

CTIS Part I — objectives, methods, condition coding

Main objective

Scope: Efficacy

To assess the efficacy of starting pembrolizumab administration in the morning (08:00 to 12:00) versus in the afternoon (13:00-17:00) on 1-year survival rate.

Secondary objectives 11

1. To compare the early part of the day dosing group with the late part of the day dosing group on Progression-free survival (PFS)
2. To compare the early part of the day dosing group with the late part of the day dosing group on Overall survival (OS)
3. To compare the early part of the day dosing group with the late part of the day dosing group on best tumor response rate, up to 1 year follow-up
4. To compare the early part of the day dosing group with the late part of the day dosing group on early tumor response rate
5. To compare the early part of the day dosing group with the late part of the day dosing group on Time to treatment discontinuation (TTD) (and cause of treatment withdrawal)
6. To compare the early part of the day dosing group with the late part of the day dosing group on Percentages of worst toxicity grades per toxicity category and per patient, with time to reach them, both over 1 year, and up to 2 years
7. To compare the early part of the day dosing group with the late part of the day dosing group on Quality of life measured every 4 courses up to 1 year
8. To compare the early part of the day dosing group with the late part of the day dosing group on Quality of sleep measured every 4 courses, up to 1 year
9. To compare the early part of the day dosing group with the late part of the day dosing group on Chronotype measured at baseline, and at courses 4th and 8th
10. To explore Optimal time of administration through mathematical modelling
11. To evaluate Cost-utility

Conditions and MedDRA coding

Adult patients with stage IV non squamous non-small cell lung cancer (NSCLC)

Eligibility criteria

Principal inclusion / exclusion criteria as submitted by sponsor

Inclusion criteria 13

1. Patient with a histologically-confirmed or cytologically confirmed diagnosis of stage IV (M1a or M1b- AJCC 7th edition) non-squamous NSCLC.
2. Patient with a 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. Patient with a measurable disease based on RECIST 1.1 as determined by the local site investigator/radiology assessment
4. Patient who 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. Patient who 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. Patient ≥18 years of age on the day of signing informed consent.
7. Patient with a life expectancy of at least 3 months.
8. Patient with a performance status of 0 or 1 on the Eastern Cooperative Oncology Group (ECOG) Performance Status.
9. Patient who have adequate organ function (CBC, liver and kidney)
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.
11. If male subject with a female partner(s) of child-bearing potential, must agree to use an adequate method of contraception.
12. Patient who has voluntarily agreed to participate by giving written informed consent for the trial.
13. Patient with an affiliation to French social security system

Exclusion criteria 28

1. Patient with predominantly squamous cell histology NSCLC.
2. Patient who 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: a) Patient Has received prior systemic cytotoxic chemotherapy for metastatic disease b) Patient Has received antineoplastic biological therapy (e.g., erlotinib, crizotinib, cetuximab) c) Patient Had major surgery ( 30 Gy within 6 months of the first dose of trial treatment.
4. Patient who received radiation therapy to the lung that is > 30 Gy within 6 months of the first dose of trial treatment
5. Patient who completed palliative radiotherapy within 7 days of the first dose of trial treatment.
6. Patient who is expected to require any other form of antineoplastic therapy while on study.
7. Patient who has received a live-virus vaccination within 30 days of planned treatment start.
8. Patient who has clinically active diverticulitis, intra-abdominal abscess, GI obstruction, abdominal carcinomatosis.
9. Patient who 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.
10. Patient who has known active central nervous system (CNS) metastases and/or carcinomatous meningitis.
11. Patient who previously had a severe hypersensitivity reaction to treatment with another mAb.
12. Patient who has a known sensitivity to any component of carboplatin or pemetrexed
13. Patient with Contraindication to investigational medicinal products or to auxiliary medicinal products
14. Patient who 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).
15. Patient who 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. Patient who 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 long-acting agents, such as piroxicam).
17. Patient who is unable or unwilling to take folic acid or vitamin B12 supplementation.
18. Patient who 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.
19. Patient who has an active infection requiring therapy.
20. Patient who has known history of Human Immunodeficiency Virus (HIV) (known HIV 1/2 antibodies positive).
21. Patient who has known active Hepatitis B or C.
22. Patient who 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. Patient who has known psychiatric or substance abuse disorder that would interfere with cooperation with the requirements of the trial.
24. Patient who has interstitial lung disease or a history of pneumonitis that required oral or intravenous glucocorticoids to assist with management.
25. Patient who 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

Endpoints

Primary and secondary outcome measures (English text)

Primary endpoints 1

1. The main endpoint will be 1-year milestone survival rate, defined as the survival probability at one year

Secondary endpoints 11

1. PFS defined as delay from randomisation until all-cause death or tumor progression whichever comes first.
2. OS defined as delay from randomisation until all-cause death.
3. Best tumor response rate according to RECIST criteria (assessed with TAP/brain scan and/or PET scan and/or MRI over 1 year).
4. Early response rate according to RECIST criteria (assessed with TAP/brain scan and/or PET scan and/or MRI) at the first evaluation (i.e. usually at 6 weeks).
5. Time to treatment discontinuation (TTD) as the delay from randomization until treatment stop irrespective of cause (progression, toxicities, loss of follow up, refusal, end of protocol or death).
6. Adverse events categorized by severity and type (grade 1, 2, 3, 4, or 5 according to CTCAE v5.0 criteria).
7. Self-assessment of quality of life measured using EQ-5D-5L and EORTC-QLQ C30 at baseline and every 4 courses up to 1 year (C4, C8, C12, C16).
8. Quality of sleep measured using Pittsburgh questionnaire and assessed at baseline and every 4 courses of treatment up to 1 year(C4, C8, C12, C16).
9. Chronotype measured using Horne-Ostberg questionnaire and assessed at baseline, and at courses 4 and 8 (C4 and C8).
10. Analysis of PFS/OS as a function of the real time of pembrolizumab infusion start, taken as a continuous variable
11. Incremental cost-utility ratio is calculated as Δ costs (between arms) / Δ QALYs (between arms)

Investigational products

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

Test 3

Sponsors and contacts

Sponsor organisations, regulatory contacts, third parties

Assistance Publique Hopitaux De Paris

Sponsor organisation

Assistance Publique Hopitaux De Paris

Address

Porte 23, 1 Avenue Claude Vellefaux 1 Avenue Claude Vellefaux

City

Paris Cedex 10

Postcode

75475

Country

France

Scientific contact point

Organisation

Assistance Publique Hopitaux De Paris

Contact name

Boris Duchemann

Public contact point

Organisation

Assistance Publique Hopitaux De Paris

Contact name

Boris Duchemann

Locations

1 EU/EEA country · 20 investigational sites

By country

Investigational sites

Results and documents

Annex IV summary of results, Annex V layperson summary, and all documents registered in CTIS for this trial

Documents 19 files

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

Application history

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