Clinical trial NCT05692999: Maintenance Pembrolizumab at Usual or Low doSE in Non-squamous Lung Cancer: a Non-inferiority Study
Official title: Maintenance Pembrolizumab at Usual or Low doSE in Non-squamous Lung Cancer: a Non-inferiority Study
Study type: INTERVENTIONAL
Overall status: RECRUITING
Phase: PHASE3
Conditions: Metastatic Non-squamous Lung Cancer
Lead sponsor: Gustave Roussy, Cancer Campus, Grand Paris
Sponsor class: OTHER
First posted: 2023-01-20
Enrollment: 1166
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: Pulse is a randomized non-inferiority phase III clinical trial assessing a new mode of immunotherapy administration based on increased interval time between 2 infusions as maintenance treatment in Pulse arm compared with the conventional administration in Control arm.

In both treatment arms, pembrolizumab alone or combined with pemetrexed is allowed as maintenance treatment. Indeed :

In Pulse arm : Pembrolizumab 200 mg will be administered to patients every 6 weeks (Q6W) plus, in the absence of contra-indication pemetrexed 500 mg/m\^2 will be administered every 3 weeks (Q3W).

In control arm : Pembrolizumab 200 mg will be administered to patients every 3 weeks (Q3W) or 400 mg every 6 weeks plus,in the absence of contra-indication pemetrexed 500 mg/m\^2 will be administered every 3 weeks (Q3W).


Eligibility criteria: Inclusion Criteria:

A) To be checked before the induction phase (only for patient included before induction phase) :

1. Histologically or cytologically confirmed diagnosis of non-squamous non-small cell lung cancer (NSCLC).
2. Non-operable / non-irradiable stage III or stage IV.
3. Patient must be eligible to receive 3 or 4 cycles of induction treatment combination with pembrolizumab plus platinum (cisplatin or carboplatin) and pemetrexed.
4. In the presence of an EGFR mutation, an ALK or ROS1 rearrangement the patient must have received at least one specific targeted therapy line.
5. Age ≥ 18 years old.
6. Performance status 0 or 1.
7. Signed informed consent.
8. Patient affiliated to a social security system or beneficiary of the same.

B) To be checked before the maintenance phase (for all patient) :

1. Histologically or cytologically confirmed diagnosis of non-squamous non-small cell lung cancer (NSCLC).
2. Non-operable / non-irradiable stage III or stage IV.
3. Received 3 or 4 cycles of induction treatment combination with pembrolizumab plus platinum (cisplatin or carboplatin) and pemetrexed.
4. Patient must be eligible to receive maintenance pembrolizumab with or without pemetrexed, last induction chemotherapy cycle within 42 days before randomization.
5. Stable disease, partial or complete response according to RECIST 1.1 criteria after induction chemotherapy and pembrolizumab. Targets lesions are not required before randomization.
6. In the presence of an EGFR mutation, an ALK or ROS1 rearrangement the patient must have received at least one specific targeted therapy line (not needed a second time if already checked before induction phase).
7. Patients with baseline brain metastases will be eligible in case of stability or no evidence of progression and if they remain clinically stable.
8. Age ≥ 18 years old.
9. Performance status 0 or 1.
10. Signed informed consent (only for patient included after induction phase).
11. Patient affiliated to a social security system or beneficiary of the same.
12. Creatinine clearance \> 30 ml/min by Cockcroft-Gault\* or MDRD in case that patient will start maintenance just with pembrolizumab but ≥ 45 ml/min if the patient will receive pemetrexed plus pembrolizumab.

    \*Cockcroft- Gault Formula:
    * Female CrCl = \[(140 - age in years) x weight in kg x 0.85\] / 72 x serum creatinine in mg/dL;
    * Male CrCl = \[(140 - age in years) x weight in kg x 1.00\] /72 x serum creatinine in mg/dL.
13. Neutrophils ≥ 1500/μL and platelets ≥ 100 000/μL.
14. Bilirubin ≤ 1.5 upper limit normal (ULN).
15. Transaminases, Alkaline phosphatase ≤ 2.5 x the ULN except in case of liver metastases (5 x ULN).
16. Patients might have received platinum-based chemotherapy as an adjuvant or neoadjuvant treatment, or with radiotherapy for a localized lung cancer, provided that the chemotherapy was ended more than 6 months before the first cycle of induction chemotherapy.
17. Patients might have received previous immune checkpoint inhibitors as an adjuvant or neoadjuvant treatment, or as a consolidation treatment after radiotherapy for a localized lung cancer, but the immune checkpoint inhibitors must be finished at least than 12 months before the first cycle of induction chemotherapy for advanced stage.
18. A woman is eligible for the study if she is no longer likely to procreate (physiologically unfit to carry out a pregnancy), which includes women who have had: a hysterectomy, an oophorectomy, a bilateral tubal ligation.

    Post-menopausal women:
    * Patients not using hormone replacement therapy should have had a complete cessation of menstruation for at least one year and be over 40 years of age, or, if in doubt, have an FSH (Follicle Stimulating Hormone) level \> 40 mIU/mL and an estradiol level \< 40 pg/mL (\< 150 pmol/L).
    * Patients using hormone replacement therapy must have had a complete cessation of menstruation for at least one year and be over 45 years of age or have evidence of menopause (FSH and estradiol levels) before starting hormone replacement therapy.
19. Women who are likely to procreate are eligible if they have a negative serum pregnancy test in the week before the first dose of treatment and preferably as close as possible to the first dose and if they agree to use an effective contraceptive method during the course of the study through 4 months after the last dose of study medication.

Sexually active males patients must agree to use condom during the study and for at least 4 months after the last study treatment administration. Also, it is recommended their women of childbearing potential partner use a highly effective method of contraception.

Exclusion Criteria:

A) To be checked before the induction phase (only for patient included before induction phase) :

1. Mixed small-cell, squamous-cell carcinoma.
2. Mental or psychological illness that does not allow the patient to give informed consent.
3. Pregnant or breastfeeding women.
4. History of HIV or chronic hepatitis B or C.
5. Active or uncontrolled infection.
6. History of one or more of the following cardiovascular disorders in the previous 6 months:

   * Coronary artery bypass or peripheral arterial bypass, cardiac angioplasty or stent.
   * Myocardial infarction
   * Severe or unstable angina pectoris
   * Peripheral vascular disease, pulmonary embolism or untreated thromboembolic events, stroke or transient ischemic attack. Note: Patients with recent deep vein thrombosis (including pulmonary embolism) treated with anticoagulant for at least 4 weeks and clinically stable are eligible.
   * Congestive heart failure class III or IV as defined by the NYHA
7. Concomitant treatment with another experimental treatment or participation in another clinical trial.

B) To be checked before the maintenance phase (for all patient) :

1. Presence of grade 3 or 4 toxicity related to pembrolizumab limiting maintenance treatment continuation.
2. Mixed small-cell, squamous-cell carcinoma.
3. Corticosteroids at a dose greater than 20 mg per day of prednisone or equivalent.
4. Patient unable to follow the therapeutic program.
5. Mental or psychological illness that does not allow the patient to give informed consent.
6. Pregnant or breastfeeding women.
7. Ongoing immunosuppressive systemic therapy (cyclophosphamide, aziatropin, methotrexate, thalidomide and anti-TNF).
8. Active autoimmune diseases. History of autoimmune diseases including myasthenia gravis, lupus erythematosus, rheumatoid arthritis, irritable bowel syndrome, vascular thrombosis associated with antiphospholipid syndrome, Wegener's granulomatosis, Sjögren's syndrome, Guillain-Barré syndrome, multiple sclerosis, vasculitis or glomerulonephritis. Patients with a history of autoimmune hypothyroidism treated with a stable dose of hormone replacement therapy are eligible. Patients with diabetes treated with insulin are eligible.
9. History of idiopathic pulmonary fibrosis, organized pneumonia (i.e., obliterating bronchiolitis), drug-induced lung disease or active signs of pneumonia, pulmonary infiltration (regardless of cause) detected on the baseline chest CT-scan.
10. History of any other hematologic or primary solid tumor malignancy unless in remission for at least 2 years and without specific treatment (as example, not allowed hormonal therapy to replace for breast cancer or hormonal therapy substitution in prostate cancer). pT1-2 prostatic cancer Gleason score \< 6, superficial bladder cancer, non-melanoma skin cancer or carcinoma in situ of the cervix are allowed.
11. Presence of a condition or condition that makes patient participation in the study inappropriate, including serious unresolved or unstable toxicities from previous administration of another experimental treatment or any medical condition that could interfere with patient safety, obtaining consent or compliance with study procedures.
12. Administration of a live attenuated vaccine within the 4 weeks before day 1 of Cycle 1 or administration of a live attenuated vaccine planned for the duration of the study. The flu vaccine can be given during the flu season (approximately from October to May). Patients should not receive a live attenuated influenza vaccine during the 4 weeks preceding day 1 of Cycle 1 and should not receive this type of vaccine during the study.
13. History of HIV or chronic hepatitis B or C (not needed a second time if already checked before induction phase).
14. Active or uncontrolled infection.
15. History of one or more of the following cardiovascular disorders in the previous 6 months:

    * Coronary artery bypass or peripheral arterial bypass, cardiac angioplasty or stent.
    * Myocardial infarction
    * Severe or unstable angina pectoris
    * Peripheral vascular disease, pulmonary embolism or untreated thromboembolic events, stroke or transient ischemic attack. Note: Patients with recent deep vein thrombosis (including pulmonary embolism) treated with anticoagulant for at least 4 weeks and clinically stable are eligible.
    * Congestive heart failure class III or IV as defined by the NYHA
16. Concomitant treatment with another experimental treatment or participation in another clinical trial.

Primary outcomes:
measure: Overall survival
timeFrame: 6 years
Secondary outcomes:
measure: Progression-free survival
timeFrame: 6 years
measure: Duration of response between both treatment arms.
timeFrame: 6 years
measure: Assessment of quality of life between both treatment arms via the EORTC QLQ-C30 questionnaire.
timeFrame: 6 years
measure: Assessment of quality of life between both treatment arms via the EORTC QLQ-LC13 questionnaire.
timeFrame: 6 years
measure: Assessment of quality of life between both treatment arms via the EQ-5D-5L questionnaire.
timeFrame: 6 years
measure: Treatment tolerance in both treatment arms
timeFrame: 6 years
measure: Economic evaluation
timeFrame: 6 years
measure: Population pharmacokinetic analysis in both arms (primary objective)
timeFrame: 6 years
measure: Population pharmacokinetic analysis in both arms (secondary objective)
timeFrame: 6 years
measure: Evaluate the saturation of PD-1 on circulating lymphocytes in both arms
timeFrame: 6 years
measure: Evaluate the target engagement pharmacodynamics (PD) in both arms
timeFrame: 6 years
Other outcomes:
Locations:
city: Carcassonne
country: France
facility: Centre Hospitalier de Carcassonne
state: Aude
city: Strasbourg
country: France
facility: Clinique Sainte Anne - Strasbourg
state: Bas-Rhin
city: Strasbourg
country: France
facility: Institut de Cancérologie Strasbourg Europe (ICANS)
state: Bas-Rhin
city: Marseille
country: France
facility: Hôpital Européen de Marseille
state: Bouches-du-Rhône
city: La Rochelle
country: France
facility: Groupe Hospitalier La Rochelle
state: Charente-Maritime
city: Brest
country: France
facility: Centre Hospitalier Régional Universitaire de Brest (Hôpital Morvan)
state: Finistère
city: Morlaix
country: France
facility: Centre Hospitalier des Pays de Morlaix
state: Finistère
city: Mulhouse
country: France
facility: Groupe Hospitalier de la Région de Mulhouse et Sud Alsace
state: Haut-Rhin
city: Tarbes
country: France
facility: Centre Hospitalier de Bigorre
state: Hautes-Pyrénées
city: Suresnes
country: France
facility: Hôpital Foch
state: Hauts-de-Seine
city: Béziers
country: France
facility: Centre Hospitalier de Béziers
state: Hérault
city: Rennes
country: France
facility: CHU Rennes
state: Ille-et-Vilaine
city: Saint-Malo
country: France
facility: Centre Hospitalier de Saint-Malo
state: Ille-et-Vilaine
city: Tours
country: France
facility: Centre Hospitalier Régional Universitaire de Tours
state: Indre-et-Loire
city: Saint-Denis
country: France
facility: Centre Hospitalier Universitaire - La Réunion - Site Felix Guyon
state: La Réunion
city: Saint-Pierre
country: France
facility: Centre Hospitalier Universitaire - La Réunion - Site Sud
state: La Réunion
city: Orléans
country: France
facility: Centre Hospitalier Régional d'Orléans - NHO
state: Loiret
city: Saint Priest en Jarez
country: France
facility: CHU St-Etienne
state: Loire
city: Bron
country: France
facility: Hospices Civils de Lyon - Hôpital Louis Pradel
state: Lyon
city: Cholet
country: France
facility: Centre Hospitalier de Cholet
state: Maine-et-Loire
city: Compiègne
country: France
facility: Centre Hospitalier Intercommunal de Compiègne-Noyon
state: Oise
city: Bayonne
country: France
facility: Centre Hospitalier de la Côte Basque
state: Pyrénées-Atlantiques
city: Créteil
country: France
facility: Centre Hospitalier Intercommunal Créteil
state: Val-de-Marne
city: Saint-Mandé
country: France
facility: Hôpital d'Instruction des Armées Bégin
state: Val-de-Marne
city: Villejuif
country: France
facility: Institut Gustave Roussy
state: Val-de-Marne
city: Auxerre
country: France
facility: Centre Hospitalier d'Auxerre
state: Yonne
city: Paris
country: France
facility: Hôpital Pitié-Salpêtrière - APHP
city: Paris
country: France
facility: Hôpital Cochin - APHP
city: Paris
country: France
facility: Hôpital Tenon - APHP
city: Paris
country: France
facility: Hôpital Paris Saint-Joseph
Study officials:
affiliation: Gustave Roussy, Cancer Campus, Grand Paris
name: Benjamin BESSE
role: PRINCIPAL_INVESTIGATOR
References: