Clinical Trials Register

Summary
EudraCT Number:	2021-006795-16
Sponsor's Protocol Code Number:	2021-3336
National Competent Authority:	France - ANSM
Clinical Trial Type:	EEA CTA
Trial Status:	Trial now transitioned
Date on which this record was first entered in the EudraCT database:	2022-07-12
Trial results

Index
A. PROTOCOL INFORMATION
B. SPONSOR INFORMATION
C. APPLICANT IDENTIFICATION
D. IMP IDENTIFICATION
D.8 INFORMATION ON PLACEBO
E. GENERAL INFORMATION ON THE TRIAL
F. POPULATION OF TRIAL SUBJECTS
G. INVESTIGATOR NETWORKS TO BE INVOLVED IN THE TRIAL
N. REVIEW BY THE COMPETENT AUTHORITY OR ETHICS COMMITTEE IN THE COUNTRY CONCERNED
P. END OF TRIAL

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A. Protocol Information

A.1

Member State Concerned

France - ANSM

A.2

EudraCT number

2021-006795-16

A.3

Full title of the trial

Maintenance Pembrolizumab at Usual or Low doSE in non-squamous lung cancer: a non-inferiority study- PULSE

A.3.1

Title of the trial for lay people, in easily understood, i.e. non-technical, language

PULSE: Pembrolizumab en maintenance à dose conventionnelle ou adaptée dans le cancer bronchique non à petites cellules : une étude de non infériorité

A.3.2

Name or abbreviated title of the trial where available

PULSE

A.4.1

Sponsor's protocol code number

2021-3336

A.7

Trial is part of a Paediatric Investigation Plan

A.8

EMA Decision number of Paediatric Investigation Plan

B. Sponsor Information
B.Sponsor: 1
B.1.1	Name of Sponsor	GUSTAVE ROUSSY
B.1.3.4	Country	France
B.3.1 and B.3.2	Status of the sponsor	Non-Commercial
B.4 Source(s) of Monetary or Material Support for the clinical trial:
B.4.1	Name of organisation providing support	Gustave Roussy
B.4.2	Country	France
B.5 Contact point designated by the sponsor for further information on the trial
B.5.1	Name of organisation	Gustave ROUSSY
B.5.2	Functional name of contact point	Aqsa YAR
B.5.3	Address:
B.5.3.1	Street Address	114, rue Edouard Vaillant
B.5.3.2	Town/ city	Villejuif
B.5.3.3	Post code	94805
B.5.3.4	Country	France
B.5.4	Telephone number	330142116717
B.5.5	Fax number	330142116290
B.5.6	E-mail	aqsa.yar@gustaveroussy.fr

D. IMP Identification
D.IMP: 1
D.1.2 and D.1.3	IMP Role	Test
D.2	Status of the IMP to be used in the clinical trial
D.2.1	IMP to be used in the trial has a marketing authorisation	Yes
D.2.1.1.1	Trade name	KEYTRUDA 50 mg - Powder for concentrate for solution for infusion
D.2.1.1.2	Name of the Marketing Authorisation holder	Merck Sharp & Dohme B.V. Waarderweg 39 2031 BN Haarlem Pays-Bas
D.2.5	The IMP has been designated in this indication as an orphan drug in the Community	No
D.2.5.1	Orphan drug designation number
D.3 Description of the IMP
D.3.1	Product name	Keytruda 50 mg- Powder for concentrate for solution for infusion
D.3.4	Pharmaceutical form	Powder for concentrate for solution for infusion
D.3.4.1	Specific paediatric formulation	No
D.3.7	Routes of administration for this IMP	Intravenous use
D.3.11 The IMP contains an:
D.3.11.1	Active substance of chemical origin	No
D.3.11.2	Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP)	Yes
	The IMP is a:
D.3.11.3	Advanced Therapy IMP (ATIMP)	No
D.3.11.3.1	Somatic cell therapy medicinal product	No
D.3.11.3.2	Gene therapy medical product	No
D.3.11.3.3	Tissue Engineered Product	No
D.3.11.3.4	Combination ATIMP (i.e. one involving a medical device)	No
D.3.11.3.5	Committee on Advanced therapies (CAT) has issued a classification for this product	No
D.3.11.4	Combination product that includes a device, but does not involve an Advanced Therapy	No
D.3.11.5	Radiopharmaceutical medicinal product	No
D.3.11.6	Immunological medicinal product (such as vaccine, allergen, immune serum)	No
D.3.11.7	Plasma derived medicinal product	No
D.3.11.8	Extractive medicinal product	No
D.3.11.9	Recombinant medicinal product	No
D.3.11.10	Medicinal product containing genetically modified organisms	No
D.3.11.11	Herbal medicinal product	No
D.3.11.12	Homeopathic medicinal product	No
D.3.11.13	Another type of medicinal product	No

D.8 Information on Placebo

E. General Information on the Trial

E.1 Medical condition or disease under investigation

E.1.1

Medical condition(s) being investigated

Maintenance treatment in metastatic non-squamous lung cancer

E.1.1.1

Medical condition in easily understood language

Maintenance treatment in metastatic non-squamous lung cancer

E.1.1.2

Therapeutic area

Diseases [C] - Cancer [C04]

MedDRA Classification

E.1.3

Condition being studied is a rare disease

E.2 Objective of the trial

E.2.1

Main objective of the trial

To assess the non-inferiority on overall survival (OS) of a reduced dose intensity of pembrolizumab (PULSE dose, 200 mg every 6 weeks) compared with conventional schedule (200mg every 3 weeks or 400mg every 6 weeks) in combination with pemetrexed as maintenance treatment.

E.2.2

Secondary objectives of the trial

To compare the progression-free survival between both treatment arms
To compare duration of response between both treatment arms
To compare treatment duration between both treatment arms
To compare quality of life between both treatment arms
To assess and compare treatment tolerance in both treatment arms
To assess the cost-effectiveness and potential savings associated with the pulse modality of administration
To perform a pharmacokinetic analysis in both arms (i.e. dosage of pembrolizumab in the plasma)
To evaluate the target engagement (i.e. saturation of PD-1 on circulating lymphocytes) in both arms.
Exploratory objective:
To assess the survival outcome (PFS, OS) according to PD-L1 expression
(...)
To allow a molecular analysis of the primary tumor (treatment-naive) to improve their post-progression clinical management.

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

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
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.Age ≥ 18 years old.
8.Patients with baseline brain metastases will be eligible in case of stability or no evidence of progression and if they remain clinically stable.
9.Performance status 0 or 1
10.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 pembrolizuamb.
*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.
11.Neutrophils ≥ 1500/µL and platelets ≥ 100 000/µL
12.Bilirubin ≤ 1.5 upper limit normal (ULN)
13.Transaminases, Alkaline phosphatase ≤ 2.5 x the ULN except in case of liver metastases (5 x ULN).
14.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.
15.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.
16.Signed informed consent.
17.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.
18.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.
20.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.
21.Patient affiliated to a social security system or beneficiary of the same

E.4

Principal exclusion criteria

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. Active or uncontrolled infection.
5.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
6.Concomitant treatment with another experimental treatment or participation in another clinical trial.
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.. 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.. History of HIV or chronic hepatitis B or C. (not needed a second time if already cheked before induction phase).
12.Active or uncontrolled infection.

E.5 End points

E.5.1

Primary end point(s)

Overall survival is defined as the time elapsed between the date of randomization and the date of death whatever the cause. Patients alive at the date of last follow-up will be censored at that date.

E.5.2

Secondary end point(s)

Progression-free survival (PFS) between both treatment arms.
Duration of response between both treatment arms.
Quality of life between both treatment arms.
Treatment tolerance in both treatment arms.
Cost-effectiveness and potential savings associated with the PULSE modality of administration.
Pharmacokinetic analysis in both arms.
Evaluate the target saturation and engagement in both arms.
Exploratory objective:
PFS, OS according to PD-L1 expression.
PFS, OS according to dynamic evolution of circulating tumor DNA.
PFS, OS according to the occurrence of antidrug-antibodies (ADA).
PFS, OS according to the Lung Immune Prognostic Index (LIPI)-score.
PFS, OS according to the administration or not of pemetrexed

E.6 and E.7 Scope of the trial

E.6

Scope of the trial

E.6.1

Diagnosis

E.6.2

Prophylaxis

E.6.3

Therapy

Yes

E.6.4

Safety

E.6.5

Efficacy

E.6.6

Pharmacokinetic

E.6.7

Pharmacodynamic

E.6.8

Bioequivalence

E.6.9

Dose response

E.6.10

Pharmacogenetic

E.6.11

Pharmacogenomic

E.6.12

Pharmacoeconomic

E.6.13

Others

E.7

Trial type and phase

E.7.1

Human pharmacology (Phase I)

E.7.1.1

First administration to humans

E.7.1.2

Bioequivalence study

E.7.1.3

Other

E.7.1.3.1

Other trial type description

E.7.2

Therapeutic exploratory (Phase II)

E.7.3

Therapeutic confirmatory (Phase III)

Yes

E.7.4

Therapeutic use (Phase IV)

E.8 Design of the trial

E.8.1

Controlled

E.8.1.1

Randomised

Yes

E.8.1.2

Open

E.8.1.3

Single blind

E.8.1.4

Double blind

E.8.1.5

Parallel group

E.8.1.6

Cross over

E.8.1.7

Other

Yes

E.8.1.7.1

Other trial design description

non-inferiority

E.8.2

Comparator of controlled trial

E.8.2.1

Other medicinal product(s)

E.8.2.2

Placebo

E.8.2.3

Other

E.8.2.4

Number of treatment arms in the trial

E.8.3

The trial involves single site in the Member State concerned

E.8.4

The trial involves multiple sites in the Member State concerned

Yes

E.8.4.1

Number of sites anticipated in Member State concerned

E.8.5

The trial involves multiple Member States

E.8.6 Trial involving sites outside the EEA

E.8.6.1

Trial being conducted both within and outside the EEA

E.8.6.2

Trial being conducted completely outside of the EEA

E.8.7

Trial has a data monitoring committee

Yes

E.8.8

Definition of the end of the trial and justification where it is not the last visit of the last subject undergoing the trial

LVLS

E.8.9 Initial estimate of the duration of the trial

E.8.9.1

In the Member State concerned years

E.8.9.1

In the Member State concerned months

E.8.9.1

In the Member State concerned days

E.8.9.2

In all countries concerned by the trial years

F. Population of Trial Subjects

F.1 Age Range

F.1.1

Trial has subjects under 18

F.1.1.1

In Utero

F.1.1.2

Preterm newborn infants (up to gestational age < 37 weeks)

F.1.1.3

Newborns (0-27 days)

F.1.1.4

Infants and toddlers (28 days-23 months)

F.1.1.5

Children (2-11years)

F.1.1.6

Adolescents (12-17 years)

F.1.2

Adults (18-64 years)

Yes

F.1.2.1

Number of subjects for this age range:

583

F.1.3

Elderly (>=65 years)

Yes

F.1.3.1

Number of subjects for this age range:

583

F.2 Gender

F.2.1

Female

Yes

F.2.2

Male

Yes

F.3 Group of trial subjects

F.3.1

Healthy volunteers

F.3.2

Patients

Yes

F.3.3

Specific vulnerable populations

Yes

F.3.3.1

Women of childbearing potential not using contraception

F.3.3.2

Women of child-bearing potential using contraception

Yes

F.3.3.3

Pregnant women

F.3.3.4

Nursing women

F.3.3.5

Emergency situation

F.3.3.6

Subjects incapable of giving consent personally

F.3.3.6.1

Details of subjects incapable of giving consent

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 (..) medication.

F.3.3.7

Others

F.4 Planned number of subjects to be included

F.4.1

In the member state

1166

F.4.2

For a multinational trial

F.4.2.1

In the EEA

1166

F.4.2.2

In the whole clinical trial

1166

F.5

Plans for treatment or care after the subject has ended the participation in the trial (if it is different from the expected normal treatment of that condition)

NONE

G. Investigator Networks to be involved in the Trial

N. Review by the Competent Authority or Ethics Committee in the country concerned

Competent Authority Decision

Authorised

Date of Competent Authority Decision

2022-11-18

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2022-09-12

P. End of Trial
P.	End of Trial Status	Trial now transitioned

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