Clinical Trials Register

Summary
EudraCT Number:	2020-004052-15
Sponsor's Protocol Code Number:	202000570
National Competent Authority:	Netherlands - Competent Authority
Clinical Trial Type:	EEA CTA
Trial Status:	Ongoing
Date on which this record was first entered in the EudraCT database:	2020-12-21
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

Netherlands - Competent Authority

A.2

EudraCT number

2020-004052-15

A.3

Full title of the trial

ImmunoPET imaging with 89Zr-DFO-REGN3767 in patients with advanced solid cancer prior to and during treatment with cemiplimab with or without platinum-based chemotherapy

A.3.1

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

ImmunoPET imaging with 89Zr-DFO-REGN3767 in patients with advanced solid cancer prior to and during treatment with cemiplimab with or without platinum-based chemotherapy

A.3.2

Name or abbreviated title of the trial where available

LAG3 PET imaging in advanced solid tumors

A.4.1

Sponsor's protocol code number

202000570

A.5.2

US NCT (ClinicalTrials.gov registry) number

NCT03005782

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	University Medical Center Groningen
B.1.3.4	Country	Netherlands
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	Regeneron Pharmaceuticals, Inc.
B.4.2	Country	United States
B.5 Contact point designated by the sponsor for further information on the trial
B.5.1	Name of organisation	University Medical Center Groningen
B.5.2	Functional name of contact point	Researchcoordinator Med. Oncology
B.5.3	Address:
B.5.3.1	Street Address	Hanzeplein 1
B.5.3.2	Town/ city	Groningen
B.5.3.3	Post code	9713 GZ
B.5.3.4	Country	Netherlands
B.5.4	Telephone number	+31503611847
B.5.5	Fax number	+31503614862
B.5.6	E-mail	researchcoordinator@onco.umcg.nl

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	No
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	89Zr-DFO-REGN3767
D.3.4	Pharmaceutical form	Solution for injection
D.3.4.1	Specific paediatric formulation	No
D.3.7	Routes of administration for this IMP	Intravenous use
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	89Zr-DFO-REGN3767
D.3.9.3	Other descriptive name	REGN3767
D.3.9.4	EV Substance Code	SUB184508
D.3.10	Strength
D.3.10.1	Concentration unit	MBq megabecquerel(s)
D.3.10.2	Concentration type	equal
D.3.10.3	Concentration number	37
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	Yes
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.IMP: 2
D.1.2 and D.1.3	IMP Role	Comparator
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	Libtayo
D.2.1.1.2	Name of the Marketing Authorisation holder	Regeneron Pharmaceuticals, Inc.
D.2.1.2	Country which granted the Marketing Authorisation	Netherlands
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	Libtayo
D.3.4	Pharmaceutical form	Concentrate 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.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	CEMIPLIMAB
D.3.9.3	Other descriptive name	Libtayo
D.3.9.4	EV Substance Code	SUB189482
D.3.10	Strength
D.3.10.1	Concentration unit	mg milligram(s)
D.3.10.2	Concentration type	equal
D.3.10.3	Concentration number	350
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)	Yes
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

Patients with metastatic solid tumors, where clinical data has shown a rationale for ICI therapy with or without platinum-based chemotherapy, will be included in this study.

E.1.1.1

Medical condition in easily understood language

metastatic solid tumors

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 determine the optimal 89Zr-DFO-REGN3767 dose and optimal PET imaging timepoint.
• To evaluate the PK of 89Zr-DFO-REGN3767 by measuring SUV on 89Zr-DFO-REGN3767 PET scans in patients with histologically or cytologically documented locally advanced or metastatic solid tumors who based on available clinical data may benefit from treatment with cemiplimab +/- platinum-based chemotherapy.
• To evaluate safety of 89Zr-DFO-REGN3767.

E.2.2

Secondary objectives of the trial

Secondary objectives:
• To assess the heterogeneity of 89Zr-DFO-REGN3767 antibody tumor uptake within a lesion and between lesions
• To correlate tumor tracer uptake with tumor and immune cell LAG3 expression as assessed by biopsy.
• To correlate the tumor tracer uptake with response to cemiplimab with or without platinum-based chemotherapy.
• To assess changes in tumor and normal organ uptake after 2 cycles of cemiplimab with or without chemotherapy

Exploratory objectives:
• To correlate the normal organ tracer uptake with potential immune-related adverse events.
• Evaluate the correlation of 89Zr-DFO-REGN3767 uptake with immune infiltrates and other molecular biomarkers, determined by immunohistochemistry (IHC).
• To assess immunogenicity by ADA formation at baseline and during therapy.
• To evaluate the PK of REGN3767.

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

1. Age ≥ 18 years at the time of signing informed consent.
2. Patients with histologically confirmed diagnosis of locally advanced or metastatic solid cancer types who, according to the opinion of the investigator, based on available clinical data, may benefit from PD1 antibody with or without platinum-based chemotherapy.
3. At least 1 lesion that is accessible per investigator’s assessment and eligible for biopsy according to standard clinical care procedures.
4. Measurable disease, as defined by standard RECIST v1.1. Previously irradiated lesions should not be counted as target lesions except for lesions that have progressed after radiotherapy.
5. Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1.
6. Life expectancy ≥ 12 weeks.
7. Adequate organ and bone marrow function as defined below:
a. Hemoglobin ≥9.0 g/dL
b. Absolute neutrophil count ≥1.5 x 109/L
c. Absolute lymphocyte count ≥0.75 x 109/L
d. Platelet count ≥100 x 109/L
e. Serum creatinine ≤1.5 x upper limit of normal (ULN) or estimated glomerular filtration rate > 30 mL/min/1.73 m2. A 24-hour urine creatinine collection may substitute for the calculated creatinine clearance to meet eligibility criteria.
f. Adequate hepatic function:
i. Total bilirubin ≤1.5 x ULN (≤3 x ULN if liver tumor involvement); Patients with Gilbert’s syndrome do not need to meet total bilirubin requirements, provided their total bilirubin is unchanged from their baseline. Gilbert’s syndrome must be documented appropriately as past medical history.
ii. Aspartate aminotransferase (AST) ≤2.5 x ULN (≤5 x ULN if liver tumor involvement)
iii. Alanine aminotransferase (ALT) ≤2.5 x ULN (≤5 x ULN if liver tumor involvement)
iv. Alkaline phosphatase (ALP) ≤2.5 x ULN (≤5 x ULN if liver or bone tumor involvement)
8. Signed informed consent.
9. Willingness and ability to comply with all protocol required procedures.

E.4

Principal exclusion criteria

1. Treatment with any approved anti-cancer therapy, investigational agent, or participation in another clinical trial with therapeutic intent within 28 days prior to 89Zr-DFO-REGN3767 injection.
2. Prior ICI treatment, including but not limited to anti-PD1 and anti-PD-L1 therapeutic antibodies in the past 12 months or ≥ 12 months ago, in case the ICI treatment was terminated for progressive disease or toxicity.
3. Encephalitis, meningitis, or uncontrolled seizures in the year prior inclusion.
4. Any unresolved toxicity (>CTCAE grade 2) from previous anti-cancer therapy. Subjects with irreversible toxicity that is not reasonably expected to be exacerbated by the investigational product may be included (e.g., hearing loss, peripherally neuropathy)
5. Symptomatic, untreated brain metastasis, leptomeningeal disease, or spinal cord compression. Patients are eligible if central nervous system (CNS) metastases are adequately treated and neurologically stable for at least 2 weeks prior to enrollment.
6. Documented allergic or acute hypersensitivity reaction attributed to antibody treatments
7. Major surgical procedure other than for diagnosis within 28 days prior to 89Zr-DFO-REGN3767 injection or anticipation of need for a major surgical procedure during the course of the study.
8. For patients that will be treated with cemiplimab in combination with platinum containing chemotherapy, the following additional criteria apply:
• Leucopenia <3 x 109/L
• Estimated glomerular filtration rate < 60 mL/min/1.73 m2
• Cardiovascular disease, such as New York Heart Association cardiac disease (Class II or greater), unstable angina, unstable cardiac arrhythmias, myocardial infarction < 3 months ago, or cerebrovascular accident < 6 months ago.
• Hearing loss
• Any other exclusion criteria, according to the local clinical practice guidelines for the chosen chemotherapy regimen.
9. History of autoimmune disease, including but not limited to myasthenia gravis, myositis, autoimmune hepatitis, systemic lupus erythematous, rheumatoid arthritis, inflammatory bowel disease, 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-related hypothyroidism on a stable dose of thyroid replacement hormone may be eligible for his study.
• Patients with controlled type I diabetes mellitus on a stable dose of insulin regimen may be eligible for this study.
10. History of idiopathic pulmonary fibrosis, organizing pneumonia (e.g., bronchiolitis obliterans), drug-induced pneumonitis, or idiopathic pneumonitis.
• History of radiation pneumonitis in the radiation field (fibrosis) is permitted.
11. Treatment with systemic immunosuppressive medications (including but not limited to prednisone, cyclophosphamide, azathioprine, methotrexate, thalidomide, and anti-tumor necrosis factor agents) within 4 weeks prior to 89Zr-DFO-REGN3767 injection.
• Patients who have received acute, low-dose, systemic immunosuppressant medications (e.g., a one-time of dexamethasone for nausea) may be enrolled in the study after discussion with and approval by the sponsor.
• The use of inhaled corticosteroids for chronic obstructive pulmonary disease, mineralocorticoids (e.g., fludrocortisone) for patients with orthostatic hypotension, and low-dose supplemental corticosteroids for adrenocortical insufficiency are allowed.
12. Prior allogeneic bone marrow transplantation or solid organ transplant.
13. Active infection with human immunodeficiency virus (HIV), hepatitis B, hepatitis C or tuberculosis infection; or diagnosis of immunodeficiency
14. Active infection that requires systemic antibiotics within 2 weeks prior to 89Zr-DFO-REGN3767 injection.
15. Any other diseases, metabolic dysfunction, physical examination finding, or clinical laboratory finding giving reasonable suspicion of a disease or condition that contraindicates the use of 89Zr-DFO-REGN3767, or that may affect the interpretation of the results or render the patient at high risk from complications.
16. Receipt of a live vaccine (including attenuated) within 30 days of planned start of study medication.
17. Altered mental status, or any psychiatric condition that would prohibit the understanding or rendering of informed consent.
18. Sponsor employee/member of the clinical site study team and/or his or her immediate family
19. Women with a positive serum chorionic gonadotropin HCG pregnancy test at the screening/baseline visit. Breastfeeding women are also excluded.
20. Women of childbearing potential* and sexually active men who are unwilling to practice highly effective contraception prior to the first dose of study therapy, during the study, and for at least 6 months after the last dose.

E.5 End points

E.5.1

Primary end point(s)

• Comparison of standardized uptake values in tumor lesions and tumor-to-blood ratios at different time points and different 89Zr-DFO-REGN3767 antibody dose levels.
• To evaluate the biodistribution and PK of 89Zr-DFO-REGN3767 antibody by measuring standardized uptake value (SUV) on 89Zr-DFO-REGN3767 PET scans in patients with histologically or cytologically documented locally advanced or metastatic solid tumors who based on available clinical data may benefit from treatment with cemiplimab with or without platinum-based chemotherapy.
• Safety evaluation through summaries of adverse events, changes in laboratory test results and changes in vital signs after exposure to 89Zr-DFO-REGN3767.

E.5.1.1

Timepoint(s) of evaluation of this end point

Analysis will be performed on an ongoing base after every patient.

E.5.2

Secondary end point(s)

• Comparison of tracer uptake, expressed as standardized uptake values, in different tumor lesions within and between patients on 89Zr-PET scans.
• Correlation of tumor tracer uptake with tumor and immune cell LAG3 expression as assessed by immunohistochemistry on a tumor biopsy sample.
• Correlation of tumor tracer uptake with response to cemiplimab with or without platinum-based chemotherapy, according to RECIST v1.1.
• Assessment of change in tumor and normal organ tracer uptake after 2 cycles of cemiplimab with or without chemotherapy

E.5.2.1

Timepoint(s) of evaluation of this end point

Analysis will be performed on an ongoing base after every patient.

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

E.6.4

Safety

Yes

E.6.5

Efficacy

E.6.6

Pharmacokinetic

Yes

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)

Yes

E.7.3

Therapeutic confirmatory (Phase III)

E.7.4

Therapeutic use (Phase IV)

E.8 Design of the trial

E.8.1

Controlled

E.8.1.1

Randomised

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

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.8.3

The trial involves single site in the Member State concerned

Yes

E.8.4

The trial involves multiple sites in the 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

The end of study is defined as the date of the last treatment discontinuation visit of the last subject.

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

E.8.9.2

In all countries concerned by the trial months

E.8.9.2

In all countries concerned by the trial days

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:

F.1.3

Elderly (>=65 years)

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.3.3.7

Others

F.4 Planned number of subjects to be included

F.4.1

In the member state

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)

standard of care treatment

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

2020-12-21

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2021-11-24

P. End of Trial
P.	End of Trial Status	Ongoing

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