Clinical Trials Register

Summary
EudraCT Number:	2018-002551-15
Sponsor's Protocol Code Number:	8951-CL-5201
National Competent Authority:	Ireland - HPRA
Clinical Trial Type:	EEA CTA
Trial Status:	Ongoing
Date on which this record was first entered in the EudraCT database:	2018-12-21
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

Ireland - HPRA

A.2

EudraCT number

2018-002551-15

A.3

Full title of the trial

A Phase 2, Open-Label, Randomized Study to Assess the Efficacy and Safety of Zolbetuximab (IMAB362) in Combination with Nab-Paclitaxel and Gemcitabine (Nab-P + GEM) as First Line Treatment in Subjects with Claudin 18.2 (CLDN18.2) Positive, Metastatic Pancreatic Adenocarcinoma

A.3.1

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

A clinical trial to evaluate a new medicine (Zolbetuximab) for the treatment of pancreatic cancer

A.4.1

Sponsor's protocol code number

8951-CL-5201

A.5.4

Other Identifiers

Name:

IND

Number:

129598

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	Astellas Pharma Global Development, Inc. (APGD)
B.1.3.4	Country	United States
B.3.1 and B.3.2	Status of the sponsor	Commercial
B.4 Source(s) of Monetary or Material Support for the clinical trial:
B.4.1	Name of organisation providing support	Astellas Pharma Global Development, Inc. (APGD)
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	Astellas Pharma Europe B.V.
B.5.2	Functional name of contact point	Global Development Operations
B.5.3	Address:
B.5.3.1	Street Address	Sylviusweg 62
B.5.3.2	Town/ city	Leiden
B.5.3.3	Post code	2333 BE
B.5.3.4	Country	Netherlands
B.5.4	Telephone number	+31715455050
B.5.6	E-mail	ctu@astellas.com

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	Yes
D.2.5.1	Orphan drug designation number	EU/3/13/1177
D.3 Description of the IMP
D.3.1	Product name	Zolbetuximab
D.3.2	Product code	IMAB362
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.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	Zolbetuximab
D.3.9.1	CAS number	1496553-00-4
D.3.9.2	Current sponsor code	IMAB362
D.3.9.3	Other descriptive name	IMAB362
D.3.9.4	EV Substance Code	SUB190351
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	105
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	Yes
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	Yes
D.3.11.13.1	Other medicinal product type	Monoclonal Antibody

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

First Line Treatment in Subjects with Claudin 18.2 (CLDN18.2) Positive, Metastatic Pancreatic Adenocarcinoma

E.1.1.1

Medical condition in easily understood language

Pancreatic cancer

E.1.1.2

Therapeutic area

Diseases [C] - Cancer [C04]

MedDRA Classification

E.1.2 Medical condition or disease under investigation

E.1.2	Version	21.0
E.1.2	Level	LLT
E.1.2	Classification code	10033599
E.1.2	Term	Pancreatic adenocarcinoma metastatic
E.1.2	System Organ Class	100000004864

E.1.3

Condition being studied is a rare disease

Yes

E.2 Objective of the trial

E.2.1

Main objective of the trial

-To confirm the recommended phase 2 dose (RP2D) of zolbetuximab in combination with Nab-P + GEM for subjects with CLDN18.2 positive, metastatic pancreatic adenocarcinoma (Safety Lead-in Phase)
-To assess whether treatment with zolbetuximab in combination with Nab-P + GEM improves overall survival (OS) compared to Nab-P + GEM in subjects with CLDN18.2 positive, metastatic pancreatic adenocarcinoma (Randomization Phase)
-To assess the safety and tolerability of zolbetuximab in combination with Nab-P + GEM

E.2.2

Secondary objectives of the trial

Key Secondary:
- To assess whether treatment with zolbetuximab in combination with Nab-P + GEM improves progression-free survival (PFS) and objective response rate (ORR) compared to Nab-P + GEM in subjects with CLDN18.2 positive, metastatic pancreatic adenocarcinoma (Randomization Phase)

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

1. Institutional Review Board (IRB)/Independent Ethics Committee (IEC) approved written informed consent and privacy language as per national regulations (e.g., Health Insurance Portability and Accountability Act Authorization for United States sites) must be obtained from the subject or legally authorized representative prior to any study related procedures (including withdrawal of prohibited medication, if applicable).
2. Subject is considered an adult according to local regulation at the time of signing informed consent.
3. Subject agrees not to participate in another interventional study while
receiving study drug in present study.
4. A female subject is eligible to participate if she is not pregnant or lactating and at least 1 of the following conditions applies:
● Not a woman of childbearing potential (WOCBP) as defined in the Protocol.
OR
● WOCBP who agrees to follow the contraceptive guidance as defined in the Protocol throughout the treatment period and for at least 6 months after the final study drug administration.
5. Female subject must agree not to breastfeed starting at screening and
throughout the study period, and for 6 months after the final study drug administration.
6. Female subject must not donate ova starting at screening and throughout the study period, and for 6 months after the final study drug administration.
7. A male subject with female partner(s) of child-bearing potential must agree to use contraception as detailed in the Protocol during the treatment period and for at least 6 months after the final study drug administration.
8. A male subject must not donate sperm during the treatment period and for 6 months after the final study drug administration.
9. Male subject with a pregnant or breastfeeding partner(s) must agree to remain abstinent or use a condom for the duration of the pregnancy or time partner is breastfeeding throughout the study period and for 6 months after the final study drug administration.
Disease Specific Criteria
10. Subject has histologically or cytologically confirmed adenocarcinoma of pancreas.
11. Subjects must have metastatic pancreatic adenocarcinoma that has not been previously treated with chemotherapy.
• Prior treatment with 5-FU or GEM administered as a radiation sensitizer during and up to 4 weeks after radiation therapy is allowed (if there is lingering toxicity, then the sponsor should be consulted).
• If a subject received adjuvant therapy, tumor recurrence or disease progression must have occurred at least 6 months after completing the last dose of the adjuvant therapy.
• Subjects whose disease progressed on prior treatment with Nab-P and GEM are not eligible.
12. Subject has a measurable lesion(s) on at least 1 metastatic site based on RECIST 1.1 within 28 days prior to randomization. For subjects with only 1 measureable lesion and prior radiotherapy, the lesion must be outside the field of prior radiotherapy or must have documented progression following radiation therapy.
13. Subject's tumor sample has CLDN18.2 expression in ≥ 75% of tumor cells demonstrating moderate to strong membranous staining as determined by central IHC testing.

Physical or Laboratory Findings
14. Subject has ECOG performance status of 0 or 1.
15. Subject has predicted life expectancy ≥ 12 weeks in the opinion of the investigator.
16. Subject must meet all of the following criteria based on the laboratory tests collected within 14 days prior to randomization. In case of multiple laboratory data within this period, the most recent data should be used.
•Hemoglobin ≥ 9 g/dl (no transfusion within 14 days of start of study treatment)
•Absolute neutrophil count ≥ 1.5 x 109 /L
•Platelets ≥ 100 x 109 /L
•Albumin ≥ 2.5 g/dL
•Total bilirubin ≤ 1.5 x upper limit of normal (ULN)
•Aspartate aminotransferase and alanine aminotransferase ≤ 2.5 x ULN without liver metastases (≤ 5 x ULN if liver metastases are present)
•Estimated creatinine clearance ≥ 30 mL/min
•Prothrombin time/international normalized ratio and partial thromboplastin time ≤ 1.5 x ULN (except for subjects receiving anticoagulation therapy)

E.4

Principal exclusion criteria

Subject will be excluded from participation if any of the following apply:
Prohibited Treatment or Therapies
1. Subject has received other investigational treatment within 28 days prior to randomization.
2. Subject has received radiotherapy for metastatic pancreatic adenocarcinoma ≤ 14 days prior to randomization and has not recovered from any related toxicity.
3. Subject has received systemic immunosuppressive therapy, including systemic corticosteroids within 14 days prior to randomization. Subject using a physiologic replacement dose of hydrocortisone or its equivalent (defined as up to 30 mg per day of hydrocortisone or up to 10 mg per day of prednisone), receiving a single dose of systemic corticosteroids or receiving systemic corticosteroids as premedication for radiologic imaging contrast use are allowed.
4. Subject has prior severe allergic reaction or intolerance to known ingredients of zolbetuximab or other monoclonal antibody, including humanized or chimeric
antibodies.
5. Subject has known immediate or delayed hypersensitivity, intolerance or
contraindication to any component of study treatment.
6. Subject has a known history of a positive test for human immunodeficiency virus infection or known active Hepatitis B (positive HBs antigen [Ag]) or
Hepatitis C infection. NOTE: Screening for these infections should be conducted per local requirements.
For subjects who are negative for HBs Ag, but Hepatitis B core antibody positive, a Hepatitis B virus DNA test will be performed and if positive, the subject will be excluded. Subjects with positive serology but negative Hepatitis C virus RNA test results are eligible. Subjects treated for hepatitis C with undetectable viral load results are eligible.
7. Subject has a history of interstitial pneumonia or pulmonary fibrosis.
8. Subject has pleural effusion or ascites ≥ Grade 3 per CTCAE v 4.03.
9. Subject has an active autoimmune disease that has required systemic treatment in the past 3 months prior to randomization.
10. Subject has active infection requiring systemic therapy that has not completely resolved per investigator judgment within 7 days prior to randomization.
11. Subject has significant cardiovascular disease, including:
● Congestive heart failure (defined as New York Heart Association Class III or IV), myocardial infarction, unstable angina, coronary angioplasty, coronary stenting, coronary artery bypass graft, cerebrovascular accident or hypertensive crisis within 6 months prior to randomization;
● History of clinically significant ventricular arrhythmias (i.e., sustained ventricular tachycardia, ventricular fibrillation or Torsades de Pointes);
● QTc interval > 450 msec for male subjects; QTc interval > 470 msec for female subjects;
● Cardiac arrhythmias requiring anti-arrhythmic medications (Subjects with rate controlled atrial fibrillation for > 1 month prior to randomization are eligible.)
12. Subject has a history of central nervous system metastases and/or carcinomatous meningitis from pancreatic adenocarcinoma.
13. Subject has known peripheral sensory neuropathy ≥ Grade 2 per CTCAE v.4.03 unless the absence of deep tendon reflexes is the sole neurological abnormality.
14. Subject has had a major surgical procedure ≤ 28 days prior to randomization.
15. Subject without complete recovery from a major surgical procedure ≤ 14 days prior to randomization.
16. Psychiatric illness or social situations that would preclude study compliance per investigator's judgment.
17. Subject has another malignancy for which treatment is required per investigator's clinical judgment.
18. Subject has any concurrent disease, infection or co-morbid condition that interferes with the ability of the subject to participate in the study, which places the subject at undue risk or complicates the interpretation of data in the opinion of the investigator.

E.5 End points

E.5.1

Primary end point(s)

Primary Endpoints
● Confirm RP2D as assessed by DLTs (Safety Lead-in Phase)
● Safety and tolerability as measured by AEs, laboratory test results, vital signs, ECGs and ECOG performance status.
● OS, defined as the time from the date of randomization until the date of death from any cause

E.5.1.1

Timepoint(s) of evaluation of this end point

There will be 2 futility and 1 efficacy interim analyses performed for OS. The futility interim analyses will be performed when at least 42 OS events and 100 OS events have been observed, respectively. An interim efficacy analysis of OS will be performed when at least 212 OS events have been observed.

E.5.2

Secondary end point(s)

Key Secondary (Randomization):
● PFS, defined as the time from the date of randomization until the date of radiological PD per RECIST 1.1 by local investigator evaluation, or death from any cause, whichever is earliest
● ORR, defined as the proportion of subjects who have a best overall response of CR or PR as assessed by local investigator evaluation per RECIST 1.1
Secondary:
● Pharmacokinetic parameters of zolbetuximab, Nab-P and GEM (AUCinf, AUCinf [%extrap], AUClast, Cmax, Ctrough, tmax, t1/2, tlast, CL, Vz, as appropriate)
● Pharmacokinetic parameters of zolbetuximab, Nab-P (measured as PTX) and GEM (AUCinf, AUCinf [%extrap], AUClast, Cmax, Ctrough, tmax, t1/2, , tlast, CL, Vz, as appropriate)
● DCR, defined as the proportion of subjects who have a best overall response of CR, PR or stable disease (SD) as assessed by local investigator evaluation per RECIST 1.1
● DOR, defined as the time from the date of the first response (CR/PR) until the date of PD as assessed by local investigator evaluation per RECIST 1.1 or date of death from any cause, whichever is earliest
● Time to worsening of pancreatic pain and GHS/QoL as measured by QLQ-C30, QLQ-PAN26, and PGIS as key HRQOL endpoints
● HRQoL, as collected via measured by EORTC QLQ-C30, EORTC QLQPAN26 (including remaining domains besides pancreatic pain), EORTC QLQ-C30 (including remaining domains besides GHS/QoL), EQ-5D-5L, PGIS and PGIC questionnaires
● HRQoL, as collected via EORTC QLQ-C30, EORTC QLQ-PAN26, EQ-5D-5L, PGIC and PGIS questionnaires
● Serum CA19-9 change from baseline
● Immunogenicity of zolbetuximab as measured by the frequency of anti-drug antibody (ADA) positive subjects

E.5.2.1

Timepoint(s) of evaluation of this end point

All endpoints will be evaluated at the primary analysis.

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

Yes

E.6.5

Efficacy

Yes

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

Yes

E.6.13.1

Other scope of the trial description

Immunogenicity

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

Yes

E.8.1.1

Randomised

Yes

E.8.1.2

Open

Yes

E.8.1.3

Single blind

E.8.1.4

Double blind

E.8.1.5

Parallel group

Yes

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)

Yes

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

Yes

E.8.5.1

Number of sites anticipated in the EEA

E.8.6 Trial involving sites outside the EEA

E.8.6.1

Trial being conducted both within and outside the EEA

Yes

E.8.6.2

Trial being conducted completely outside of the EEA

E.8.6.3

If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned

Ireland

Taiwan

Australia

China

France

Italy

Japan

Korea, Republic of

Mexico

Spain

Turkey

United States

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 last visit or scheduled procedure for the last study participant in the study

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

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:

108

F.1.3

Elderly (>=65 years)

Yes

F.1.3.1

Number of subjects for this age range:

252

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.4.2

For a multinational trial

F.4.2.1

In the EEA

F.4.2.2

In the whole clinical trial

369

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)

Zolbetuximab may be made available after the conclusion of the study to subjects who are still receiving and benefiting from study treatment until study defined treatment discontinuation criterion is met.

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

2019-03-08

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2019-10-01

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

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