Clinical Trials Register

Summary
EudraCT Number:	2020-001075-32
Sponsor's Protocol Code Number:	RE-ExPEL
National Competent Authority:	Germany - PEI
Clinical Trial Type:	EEA CTA
Trial Status:	Completed
Date on which this record was first entered in the EudraCT database:	2020-05-04
Trial results	View 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

Germany - PEI

A.2

EudraCT number

2020-001075-32

A.3

Full title of the trial

RE-ExPEL
A pilot study of ramucirumab beyond progression plus TAS-102 in patients with advanced or metastatic adenocarcinoma of the stomach or the gastroesophageal junction, after treatment failure on a ramucirumab based therapy

Re-ExPEL
Eine Pilotstudie mit Ramucirumab über den Progress hinaus in Kombination mit TAS-102 bei Patienten mit fortgeschrittenem oder metastasierten Adenokarzinom des Magens oder des ösophagogastralen Übergangs, nach Therapieversagen einer Ramucirumab-basierten Therapie

A.3.1

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

A pilot study of ramucirumab beyond progression plus TAS-102 in patients with advanced or metastatic adenocarcinoma of the stomach or the gastroesophageal junction, after treatment failure on a ramucirumab based therapy

Eine Pilotstudie mit Ramucirumab über den Progress hinaus in Kombination mit TAS-102 bei Patienten mit fortgeschrittenem oder metastasiertem
Adenokarzinom des Magens oder des ösophagogastralen Übergangs,
nach Therapieversagen einer Ramucirumab-basierten Therapie

A.3.2

Name or abbreviated title of the trial where available

RE-ExPEL

A.4.1

Sponsor's protocol code number

RE-ExPEL

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	Institut für Klinische Krebsforschung IKF GmbH
B.1.3.4	Country	Germany
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	Lilly Deutschland GmbH
B.4.2	Country	Germany
B.5 Contact point designated by the sponsor for further information on the trial
B.5.1	Name of organisation	Institut für Klinische Krebsforschung IKF GmbH
B.5.2	Functional name of contact point	Clinical Trial Unit
B.5.3	Address:
B.5.3.1	Street Address	Steinbacher Hohl 2-26
B.5.3.2	Town/ city	Frankfurt
B.5.3.3	Post code	60488
B.5.3.4	Country	Germany
B.5.4	Telephone number	00496976014420
B.5.5	Fax number	00496976013655
B.5.6	E-mail	pauligk.claudia@ikf-khnw.de

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	Cyramza® 10 mg/ml Konzentrat zur Herstellung einer Infusionslösung
D.2.1.1.2	Name of the Marketing Authorisation holder	Eli Lilly Nederland B.V.
D.2.1.2	Country which granted the Marketing Authorisation	European Union
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/3/12/1004
D.3 Description of the IMP
D.3.1	Product name	Ramucirumab
D.3.4	Pharmaceutical form	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	RAMUCIRUMAB
D.3.9.1	CAS number	947687-13-0
D.3.9.3	Other descriptive name	RAMUCIRUMAB
D.3.9.4	EV Substance Code	SUB32795
D.3.10	Strength
D.3.10.1	Concentration unit	mg/ml milligram(s)/millilitre
D.3.10.2	Concentration type	equal
D.3.10.3	Concentration number	10
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	No
D.IMP: 2
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	Lonsurf
D.2.1.1.2	Name of the Marketing Authorisation holder	Servier
D.2.1.2	Country which granted the Marketing Authorisation	European Union
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	TAS102
D.3.4	Pharmaceutical form	Film-coated tablet
D.3.4.1	Specific paediatric formulation	No
D.3.7	Routes of administration for this IMP	Oral use
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	TAS-102
D.3.9.1	CAS number	733030-01-8
D.3.9.3	Other descriptive name	TIPIRACIL HYDROCHLORIDE MIXTURE WITH TRIFLURIDINE
D.3.9.4	EV Substance Code	SUB78359
D.3.10	Strength
D.3.10.1	Concentration unit	mg/m2 milligram(s)/square meter
D.3.10.2	Concentration type	equal
D.3.10.3	Concentration number	35
D.3.11 The IMP contains an:
D.3.11.1	Active substance of chemical origin	Yes
D.3.11.2	Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP)	No
	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

advanced or metastatic adenocarcinoma of the stomach or the gastroesophageal junction

E.1.1.1

Medical condition in easily understood language

advanced or metastatic adenocarcinoma of the stomach or the gastroesophageal junction

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	21.1
E.1.2	Level	PT
E.1.2	Classification code	10063916
E.1.2	Term	Metastatic gastric cancer
E.1.2	System Organ Class	10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps)

E.1.2 Medical condition or disease under investigation

E.1.2	Version	20.1
E.1.2	Level	PT
E.1.2	Classification code	10062878
E.1.2	Term	Gastrooesophageal cancer
E.1.2	System Organ Class	10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps)

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 whether a combination of ramucirumab, beyond progression after a SOC 2nd line ramucirumab based pre-treatment (Ram beyond progression) in patients with locally advanced or metastatic adenocarcinoma, plus TAS-102 shows good tolerability without safety issues regarding the serious adverse event rate of any cause.

E.2.2

Secondary objectives of the trial

To determine whether the combination shows positive signals regarding efficacy in the secondary endpoints (e.g. prolongation of progression-free survival of TAS-102 plus ramucirumab compared with TAS-102 monotherapy - historical data according to TAGS trial).

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

1. Signed informed consent form.
2. Men or women* ≥ 18 years of age. Patients of reproductive age must be prepared to use a suitable contraceptive method during the study and up to 3 months after the end of ramucirumab treatment. A suitable method of contraception is defined as surgical sterilization (e.g. bilateral fallopian tube ligation, vasectomy), hormonal contraception (implantable, patch, oral), and double barrier methods (each two-fold combination of intrauterine pessary, condom for men, or women with spermicidal gel, diaphragm, contraceptive sponge, cervical cap). Women of child-bearing potential must have a negative pregnancy test within the last 7 days prior to the start of study therapy.
*There is no data that indicates a specific gender distribution. Therefore, patients are included regardless of their gender.
3. Histologically proven adenocarcinoma of the stomach, including adenocarcinoma of the gastroesophageal junction (note: previous histological assessment during disease history of patient sufficient, current biopsy during screening for this trial is not mandatory)
4. Documented, objective, radiological or clinical progression of the disease during or within 4-6 weeks after the last dose of a ramucirumab based second-line therapy (ramucirumab monotherapy or a combination of ramucirumab + paclitaxel, respectively ramucirumab + FOLFIRI).
5. Measurable or non-measurable but evaluable disease.
6. ECOG Performance status 0-2.
7. Life expectancy > 8 weeks.
8. Appropriate haematological, hepatic and renal function:
a. Absolute number of neutrophils (ANC) ≥ 1.5 x 109/L
b. Platelets ≥ 100 x 109/L
c. Hemoglobin ≥ 9 g/dL (5.58 mmol/L)
d. Total bilirubin ≤ 1.5 times the upper limit of normal (UNL)
e. AST (SGOT) and ALT (SGPT) ≤ 2.5 x UNL without existing liver metastases, or ≤ 5 x UNL in the presence of liver metastases; AP ≤ 5 x UNL
9. Serum creatinine ≤ 1.5 x UNL or creatinine clearance (measured by 24h urine) ≥ 40 mL / min (i.e. if the serum creatinine level is > 1.5 x UNL, then a 24h urine test must be performed to check the creatinine clearance to be determined). Protein level in urine ≤ 1+ by dipstick analysis or routine urine measurement (if the dipstick analysis or the routine test ≥ 2+, a subsequent 24h urine protein measurement must show a value of < 1000mg of protein within 24h of participation to ensure the study.
10. Adequate coagulability, as determined by the International Normalized Ratio (INR) ≤ 1.5 and partial thromboplastin time (PTT) ≤ 5 seconds above the UNL (unless anti-coagulation therapy has been given). Patients receiving warfarin / phenoprocoumon must be switched to low molecular weight heparin and must have a stable coagulation profile before starting study-specific therapy.
11. Subject is willing and able to comply with the protocol (including contraceptive measures) for the duration of the study including undergoing treatment and scheduled visits and examinations including follow up.

E.4

Principal exclusion criteria

1. Presence of tumors other than adenocarcinomas (e.g., leiomyosarcoma, lymphoma) or a secondary tumor other than squamous or basal cell carcinomas of the skin or in situ carcinomas of the cervix which have been effectively treated. The sponsor decides to include patients who have received curative treatment and have been disease-free for at least 5 years.
2. Squamous cell carcinoma of the stomach or gastroesophageal junction.
3. Simultaneous, ongoing, systemic immunotherapy, chemotherapy, or hormone therapy not described in the study protocol.
4. Simultaneous treatment with a different anti-cancer therapy other than that provided for in the study (excluding palliative radiotherapy for symptom control).
5. The patient is receiving chronic antiplatelet therapy, including aspirin, nonsteroidal anti-inflammatory drugs (NSAIDs, including ibuprofen, naproxen, and others), dipyridamole or clopidogrel, or similar agents. Once-daily aspirin use (maximum dose 325 mg/day) is permitted
6. The patient has undergone major surgery within the last 28 days prior to the start of study-specific therapy or has undergone minor surgery within the last 7 days prior to the start of study therapy. The patient had subcutaneous venous access within the last 7 days prior to the start of the study-specific therapy. The patient plans to undergo major surgery while participating in the clinical trial.
7. Gastrointestinal bleeding grade 3-4 within the last 3 months prior to enrollment in the study.
8. History of deep vein thrombosis (DVT), pulmonary embolism (PE), or any other clinically important thromboembolic event during the last 3 months prior to the start of study-specific therapy (thrombosis caused by venous ports, catheters, or superficial venous thrombosis are not considered "clinically meaningful").
9. Stage B cirrhosis according to Child-Pugh criteria (or worse) or cirrhosis (of any grade) with a history of hepatic encephalopathy or clinically significant ascites resulting from cirrhosis. Clinically significant ascites is defined as ascites resulting from cirrhosis requiring diuretics or paracentesis.
10. Known brain or leptomeningeal metastases.
11. Known allergic / hypersensitive reactions to at least one of the treatment components.
12. Other serious illnesses or medical ailments within the last 12 months prior to the start of the study.
13. Any arterial thromboembolic event which includes, but is not limited to, the following: myocardial infarction, transient ischemic attack, cerebrovascular insult, unstable angina within the last 6 months prior to the initiation of study therapy.
14. Uncontrolled or under-adjusted hypertension (> 160 mmHg systolic or > 100 mmHg diastolic hypertension for more than 4 weeks) despite standard medical treatment.
15. Presence of an active, uncontrollable infection.
16. Chronic inflammatory bowel disease.
17. Active disseminated intravascular coagulation.
18. Any other serious concomitant or medical condition that, in the opinion of the investigator, presents a high risk of complications to the patient or reduces the likelihood of clinical effect.
19. Known dihydropyrimidine dehydrogenase (DPD) deficiency.
20. History of gastrointestinal perforation / fistula (within the last 6 months prior to the start of study-specific therapy) or presence of risk factors favoring perforation.
21. Serious or non-healing wounds, ulcers, or broken bones within the last 28 days prior to the start of study-specific therapy.
22. The patient is pregnant or breast-feeding.

E.5 End points

E.5.1

Primary end point(s)

The primary endpoint of the study is tolerability and toxicity, defined by the rate of serious adverse events (SAEs) of any cause according to CTCAE v5.0

E.5.1.1

Timepoint(s) of evaluation of this end point

The final analysis will be conducted when the last patient reached EOT + 30 days of follow-up and all patients are fully documented.

E.5.2

Secondary end point(s)

• Rate of treatment-related AEs and SAEs according to CTCAE v5.0
• Rate of grade 3 or worse adverse events for neutropenia
• Rate of grade 3 or worse adverse events for anemia
• Rate of grade 3 or worse adverse events for leucopenia
• Rate of grade 3 or worse adverse events for thrombocytopenia
• Frequency of abnormal laboratory parameters
• Progression Free Survival (PFS) according to RECIST 1.1
• Objective Response Rate (ORR)
• Overall survival (OS)

E.5.2.1

Timepoint(s) of evaluation of this end point

Progression free survival
Progression free survival (PFS) is defined as the time from enrollment to the first documented evidence of disease progression or death. If no information will be available for the evaluation of progression, patients will be censored at the timepoint of last tumor assessment.
Objective response rate
Objective response rate is defined as proportion of patients with a best overall response of complete response (CR) or partial response (PR). Tumor response will be evaluated using RECIST 1.1 criteria.
Overall survival
Overall survival (OS) is defined as the time from enrollment to the date of death from any cause.

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

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

Yes

E.8.1.1

Randomised

E.8.1.2

Open

Yes

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

Yes

E.8.2.3.1

Comparator description

historic control

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

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)

Yes

F.1.3.1

Number of subjects for this age range:

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)

The investigators are responsible for the further treatment of the
patient after the end of the study. The investigators shall support and
advise the patient and – if required – help to organize appointments
with other specialized physicians.

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

2020-06-15

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2020-08-03

P. End of Trial
P.	End of Trial Status	Completed
P.	Date of the global end of the trial	2023-01-20

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