Clinical Trials Register

Summary
EudraCT Number:	2017-004162-99
Sponsor's Protocol Code Number:	RAMTAS
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:	2018-04-04
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

Expand All Collapse All

A. Protocol Information

A.1

Member State Concerned

Germany - PEI

A.2

EudraCT number

2017-004162-99

A.3

Full title of the trial

RAMTAS
A Phase III study of RAMucirumab in combination with TAS102 vs. TAS102 monotherapy in chemotherapy refractory metastatic colorectal cancer patients

RAMTAS
Ramucirumab in Kombination mit TAS102 oder TAS102 allein bei Patienten mit Chemotherapie-refraktärem, metastasiertem kolorektalen Karzinom - eine Phase III-Studie

A.3.1

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

Comparison of a standard chemotherapy with additional medication (Ramucirumab) in one group for patients with metastatic colorectal cancer after chemotherapie

Vergleich einer standardmäßig gegebenen Chemotherapie mit zusätzlicher Medikation (Ramucirumab) in einer der Gruppen für Patienten mit metastasiertem Darmkrebs nach vorausgegangener Chemotherapie

A.3.2

Name or abbreviated title of the trial where available

RAMTAS

A.4.1

Sponsor's protocol code number

RAMTAS

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	Frankfurter Institut für Klinische Krebsforschung IKF GmbH am Krankenhaus Nordwest
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
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	Frankfurter Institut für Klinische Krebsforschung IKF GmbH am Krankenhaus Nordwest
B.5.2	Functional name of contact point	IKF GmbH
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	ramtas@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	TAS102
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 metastatic colorectal cancer

E.1.1.1

Medical condition in easily understood language

Advanced metastatic colorectal 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	27.0
E.1.2	Level	LLT
E.1.2	Classification code	10052362
E.1.2	Term	Metastatic colorectal 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 compare the efficacy of ramucirumab in combination with TAS102 (Trifluridin/Tipiracil-Lonsurf®) vs. TAS102 monotherapy in patients with refractory mCRC.

E.2.2

Secondary objectives of the trial

To determine overall response rate, disease control rate, progression free survival, overall survival (6 and 12 months), efficacy (ORR, PFS, OS) in patients who develop neutropenia ≥ grade 2 (ANC ≤ 1500/μl) in cycle 1, toxicity/safety, quality of life (QoL)

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

1. Metastatic and inoperable, colorectal cancer who has progressed on/after, did not tolerate, refuse or have contraindications to:
- fluoropyrimidines, oxaliplatin, irinotecan, anti-angiogenic therapies (bevacizumab, aflibercept, regorafenib or ramucirumab) and if indicated anti-EGFR antibodies (cetuximab or panitumumab)
Intolerance is defined as a permanent discontinuation of the respective treatment resulting from toxicity
2. Signed informed consent before start of specific protocol procedure
3. Histologically or cytologically documented diagnosis of adenocarcinoma of the colon or rectum
4. Presence of at least one measurable site of disease following RECIST 1.1 criteria
5. ECOG performance 0-1
6. Known RAS and BRAF V600E mutational status
Note: If KRAS (or NRAS) is mutated, NRAS (or KRAS, respectively) and BRAF mutational status is not required as the mutations are mutually exclusive and NRAS (or KRAS, respectively) and BRAF is assumed as wildtype then.
7. Life expectancy of at least 3 months
8. Adequate hematological, hepatic and renal function parameters:
a. Leukocytes ≥ 3000/mm³, platelets ≥ 100,000/mm³, neutrophil count (ANC) ≥1500/μL, hemoglobin ≥9 g/dL (5.58 mmol/L),
b. Adequate coagulation function as defined by International Normalized Ratio (INR) ≤ 1.5, and a partial thromboplastin time (PTT) ≤ 5 seconds above the ULN (unless receiving anticoagulation therapy). Patients receiving warfarin/ phenprocoumon must be switched to low molecular weight heparin and have achieved stable coagulation profile prior to first dose of protocol therapy.
c. Serum creatinine ≤ 1.5 x upper limit of normal or creatinine clearance (measured via 24-hour urine collection) ≥40 mL/minute (that is, if serum creatinine is >1.5 times the ULN, a 24-hour urine collection to calculate creatinine clearance must be performed)
d. Urinary protein ≤1+ on dipstick or routine urinalysis (UA; if urine dipstick or routine analysis is ≥2+, a 24-hour urine collection for protein must demonstrate <1000 mg of protein in 24 hours to allow participation in this protocol)
e. Bilirubin ≤ 1.5 x upper limit of normal, AST and ALT ≤ 3.0 x upper limit of normal, ≤ 5xULN if liver metastasis present, alkaline phosphatase ≤ 6 x upper limit of normal
9. Patient able and willing to provide written informed consent and to comply with the study protocol
10. Female and male patients ≥ 18. Patients in reproductive age must be willing to use adequate contraception during the study and for 7 months after the end of ramucirumab treatment (Appropriate contraception is defined as surgical sterilization (e.g., bilateral tubal ligation, vasectomy) or hormonal contraception (implantable, patch, oral). Women who use a hormonal contraception method should use an additional barrier method like IUD, male or female condom with spermicidal gel, diaphragm, sponge, cervical cap). Female patients with childbearing potential need to have a negative pregnancy test within 7 days before study start

E.4

Principal exclusion criteria

1. Known hypersensitivity against ramucirumab or TAS102
2. Other known contraindications against ramucirumab, TAS102, or other anti-angiogenic therapies
3. Prior therapy with TAS102
4. Drug-related severe adverse events upon pretreatment with anti-angiogenic drugs that would require permanent discontinuation and not allow re-challenge with the same class of drug (i.e. Ramucirumab) such as nonctrollable severe hypertension or thromboembolic events (see Table 16 on p. 66 for additional examples).
5. Any antineoplastic treatment including irradiation within 14 days (42 days for mitomycin c) prior to start of therapy.
6. Major surgery within 4 weeks of starting therapy within this study, or minor surgery/subcutaneous venous access device placement within 7 days prior to first dose of protocol therapy. The patient has elective or planned major surgery to be performed during the course of the clinical trial
7. Symptomatic brain metastasis
8. Clincially significant cardiovascular disease
- NYHA>II°, myocardial infarction within 6 months prior study entry
- Known clincially significant valvular defect
- Uncontrolled or poorly-controlled hypertension (> 160 mmHg systolic or > 100 mmHg diastolic for > 4 weeks) despite standard medical management
- Any arterial thromboembolic events, including but not limited to myocardial infarction, transient ischemic attack, cerebrovascular accident, or unstable angina, within 6 months prior to first dose of protocol therapy
- History of deep vein thrombosis (DVT), symptomatic pulmonary embolism (PE), or any other significant thromboembolism (venous port or catheter thrombosis or superficial venous thrombosis are not considered “significant”) during the 3 months prior to first dose of protocol therapy
9. Active clinically serious infections (> grade 2 NCI-CTC version 4.0)
10. Chronic inflammatory bowel disease
11. History of uncontrolled HIV infection or chronic hepatitis B or C
12. Patients with evidence of bleeding diathesis
13. Grade 3-4 GI bleeding within 3 months prior to first dose of protocol therapy
14. Receiving chronic antiplatelet therapy, including aspirin (Once-daily aspirin use (maximum dose 325 mg/day) is permitted), nonsteroidal anti-inflammatory drugs (including ibuprofen, naproxen, and others), dipyridamole or clopidogrel, or similar agents
15. History of gastrointestinal perforation or fistulae in past 6 months or risk factors for perforation
16. Serious or nonhealing wound, ulcer, or bone fracture within 28 days prior to first dose of protocol therapy
17. Past or current history of other malignancies not curatively treated and without evidence of disease for more than 5 years, with the exception of malignancies with a negligible risk of metastasis or death (e.g. 5-year OS rate >90%), such as adequately treated carcinoma in situ of the cervix, non-melanoma skin carcinoma, localized prostate cancer, ductal carcinoma in situ, Stage I uterine cancer or early breast cancer. Other here non-listed malignancies should be discussed with the coordinating investigatior before enrolment of the patient.
18. Any condition that could jeopardize the safety of the patient and their compliance of the study
19. Medical, psychological or social conditions that may interfere with the participation in the study
20. Cirrhosis at a level of Child-Pugh B (or worse) or cirrhosis (any degree) and a history of hepatic encephalopathy or ascites. Clinically meaningful ascites is defined as ascites from cirrhosis requiring diuretics or paracentesis
21. On-treatment participation in another clinical study or received investigational drug therapy in the period 30 days prior to inclusion and during the study
22. Subject pregnant or breast feeding, or planning to become pregnant within 7 months after the end of treatment
23. Patients in a closed institution according to an authority or court decision (AMG § 40, Abs. 1 No. 4)
24. Any other concurrent antineoplastic treatment including irradiation

E.5 End points

E.5.1

Primary end point(s)

Overall survival (OS)

E.5.1.1

Timepoint(s) of evaluation of this end point

Death

E.5.2

Secondary end point(s)

Secondary endpoints
- Overall Response Rate (ORR) (complete remission and partial remission)
- Disease control rate (DCR) (complete remission, partial remission and stable disease)
- Progression Free Survival (PFS)
- OS rate at 6 and 12 months
- Efficacy (ORR, PFS, OS) in patients who develop neutropenia ≥ grade 2 (ANC ≤ 1500/μl) in cycle 1
- Toxicity/safety
- Quality of life (QoL)
- Exploratory biomarker and radiological analysis to determine the efficacy of each therapeutic regimen

E.5.2.1

Timepoint(s) of evaluation of this end point

- Median ORR/DCR/PFS/OS/Toxicity/Safety: continuously
- QoL: D1 of each treatment cycle and end of treatment

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)

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

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

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

Database closure is defined as the end of the trial: Sites need to collect survival data of patients and are involved in the data cleaning process actively (e.g. additional source data may be requested and additonal monitoring visits may be neccessary). Therefore, database closure is considered the end of the trial.

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:

426

F.1.3

Elderly (>=65 years)

Yes

F.1.3.1

Number of subjects for this age range:

426

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

426

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

2018-07-02

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2018-08-09

P. End of Trial
P.	End of Trial Status	Completed
P.	Date of the global end of the trial	2024-07-30

Select Country:	Select Age Range:
Select Trial Status:	Select Trial Phase:
Select Gender:
Select Date Range: to
Select Rare Disease:
IMP with orphan designation in the indication
Orphan Designation Number:
Results Status:
Clear advanced search filters

Austria
Belgium
Bulgaria
Croatia
Cyprus
Czechia
Denmark
Estonia
Finland
France
Germany
Greece
Hungary
Iceland
Ireland
Italy
Latvia
Liechtenstein
Lithuania
Luxembourg
Malta
Netherlands
Norway
Poland
Portugal
Romania
Slovakia
Slovenia
Spain
Sweden
United Kingdom
Outside EU/EEA

Clinical trials