Clinical Trials Register

Summary
EudraCT Number:	2017-004570-34
Sponsor's Protocol Code Number:	01045-ATLEP
National Competent Authority:	Germany - PEI
Clinical Trial Type:	EEA CTA
Trial Status:	Ongoing
Date on which this record was first entered in the EudraCT database:	2018-07-06
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

Germany - PEI

A.2

EudraCT number

2017-004570-34

A.3

Full title of the trial

Phase II, Open-label, Study in Patients with anaplastic (ATC) or poorly differentiated thyroid carcinomas (PDTC) to investigate the Clinical Efficacy and Safety of the Combination Therapy of Lenvatinib and Pembrolizumab

Phase II, Open-label, Studie an Patienten mit anaplastischen (ATC) und schlecht-differenzierten Schilddrüsenkarzinomen (PDTC) zur Untersuchung der klinischen Effektivität und Sicherheit einer Kombinationstherapie aus Lenvatinib und Pembrolizumab

A.3.1

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

Phase II clinical trial for the combination of Lenvatinib and Pembrolizumab in patients with anaplastic- or poorly-differentiated thyroid carcinomas

KOMBINATIONSTHERAPIE MIT LENVATINIB UND PEMBROLIZUMAB IN PATIENTEN MIT ANAPLASTISCHEN UND GERING-DIFFERENZIERTEN SCHILDDRÜSENKARZINOMEN

A.3.2

Name or abbreviated title of the trial where available

ATLEP

A.4.1

Sponsor's protocol code number

01045-ATLEP

A.5.4

Other Identifiers

Name:

Deutsches Register Klinischer Studien

Number:

DRKS00013336

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	Medical Center - University of Freiburg
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	University of Freiburg, Faculty of Medicine
B.4.2	Country	Germany
B.4.1	Name of organisation providing support	EISAI 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	Medical Center - University of Freiburg
B.5.2	Functional name of contact point	Medical Clinic 1 - ECTU
B.5.3	Address:
B.5.3.1	Street Address	Hugstetter Straße 55
B.5.3.2	Town/ city	Freiburg
B.5.3.3	Post code	79106
B.5.3.4	Country	Germany
B.5.4	Telephone number	+4976127071812
B.5.5	Fax number	+4976127033180
B.5.6	E-mail	christine.dierks@uniklinik-freiburg.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	LENVIMA
D.2.1.1.2	Name of the Marketing Authorisation holder	Eisai Germany
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	LENVIMA
D.3.4	Pharmaceutical form	Capsule, hard
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	Lenvatinib
D.3.9.1	CAS number	857890-39-2
D.3.9.2	Current sponsor code	Lenvatinib
D.3.9.3	Other descriptive name	LENVATINIB MESILATE
D.3.9.4	EV Substance Code	SUB72971
D.3.10	Strength
D.3.10.1	Concentration unit	mg milligram(s)
D.3.10.2	Concentration type	range
D.3.10.3	Concentration number	4 to 10
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.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	Keytruda
D.2.1.1.2	Name of the Marketing Authorisation holder	MSD SHARP & DOHME
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	Keytruda
D.3.2	Product code	Pembrolizumab
D.3.4	Pharmaceutical form	Capsule, hard
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	PEMBROLIZUMAB
D.3.9.2	Current sponsor code	Pembrolizumab
D.3.9.3	Other descriptive name	Pembrolizumab
D.3.9.4	EV Substance Code	SUB167136
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	50
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.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

Anaplastic (ATC) or Poorly Differentiated Thyroid Carcinoma (PDTC)

Anaplastisches (ATC) oder gering-differenziertes Schilddrüsenkarzinom (PDTC)

E.1.1.1

Medical condition in easily understood language

anaplastic- or poorly-differentiated thyroid carcinoma

anaplastisches oder gering-differenziertes Schilddrüsenkarzinom

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	20.0
E.1.2	Level	PT
E.1.2	Classification code	10076603
E.1.2	Term	Poorly differentiated thyroid carcinoma
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	21.1
E.1.2	Level	PT
E.1.2	Classification code	10002240
E.1.2	Term	Anaplastic thyroid 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

Yes

E.2 Objective of the trial

E.2.1

Main objective of the trial

The primary objective of the trial is to obtain first information on the efficacy of combination therapy of lenvatinib and pembrolizumab in patients with ATC or PDTC, measured as Objective Response Rate (ORR) obtained 12 weeks after start of the study treatment.

Der primäre Endpunkt der Studie ist es erste Resultate zur Effektivität der Kombinationstherapie aus Lenvatinib und Pembrolizumab, gemessen an der Objective Response Rate (ORR) 12 Wochen nach Therapiestart, bei Patienten mit ATC und PDTC zu erhalten.

E.2.2

Secondary objectives of the trial

Secondary objective is to assess Overall Survival (OS), Progression Free Survival (PFS), Clinical Benefit Rate (CBR), response duration and safety of combination therapy.

Sekundäre Endpunkte sind das Overall Survival (OS), Progression Free Survival (PFS), Clinical Benefit Rate (CBR), Responsedauer und Sicherheit der Kombinationstherapie.

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

1. Male or female patients aged >18 years without upper age limit
2. Patient with histologically confirmed anaplastic or poorly differentiated thyroid carcinoma
3. At least one measurable target lesion according to irRECIST meeting the following criteria:
• Lymph node (LN) lesion that measures at least 1 dimension as ≥1.5 cm in the short axis
• Non-nodal lesion that measures ≥1.0 cm in the longest diameter
• The lesion is suitable for repeat measurement using computerized tomography/magnetic resonance imaging (CT/MRI). Lesions that have had external beam radiotherapy (EBRT) or locoregional therapy must show radiographic evidence of disease progression based on irRECIST to be deemed a target lesion
4. ECOG performance status of 0-1
5. Adequately controlled blood pressure (BP) with or without antihypertensive medications, defined as BP ≤160/90 mmHg at screening and no change in antihypertensive medications within 1 week before registration.
6. Adequate renal function defined as creatinine ≤1.5xULN or calculated creatinine clearance ≥30 mL/min per the Cockcroft and Gault formula if creatinine level is >1.5xULN
7. Adequate bone marrow function defined by:
• Absolute neutrophil count (ANC) ≥1,000/µL
• Platelets ≥70,000/µL
• Hemoglobin ≥8 g/dL
8. Adequate blood coagulation function defined by International Normalized ratio (INR) ≤1.5
9. Adequate liver function defined by:
• Total bilirubin ≤1.5xULN except for unconjugated hyperbilirubinemia of Gilbert’s syndrome
• Alkaline phosphatase (AP), alanine aminotransferase (ALT), and aspartate aminotransferase (AST) ≤3 xULN (in the case of liver metastases ≤5xULN), unless there are bone metastases, in which case liver specific alkaline phosphatase must be separated from the total and used to assess the liver function instead of the total alkaline phosphatase. In case alkaline phosphatase is >3 xULN (in absence of liver metastases) or >5 xULN (in presence of liver metastases) AND subject also is known to have bone metastases, the liver specific alkaline phosphatase must be separated from the total and used to assess the liver function instead of the total alkaline phosphatase
10. Written informed consent obtained according to international guidelines and local laws

1. Patienten beider Geschlechter ≥18 Jahre ohne obere Altersgrenze
2. Patient mit histologisch gesichertem anaplastischem oder gering-differenziertem Schilddrüsenkarzinom (Referenzpathologie Freiburg)
3. Mindestens eine nach irRECIST Kriterien messbare Läsion
4. ECOG Performance Status: 0-1
5. Adäquat kontrollierter Blutdruck mit oder ohne blutdrucksenkende Medikamente, definiert als BP ≤160/90 mmHg beim Screening und keine Veränderung der blutdrucksenkenden Medikamente innerhalb einer Woche vor der Registrierung
6. Adäquate Nierenfunktion definiert als Kreatinin ≥1.5xULN oder berechnete Kreatinin-Clearance ≥ 30mL/min nach der Formel Cockcroft und Gault, wenn der Kreatinininspiegel >1.5xULN ist
7. Adäquate Knochenmarksfunktion: Neutrophile/ANC ≥1.000/µL, Thrombozyten ≥70.000/µL, Hämoglobin ≥ 8 g/dL
8. Adäquat funktionierende Blutgerinnung definiert durch International Normalized Ratio (INR) ≤1.5
9. Adäquate Leberfunktion definiert durch
Total Bilirubin) ≤ 1.5xULN mit Ausnahme der unkonjugierten Hyperbilirubinämie des Gilbertsyndroms.
Alkalische Phosphatase, Alanin-Aminotransferase (ALT) und Aspartat-Aminotransferase (AST) ≤3xULN (bei Lebermetastasen ≤5xULN), sofern keine Knochenmetastasen vorhanden sind, wobei die leberspezifische alkalische Phosphatase von der Gesamtmenge getrennt und zur Beurteilung der Leberfunktion anstelle der gesamten alkalischen Phosphatase verwendet werden muss. Wenn die alkalische Phosphatase >3xULN (in Abwesenheit von Lebermetastasen) oder >5xULN (in Anwesenheit von Lebermetastasen) ist UND der Patient auch Knochenmetastasen aufweist, muss die leberspezifische alkalische Phosphatase von der Gesamtmenge getrennt und zur Beurteilung der Leberfunktion anstelle der gesamten alkalischen Phosphatase verwendet werden.
10. Vorliegen einer schriftlichen Patienten-Einwilligungserklärung, in Übereinstimmung mit den internationalen Richtlinien und den lokalen Gesetzen

E.4

Principal exclusion criteria

1. Patients who have previously received lenvatinib for more than four weeks or pembrolizumab or any other immune checkpoint inhibitor therapy (other kinase inhibitor therapies like sorafenib are permitted)
2. Patients with central nervous system (CNS) metastases, unless they have completed local therapy and have discontinued the use of corticosteroids for this indication for at least 1 week before starting treatment in this study; any signs (e.g., radiologic) or symptoms of brain metastases must be stable for at least 2 week before registration.
3. Active other malignancy within the last two years , which is not controlled by local or hormonal treatment (except for aromatase inhibitors).
4. Known intolerance to study drug (or any of the excipients)
5. Radiation therapy within 7 days prior to start of study treatment with the exception of palliative radiotherapy to bone lesions, which is allowed if completed one day prior to the first intake of lenvatinib.

1. Vortherapie mit Pembrolizumab oder Lenvatinib für mehr als 4 Wochen ist nicht erlaubt, eine Vortherapie mit Sorafenib ist erlaubt.
2. Aktive Hirnmetastasen (müssen vorher bestrahlt oder operiert werden)
3. Zeitgleiche aktive andere maligne Erkrankungen innerhalb der letzten 2 Jahre, die nicht durch lokale Massnahmen oder Hormontherapie (keine Aromataseinhibitoren) behandelbar ist.
4. Bekannte Überempfindlichkeit oder Unverträglichkeit gegen eines der Studienmedikamente oder Hilfsstoffe
5. Bestrahlung innerhalb der letzten 7 Tage (Ausnahme Bestrahlung von Knochenmetastasen)

E.5 End points

E.5.1

Primary end point(s)

Objective Response Rate (ORR) 12 weeks after start of the study treatment (Day 1).

Objective Response Rate (ORR) 12 Wochen nach Therapiebeginn (Tag 1).

E.5.1.1

Timepoint(s) of evaluation of this end point

12 weeks after start of the study treatment (Day 1)

12 Wochen nach Therapiebeginn (Tag 1)

E.5.2

Secondary end point(s)

Overall survival (OS), Progression free survival (PFS), Clinical Benefit Rate (CBR), duration of response (DOR), Quality of Life (QOL)

OS, PFS, CBR, duration of response (DOR), Lebensqualität (QOL)

E.5.2.1

Timepoint(s) of evaluation of this end point

36 months after registration of the last patient

36 Monate nach Registrierung des letzten Patienten

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

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

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

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

letzter Patientenvisit des als letztes eingeschlossenen Patienten

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)

After end of trial all patients who clinically profit from the therapy, should continue the treatment combination. Patients who do not profit from the therapy will be treated according to clinical care standards.

Am Ende der Studie sollen alle Patienten, die weiterhin von der Therapie profitieren weiterhin damit behandelt werden. Patienten die nicht von der Therapie profitieren, werden mit der Standardtherapie oder Best Supportive Care weiterbehandelt.

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

2018-11-13

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2018-11-15

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

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