Clinical Trials Register

Summary
EudraCT Number:	2016-001925-15
Sponsor's Protocol Code Number:	ISS20159321
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:	2018-08-23
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

2016-001925-15

A.3

Full title of the trial

Evaluation of immunological effects of the RANKL-inhibitor Denosumab when administered concurrently with PD1-blocking antibodies (Nivolumab, Pembrolizumab) in patients with metastatic malignant melanoma with bone involvement

Evaluierung immunologischer Effekte des RANKL-Inhibitors Denosumab bei gleichzeitiger Gabe von PD-1 blockierenden Antikörpern (Nivolumab, Pembrolizumab) bei Patienten mit metastasiertem malignem Melanom mit Knochenmetastasen

A.3.1

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

Effects of a treatment with Denosumab, applied together with either Nivolumab oder Pembrolizumab, in patients with skin cancer and bone metastases

Effekte einer Behandlung mit Denosumab in Kombination mit etnweder Nivolumab oder Pembrolizumab auf Patienten mit Hautkrebs und Knochenmetastasen

A.3.2

Name or abbreviated title of the trial where available

BONEMET

A.4.1

Sponsor's protocol code number

ISS20159321

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	Alcedis GmbH
B.1.3.4	Country	Germany
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	Amgen 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	Johannes Wesling Klinikum Minden
B.5.2	Functional name of contact point	Universitätsklinik für Dermatologie
B.5.3	Address:
B.5.3.1	Street Address	Hans-Nolte-Straße 1
B.5.3.2	Town/ city	Minden
B.5.3.3	Post code	32429
B.5.3.4	Country	Germany
B.5.4	Telephone number	+495717904500
B.5.5	Fax number	+49571790294500
B.5.6	E-mail	ralf.gutzmer@muehlenkreiskliniken.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	XGEVA
D.2.1.1.2	Name of the Marketing Authorisation holder	Amgen Europe B.V. Minervum 7061 NL-4817 ZK Breda Niederlande
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	DENOSUMAB
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	Subcutaneous use
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.2.1.2	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	OPDIVO
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	NIVOLUMAB
D.3.9.1	CAS number	946414-94-4
D.3.9.3	Other descriptive name	NIVOLUMAB
D.3.9.4	EV Substance Code	SUB122750
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: 3
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.2.1.2	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.3.4	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	PEMBROLIZUMAB
D.3.9.1	CAS number	1374853-91-4
D.3.9.4	EV Substance Code	SUB167136
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	25
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: 4
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.2.1.2	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	YERVOY
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	IPILIMUMAB
D.3.9.1	CAS number	477202-00-9
D.3.9.4	EV Substance Code	SUB29397
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	5
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

Metastatic malignant melanoma

Metastasiertes malignes Melanom

E.1.1.1

Medical condition in easily understood language

Skin cancer with bone metastases

Hautkrebs mit Knochenmetastatsen

E.1.1.2

Therapeutic area

Diseases [C] - Skin and Connective Tissue Diseases [C17]

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	10025671
E.1.2	Term	Malignant melanoma stage IV
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	10025650
E.1.2	Term	Malignant melanoma
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	10027480
E.1.2	Term	Metastatic malignant melanoma
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

This phase IV study aims to investigate possible immunologic and biologic effects of the concurrent administration of PD-1 blocking antibodies and denosumab as primary endpoint.

E.2.2

Secondary objectives of the trial

Not applicable.

E.2.3

Trial contains a sub-study

Yes

E.2.3.1

Full title, date and version of each sub-study and their related objectives

Translational Research Project

Translationales Forschungsprojekt.

E.3

Principal inclusion criteria

• Provision of tumor tissue from metastatic site of disease for biomarker analyses and confirmation by central laboratory. Tumor tissue must be obtained before PD-1 inhibitor therapy (either baseline FFPE sample or archival tissue (ideally obtained after preceding medical tumor therapies).
• Inoperable metastatic stage IV melanoma arising from a primary cutaneous site or metastatic from an unknown primary site or melanoma of mucosal or uveal origin.
• Planned therapy with PD-1 blocking antibody (nivolumab or nivolumab + ipilimumab or pembrolizumab) and denosumab as standard of care.
• Measurable disease according to RECIST1.1 and at least one documented bone metastasis.
• Age 18 years or above.
• Written, informed consent.
• Subjects must be willing and able to comply with scheduled visits, treatment schedule, laboratory testing, and other requirements of the study
• Minimum life expectancy of 6 months
• ECOG performance status of 0-2
• Screening laboratory values must meet the following criteria and should be obtained within 14 days prior to registration:
WBC ≥ 2000/μL
Neutrophils ≥ 1000/μL
Platelets ≥ 100 x103/μL
Hemoglobin ≥ 9.0 g/dL
Serum creatinine ≤ 2.0 x ULN OR
Creatinine clearance (CrCl) ≥ 35mL/min (using the Cockcroft-Gault formula)
• AST/ALT ≤ 3 x ULN, in case of liver metastases ≤ 5 x ULN
Total Bilirubin ≤ 2.0 x ULN (except subjects with Gilbert Syndrome, who may have total bilirubin up to 5 x ULN)
• Serum calcium or albumin-adjusted serum calcium within normal limits
• Prior radiotherapy must have been completed prior to study drug administration
• Negative pregnancy test for female subjects within the week before treatment start and effective contraception for both male and female subjects if the risk of conception exists

• Bereitstellung von Tumorgewebe einer Metastase des malignen Melanoms für Biomarker –Analysen und zur Bestätigung der Diagnose durch ein zentrales Labor. Das Tumorgewebe muss vor Start der PD-1-Inhibitor-Therapie entnommen werden (entweder neue FFPE Probe zur Baseline oder vorhandene Probe, die idealerweise nach vorherigen Tumortherapien entnommen wurde)
• Inoperables, metastasiertes Melanom des Stadiums IV, ausgehend von einer kutanen Primärläsion oder von einer Primärläsion unbekannter Lokalisation oder von primärem Schleimhautmelanom oder von primärem Aderhautmelanom
• Geplante Therapie mit einem PD-1 blockierenden Antikörper (Nivolumab oder Nivolumab + Ipilimumab oder Pembrolizumab) und Denosumab als Therapiestandard
• Messbare Erkrankung (Vorhandensein mindestens einer nach RECIST 1.1 messbaren Läsion) und mindestens eine dokumentierte Knochenmetastase
• Alter ≥ 18 Jahre
• Vorliegen der unterschriebenen Einverständniserklärung
• Der Patient ist willens und fähig, den Studienvorgaben (z.B. geplante Visiten, Behandlungsplan, Laboruntersuchungen) nachzukommen
• Lebenserwartung ≥ 6 Monate
• ECOG Performance Status von 0-2
• Die Laborwerte aus dem Screening müssen den folgenden Kriterien entsprechen. Die Laboruntersuchungen im Screening sollen innerhalb von 14 Tagen vor der Registrierung erfolgen.
o Leukozytenzahl (WBC) ≥ 2000/μL
o Neutrophile ≥ 1000/μL
o Thrombozyten ≥ 100 x103/μL
o Hämoglobin ≥ 9.0 g/dL
o Serumkreatinin ≤ 2.0xULN ODER
o Kreatinin Clearance ≥ 35mL/min (unter Verwendung der Cockcroft-Gault Formel)
o AST/ALT ≤ 3 x ULN, bei Lebermetastasen ≤ 5 x ULN
o Gesamtbilirubin ≤ 2.0 x ULN (ausgenommen Patienten mit Gilbert- Syndrom, für die ein Gesambilirubinwert von bis zu 5 x ULN erlaubt ist)
o Serumkalzium oder Albumin-korrigiertes Serumkalzium innerhalb üblicher Grenzwerte
• Eine vorangegangene Radiotherapie muss vor der ersten Gabe der Studientherapie abgeschlossen worden sein
• Vorliegen eines negativen Schwangerschaftstests innerhalb einer Woche vor der ersten Gabe der Studientherapie für weibliche Patienten. Weibliche und männliche Patienten müssen wirksam verhüten, falls das Risiko einer Empfängnis besteht

E.4

Principal exclusion criteria

• Prior therapy with CTLA4-inhibitor or PD-1-inhibitor or denosumab for distant metastatic disease. Treatments in the adjuvant setting are allowed in case treatment was discontinued at least 4 weeks before inclusion in this study.
• No other concurrent medical treatments for metastatic disease such as targeted therapies or chemotherapies are allowed. Treatments in the adjuvant setting are allowed in case treatment was discontinued at least 4 weeks before inclusion in this study.
• Active CNS metastases requiring local therapy or steroid therapy.
• Use of any investigational or non-registered product (drug or vaccine) within the past 30 days before study start and during study.
• Psychiatric or addictive disorders of the patient that may compromise his/her ability to give informed consent or to comply with the trial procedures.
• Significant dental/oral disease, including prior history or current evidence of osteonecrosis/osteomyelitis of the jaw, or the following: Active dental or jaw condition which requires oral surgery. Non-healed dental/oral surgery. Planned invasive dental procedures for the course of the study.
• Relevant immune deficiencies or relevant autoimmune disease, as assessed by the investigator.
• Other malignancies within the past three years which need treatment except basal or squamous skin carcinomas or carcinoma in situ of the cervix
• Serious cardiac, gastrointestinal, hepatic or pulmonary disease
• Patients with serious intercurrent illness, requiring hospitalization.
• Other serious illnesses, e.g., serious infections requiring intravenous antibiotics or bleeding disorders.
• Hypersensitivity to the active substances of study treatment or to any of the excipients (calcium, vitamin D)
• Hereditary fructose intolerance
• Women of childbearing potential: Refusal or inability to use highly effective means of contraception
• For female patients: the patient is pregnant or lactating or planning to become pregnant within 5 months after the end of the treatment.

• Vorangegangene Therapie mit einem CTLA4-Inhibitor oder einem PD-1-Inhibitor oder Denosumab für das fernmetastasierte Melanom. Behandlungen im adjuvanten Setting sind erlaubt, sofern die Behandlung mindestens 4 Wochen vor Studieneinschluss beendet wurde.
• Gleichzeitige medizinische Behandlung des metastasierten Melanoms mit einer zielgerichteten Therapie oder mit einer Chemotherapie. Behandlungen im adjuvanten Setting sind erlaubt, sofern die Behandlung mindestens 4 Wochen vor Studieneinschluss beendet wurde.
• Aktive ZNS Metastasen, die eine lokale Behandlung oder Steroidtherapie erfordern.
• Behandlung mit einer Prüfsubstanz oder einem nicht-zugelassenem Produkt (Arzneimittel oder Impfstoff) innerhalb von 30 Tagen vor Studieneinschluss und während der Studienteilnahme.
• Psychiatrische Erkrankungen oder Suchterkrankungen, durch die die Fähigkeit der Patientin/des Patienten der Studienteilnahme zuzustimmen oder die Studienvorgaben einzuhalten, beeinträchtigt wird.
• Signifikante zahnmedizinische/orale Erkrankung, inklusive
o der Vorgeschichte oder des aktuellen Vorliegens einer Osteonekrose/einer Osteomyelitis des Kieferknochens
o Aktive zahnmedizinische Erkrankung oder Kiefererkrankung, die einer Operation bedarf
o Nicht-ausgeheilte zahnmedizinische/dentale Operation
o Geplanter invasiver zahnmedizinischer Eingriff für den Zeitraum der Studienteilnahme
• Relevante Immundefizienz oder relevante Autoimmunerkrankung
• Andere behandlungsbedürftige bösartige Tumorerkrankungen innerhalb der letzten drei Jahre, ausgenommen Basalzellkarzinom, Plattenepithelkarzinom der Haut oder Carcinoma in situ des Gebärmutterhalses
• Schwere Herzerkrankung, schwere gastrointestinale Erkrankung, schwere Lungenerkrankung
• Patienten mit schwerer interkurrenter Erkrankung, die eine Hospitalisierung notwendig macht
• Andere schwere Erkrankung, z.B. schwere Infektionen für die eine intravenöse Antibiotikatherapie erforderlich ist oder Blutgerinnungsstörungen
• Überempfindlichkeit gegenüber den in der Studie angewendeten Wirkstoffen, gegenüber Hilfsstoffen der Studienmedikation sowie gegenüber ergänzender Medikation (Kalzium, Vitamin D)
• Erbliche Fruktoseintoleranz
• Für Frauen im gebärfähigen Alter: Weigerung oder Unfähigkeit, hochwirksame Methoden zur Empfängnisverhütung anzuwenden
• Schwangere, laktierende oder stillende Patientinnen, sowie Patientinnen die planen, innerhalb von 5 Monaten nach Therapieende schwanger zu werden

E.5 End points

E.5.1

Primary end point(s)

1) Dynamic changes of the numbers of central memory, effector memory and/or effector T-cells in the circulating blood (based on expression of CD45RA, CD45RO, CCR7, CD62L, and TCF-1)
2) Dynamic changes of the numbers of cytokine and chemokine present in circulating blood.

1) Dynamische Änderungen in der Anzahl von zentralen Gedächtnis-T-Zellen, Effektor-Gedächtnis-T-Zellen und/oder Effektor-T-Zellen im zirkulierenden Blut (basierend auf der Expression von CD45R, CD45RO, CCR7, CD62L undTCF-1)
2) Dynamische Änderungen in der Anzahl von Cytokinen und Chemokinen im zirkulierenden Blut

E.5.1.1

Timepoint(s) of evaluation of this end point

Variables will be determined at baseline, and after 4, 12 and 24 weeks of therapy.

Die Variablen werden vor Beginn der Studientherapie (Baseline) und 4, 12 und 24 Wochen nach Beginn der Studientherapie bestimmt.

E.5.2

Secondary end point(s)

• Safety
Occurrence of adverse events as assessed by NCI CTC-AE criteria version 5.0
• Efficacy

• Sicherheit
Auftreten unerwünschter Ereignisse (die Bestimmung erfolgt gemäß den NCI CTC-AE Kriterien Version 5.0)
• Wirksamkeit

E.5.2.1

Timepoint(s) of evaluation of this end point

1) Overall response rate at 12 and 24 weeks as determined by RECIST 1.1 criteria
2) Response rate of bone metastases after 12 and 24 weeks of treatment (size and number) as determined by RECIST 1.1 and bone scans

1) Allgemeine Ansprechrate nach 12 und 24 Wochen (die Bestimmung erfolgt gemäß den RECIST 1.1 Kriterien)
2) Ansprechrate der Knochenmetastasen nach 12 und 24 Wochen (Größe und Anzahl) (die Bestimmung erfolgt gemäß den RECIST 1.1 Kriterien und Knochen Scans)

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)

E.7.4

Therapeutic use (Phase IV)

Yes

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.8.2.4

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

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

Last patient last visit (LPLV)

Letzter Besuch des letzten Patienten (LPLV)

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)

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)

Following the end of treatment evaluation or the end of study for any other cause, patients will be treated and followed according to the guidelines of the German Cancer Society.

Nach dem Ende der Behandlung im Rahmen der Studie oder nach dem Ende der Studie für welchen Grund auch immer, werden die Patienten nach den Leitlinien der Deutschen Krebsgesellschaft weiter behandelt oder in Nachsorge übernommen .

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

2018-09-13

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2018-10-22

P. End of Trial
P.	End of Trial Status	Completed
P.	Date of the global end of the trial	2021-08-30

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