Clinical Trials Register

Summary
EudraCT Number:	2013-000699-14
Sponsor's Protocol Code Number:	CINC280X2204
National Competent Authority:	Netherlands - Competent Authority
Clinical Trial Type:	EEA CTA
Trial Status:	Prematurely Ended
Date on which this record was first entered in the EudraCT database:	2013-09-17
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

Netherlands - Competent Authority

A.2

EudraCT number

2013-000699-14

A.3

Full title of the trial

A Phase Ib/II, open-label, multicenter study of INC280 in combination with buparlisib in adult patients with recurrent glioblastoma

Fase Ib/II open label multicenter onderzoek met INC280 in combinatie met buparlisib bij volwassenen met een recidief glioblastoom

A.3.1

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

A clinical trial with investigational compounds INC280 and BKM120 in adult patients with recurrent glioblastoma

Een klinisch onderzoek met onderzoeksmiddelen INC280 en BKM120 bij volwassenen met een recidief glioblastoom

A.3.2

Name or abbreviated title of the trial where available

Fase Ib/II studie: INC280 met BKM120 bij een recidief glioblastoom

A.4.1

Sponsor's protocol code number

CINC280X2204

A.5.2

US NCT (ClinicalTrials.gov registry) number

NCT01870726

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	Novartis Pharma Services AG
B.1.3.4	Country	Switzerland
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	Novartis Pharma Services AG
B.4.2	Country	Switzerland
B.5 Contact point designated by the sponsor for further information on the trial
B.5.1	Name of organisation	Novartis Pharma BV
B.5.2	Functional name of contact point	Trial manager
B.5.3	Address:
B.5.3.1	Street Address	Raapopseweg 1
B.5.3.2	Town/ city	Arnhem
B.5.3.3	Post code	6824 DP
B.5.3.4	Country	Netherlands
B.5.4	Telephone number	+31263782359
B.5.5	Fax number	+31263782461
B.5.6	E-mail	nicole.appels@novartis.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	No
D.2.5.1	Orphan drug designation number
D.3 Description of the IMP
D.3.2	Product code	INC280
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.3.9.2	Current sponsor code	INC280
D.3.9.3	Other descriptive name	INC280
D.3.9.4	EV Substance Code	SUB31645
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	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	No
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.3.2	Product code	INC280
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.3.9.2	Current sponsor code	INC280
D.3.9.3	Other descriptive name	INC280
D.3.9.4	EV Substance Code	SUB31645
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	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: 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	No
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.3.2	Product code	BKM120
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	buparlisib
D.3.9.3	Other descriptive name	BKM120
D.3.9.4	EV Substance Code	SUB30592
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	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: 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	No
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.3.2	Product code	BKM120
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	buparlisib
D.3.9.3	Other descriptive name	BKM120
D.3.9.4	EV Substance Code	SUB30592
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	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: 5
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	No
D.2.5.1	Orphan drug designation number
D.3 Description of the IMP
D.3.2	Product code	INC280
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.3.9.2	Current sponsor code	INC280
D.3.9.3	Other descriptive name	INC280
D.3.9.4	EV Substance Code	SUB31645
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	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: 6
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	No
D.2.5.1	Orphan drug designation number
D.3 Description of the IMP
D.3.2	Product code	INC280
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.3.9.2	Current sponsor code	INC280
D.3.9.3	Other descriptive name	INC280
D.3.9.4	EV Substance Code	SUB31645
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	200
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: 7
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	No
D.2.5.1	Orphan drug designation number
D.3 Description of the IMP
D.3.2	Product code	INC280
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.3.9.2	Current sponsor code	INC280
D.3.9.3	Other descriptive name	INC280
D.3.9.4	EV Substance Code	SUB31645
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	100
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: 8
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.2.1.2	Country which granted the Marketing Authorisation	Netherlands
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.3.2	Product code	INC280
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.3.9.2	Current sponsor code	INC280
D.3.9.3	Other descriptive name	INC280
D.3.9.4	EV Substance Code	SUB31645
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	100
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

Glioblastoma

E.1.1.1

Medical condition in easily understood language

Glioblastoma

Glioblastoom

E.1.1.2

Therapeutic area

Diseases [C] - Cancer [C04]

MedDRA Classification

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

Phase Ib: To estimate the safe dose of the combination INC280 and buparlisib

Phase II: To estimate anti-tumor efficacy of INC280 single agent and in combination with buparlisib

Surgical arm: To estimate the concentrations of INC280 and buparlisib in tumor tissue

Fase Ib: Om de veilige dosis van de combinatie INC280 met buparlisib te bepalen
Fase II: Om de antitumorale werkzaamheid van INC280 alleen en in combinatie met buparlisib te bepalen
Chirurgische arm: Om de concentraties van INC280 en buparlisib in tumorweefselte bepalen

E.2.2

Secondary objectives of the trial

To characterize the safety of INC280 single agent and in combination with buparlisib.
To characterize the tolerability of INC280 single agent and in combination with buparlisib.
To determine pharmacokinetic profile of INC280 and buparlisib and to assess potential interaction of the combination.
To further assess the anti-tumor activity of INC280 (single agent and in combination with buparlisib).

Om de veilgheid van INC280 alleen en in combinatie met buparlisib te onderzoeken.
Om de verdraagbaarheid van INC280 alleen en in combinatie met buparlisib te onderzoeken.
Om het farmacokinetisch profiel van INC280 en buparlisib te bepalen en de mogelijke interactie van de combinatie te onderzoeken.
Om de antitumorale activiteit van INC280 (alleen en in combinatie met buparlisib) specifieker te onderzoeken.

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

• ≥ 18 years of age.
• Histologically confirmed diagnosis of glioblastoma after initial tumor resection with radiographic evidence of recurrent tumor per RANO criteria.
• Phase Ib: Documented evidence of PTEN mutations, homozygous deletion of PTEN or PTEN negative (H Score < 10) by IHC confirmed by local documentation (phase Ib only) or central assessment
• Phase II: Documented evidence of PTEN mutations, homozynous deletion of PTEN or PTEN negative (H score < 10) by IHC or c-Met amplification (GCN > 5) by FISH, all assessed centrally. Fusion transcripts or mutant c-Met (based on local data) may be eligible for single agent arm after documented agreement with Novartis.
• Must have received the following treatment for glioblastoma:
- Prior adjuvant treatment with radiotherapy and temozolomide;
- Note: A maximum of two prior chemotherapy/antibody regimens (including bevacizumab or other direct VEFG/VEGFR inhibitors) for recurrent disease are permitted.
• Representative archival glioblastoma sample (formalin-fixed paraffine embedded tissue) must be available.
• ECOG performance status ≥ 2.
• Able to swallow and retain oral medication.
• Patients in the surgical arm only: patients with recurrent glioblastoma must be eligible for surgical resection as deemed by the site Investigator.

• ≥ 18 jaar
• Histologisch bevestigde diagnose van het glioblastoom na een initiele tumorresectie met radiografisch bewijs van een recidieve tumor volgens de RANO criteria.
• Fase Ib: Gedocumenteerd bewijs van PTEN mutaties, homozygote deletie van PTEN of negatieve PTEN (H Score < 10) bevestigd met IHC middels lokale documentatie (alleen fase Ib) of centraal onderzoek.
• Fase II: Gedocumenteerd bewijs van PTEN mutaties, homozygote deletie van PTEN of negatieve PTEN (H Score < 10) bevestigd met IHC of c-Met amplificatie (GCN > 5) middels FISH, allen centraal bepaald. Fusion transcripten of mutant c-Met (gebaseerd op lokale data) kunnen geschikt zijn voor de monotherapiearm na gedocumenteerde overeenkomst met Novartis.
• Dient de volgende behandeling voor glioblastoma te hebben gehad:
- Eerdere adjuvante behandeling met radiotherapie en temozolomide;
- Notitie: Maximaal 2 eerdere chemotherapie/antilichaam behandelingen (inclusief bevacizumab of een andere directe VEFG/VEGFR remmer) voor de terugkerende ziekte zijn toegestaan.
• Aanwezigheid van een representatief tumormonster van het glioblastoom (uit archief)
• ECOG performance status ≥ 2.
• Dient in staat te zijn om de medicatie in te slikken en binnen te houden.
• Alleen voor patienten in de chirurgische arm: patienten met een recidiverend glioblastoom die volgens de onderzoeker geschikt zijn voor chirurgische resectie.

E.4

Principal exclusion criteria

• Prior or current treatment with a c-MET inhibitor or HGF-targeting therapy
• Prior treatment with a PI3K and/or mTOR inhibitors for glioblastoma or for pre-existing neoplasm transformed to glioblastoma (applicable for combination treatment arm only).
• Receiving treatment with medications that are known strong inhibitors or inducers of CYP3A, and cannot be discontinued 7 days prior to the start of the treatment and during the course of the study.
• Receiving treatment with medications that are known CYP3A or CYP1A2 substrates with narrow therapeutic index, and cannot be discontinued during the course of the study.
• Currently being treated with Enzyme Inducing Anti-Epileptic Drug (EIAED). If previously on an EIAED, the patient must be off of it for at least 2 weeks prior to study treatment.
• Currently receiving warfarin or other coumadin-derived anticoagulants for treatment, prophylaxis or otherwise.
• Currently receiving increasing or chronic treatment ( > 5 days) with corticosteroids or another immunosuppressive agent.
• History of acute or chronic pancreatitis or any risk factors that may increase the risk of pancreatitis.
• Active cardiac disease or a history of cardiac dysfunction.
• Impairment of gastrointestinal (GI) function or GI disease that might significantly alter the absorption of study drug
• Medically documented history of or active major depressive episode, bipolar disorder (I or II), obsessive-compulsive disorder, schizophrenia, a history of suicidal attempt or ideation, or homicidal ideation (e.g. risk of doing harm to self or others), or patients with active severe personality disorders (defined according to DSM- IV).
• Anxiety ≥ CTCAE grade 3
• Any of the following baseline laboratory values:
- Hemoglobin < 9 g/dL
- Platelet count < 75 x 109/L
- Absolute neutrophil count (ANC) < 1.0 x 109/L
-INR > 1.5
- Serum lipase > normal limits for the institution
- Asymptomatic serum amylase > grade 2
- Potassium, magnesium, and calcium (corrected for albumin) > normal limits for the institution
- Total bilirubin >1.5 x upper limit of normal (ULN)
- Serum creatinine >1.5 x ULN or creatinine clearance ≤ 45 mL/min
- Alanine aminotransferase (AST) or aspartate aminotransferase (ALT) > 3.0 x ULN (or > 5.0 X ULN if liver metastases are present)
- Fasting plasma glucose > 120mg/dL or > 6.7 mmol/L
- HbA1c > 8%.

• Eerdere of huidige behandeling met een c-MET remmer of HGF-targeting behandeling
• Eerdere behandeling met een PI3K en/of mTOR remmer voor glioblastoma of voor een bestaande neoplasme welke is getransformeerd tot een glioblastoma (alleen van toepassing voor de combinatie arm)
• Actuele behandeling met medicamenten waarvan bekend is dat het CYP3A sterk remt of induceerd, welke niet 7 dagen voor start van de studiemedicatie of tijdens de studie kan worden gestaakt.
• Actuele behandeling met medicamenten waarvan bekend is dat het CYP3A of CYP1A2 substraten met een nauwe therapautische index zijn, welke niet tijdens de studie kunnen worden gestaakt.
• Actuele behandeling met enzym-geinduceerde anti-epileptisch medicament. Laatste behandeling dient minimaal 2 weken gestaakt te zijn voor de studiemedicatie.
• Actuele behandeling met warfarine of een ander van-coumadine-afkomstige antistolling.
• Actuele toenemende of chronische behandeling ( > 5 dagen) met corticosteroiden of een ander immunosuppressief middel.
• Geschiedenis van acute of chronische pancreatitis of een mogelijke risicofactor welke de kans op pancreatitis kan vergroten.
• Actieve hartziekte of geschiedenis van hartdysfunctie.
• Schade aan het maagdarmkanaal of een maagdarmziekte welke de absorptie van de studiemedicatie aanzienlijk kan veranderen.
• Medisch gedocumenteerde geschiedenis van een actieve ernstige depressie, bipolaire stoornis (I or II), obsessieve-compulsieve stoornis, schizofrenie, geschiedenis van zelfmoorpoging of -neiging, of moordneiging (risico op het toebrengen van schade aan zichzelf of anderen), of patienten met actieve enstige persoonlijkheidsstoornissen (gedefinieerd volgens DSM- IV).
• Angst ≥ CTCAE grade 3
• Een van de volgende baseline labwaarden:
- Hemoglobine < 9 g/dL
- Bloedplaatjes < 75 x 109/L
- Absolute neutrofiel telling < 1.0 x 10e9/L
-INR > 1.5
- Serum lipase > normaalwaarden van onderzoekscentrum
- Asymptomatische serum amylase > grade 2
- Kalium, magnesium, en calcium (gecorrigeerd voor albumine) > normaalwaarden van onderzoekscentrum
- Totaal bilirubin >1.5 x bovengrens
- Serum creatinine >1.5 x bovengrens of creatinine klaring ≤ 45 mL/min
- ASAT of ALAT > 3.0 ULN (of >5.0 x bovengrens indien aanwezigheid van levermetastasen)
- Nuchter plasma glucose > 120mg/dL of > 6.7 mmol/L
- HbA1c > 8%.

E.5 End points

E.5.1

Primary end point(s)

a) Phase II: Progression free survival rate (PFSR)
b) Phase Ib: Incidence of dose limiting toxicities (DLTs)
c) Surgical arm (combination arm only): Concentrations of INC280 and buparlisib in tumor

a) Fase II: Percentage progressievrije overleving
b) Fase Ib: Incidentie van dosislimiterende toxiciteiten
c) Chirurgische arm (alleen combinatie arm): Concentraties van INC280 en buparlisib in de tumor

E.5.1.1

Timepoint(s) of evaluation of this end point

a) 6 months
b) 28 days
c) 7 days

a) 6 maanden
b) 28 dagen
c) 7 dagen

E.5.2

Secondary end point(s)

1) Type, frequency, and severity of adverse events and serious adverse events.
2) Tolerability: dose interruptions, reductions and dose intensity.
3) Plasma concentration of INC280 and buparlisib, and PK parameters, including but not limited to Cmax, Tmax, AUCtau, and T1/2.
4) Overall response rate (ORR)
5) Overall survival (OS)

1) Type, frequentie, en ernst van bijwerkingen (AEs en SAEs).
2) Verdraagbaarheid: dosisstakingen, verlagingen en dosisintensiteit.
3) Plasma concentratie van INC280 en buparlisib, en PK parameters, inclusief maar niet alleen Cmax, Tmax, AUCtau, en T1/2.
4) Percentage totale respons
5) Totale overleving

E.5.2.1

Timepoint(s) of evaluation of this end point

1) 3 months
2) 3 months
3) 3 months
4) 12 months
5) 12 months

1) 3 maanden
2) 3 maanden
3) 3 maanden
4) 12 maanden
5) 12 maanden

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

E.6.4

Safety

Yes

E.6.5

Efficacy

Yes

E.6.6

Pharmacokinetic

Yes

E.6.7

Pharmacodynamic

Yes

E.6.8

Bioequivalence

E.6.9

Dose response

Yes

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)

Yes

E.7.1.1

First administration to humans

E.7.1.2

Bioequivalence study

E.7.1.3

Other

Yes

E.7.1.3.1

Other trial type description

dose escalation study of INC280 in combination with buparlisib

dosis escalatie studie van INC280 in combinatie met buparlisib

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