Clinical Trials Register

Summary
EudraCT Number:	2019-002637-11
Sponsor's Protocol Code Number:	CBYL719H12301
National Competent Authority:	Slovakia - SIDC (Slovak)
Clinical Trial Type:	EEA CTA
Trial Status:	Ongoing
Date on which this record was first entered in the EudraCT database:	2020-02-26
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

Slovakia - SIDC (Slovak)

A.2

EudraCT number

2019-002637-11

A.3

Full title of the trial

EPIK-B3: A Phase III, multicenter, randomized, double-blind, placebo-controlled study to assess the efficacy and safety of alpelisib (BYL719) in combination with nab-paclitaxel in patients with advanced triple negative breast cancer with either phosphoinositide-3-kinase catalytic subunit alpha (PIK3CA) mutation or phosphatase and tensin homolog protein (PTEN) loss without PIK3CA mutation.

EPIK-B3: Multicentrické randomizované dvojito zaslepené placebom kontrolované klinické skúšanie fázy III na zhodnotenie účinnosti a bezpečnosti alpelisibu (BYL719) v kombinácii s nab-paklitaxelom u pacientov s pokročilým trojnásobne negatívnym karcinómom prsníka s mutáciou katalytickej podjednotky alfa fosfoinozitid 3 kinázy (PIK3CA) alebo so stratou proteínu - homológu fosfatázy a tenzínu (PTEN) bez mutácie PIK3CA

A.3.1

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

Study assessing the efficacy and safety of alpelisib plus nab-paclitaxel in subjects with advanced triple negative breast cancer who carry either a PIK3CA mutation or have PTEN loss without PIK3CA mutation

Klinické skúšanie hodnotiace účinnosť a bezpečnosť alpesilibu v kombinácii s nab-paklitaxelom v liečbe pacientov s pokročilým trojnásobne negatívnym karcinómom prsníka, ktorí majú buď mutáciu PIK3CA alerbo majú stratu PTEN bez mutácie PIK3CA.

A.3.2

Name or abbreviated title of the trial where available

EPIK-B3

A.4.1

Sponsor's protocol code number

CBYL719H12301

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 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 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 Slovakia s.r.o.
B.5.2	Functional name of contact point	DRA information desk
B.5.3	Address:
B.5.3.1	Street Address	Žižkova 22/B
B.5.3.2	Town/ city	Bratislava
B.5.3.3	Post code	811 02
B.5.3.4	Country	Slovakia
B.5.4	Telephone number	+421 2 50706116
B.5.5	Fax number	+421 2 50706100
B.5.6	E-mail	dra.slovakia@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.3.1	Product name	Alpelisib
D.3.2	Product code	BYL719
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	ALPELISIB
D.3.9.1	CAS number	1217486-61-7
D.3.9.2	Current sponsor code	BYL719
D.3.9.4	EV Substance Code	SUB180707
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: 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.3.1	Product name	Alpelisib
D.3.2	Product code	BYL719
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	ALPELISIB
D.3.9.1	CAS number	1217486-61-7
D.3.9.2	Current sponsor code	BYL719
D.3.9.4	EV Substance Code	SUB180707
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	Comparator
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.2.5	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.3.4	Pharmaceutical form	Powder for suspension for injection
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	paclitaxel
D.3.9.3	Other descriptive name	PACLITAXEL ALBUMIN-BOUND NAB-PACLITAXEL
D.3.9.4	EV Substance Code	SUB127678
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	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
D.8 Placebo: 1
D.8.1	Is a Placebo used in this Trial?	Yes
D.8.3	Pharmaceutical form of the placebo	Film-coated tablet
D.8.4	Route of administration of the placebo	Oral use
D.8 Placebo: 2
D.8.1	Is a Placebo used in this Trial?	Yes
D.8.3	Pharmaceutical form of the placebo	Film-coated tablet
D.8.4	Route of administration of the placebo	Oral use

E. General Information on the Trial

E.1 Medical condition or disease under investigation

E.1.1

Medical condition(s) being investigated

Advanced triple negative breast cancer

E.1.1.1

Medical condition in easily understood language

Advanced triple negative breast neoplasm

E.1.1.2

Therapeutic area

Diseases [C] - Cancer [C04]

MedDRA Classification

E.1.2 Medical condition or disease under investigation

E.1.2	Version	21.1
E.1.2	Level	PT
E.1.2	Classification code	10057654
E.1.2	Term	Breast cancer female
E.1.2	System Organ Class	10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps)

E.1.2 Medical condition or disease under investigation

E.1.2	Version	20.0
E.1.2	Level	PT
E.1.2	Classification code	10006187
E.1.2	Term	Breast cancer
E.1.2	System Organ Class	10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps)

E.1.2 Medical condition or disease under investigation

E.1.2	Version	20.1
E.1.2	Level	PT
E.1.2	Classification code	10055113
E.1.2	Term	Breast cancer metastatic
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

Part A and Part B2
•to determine whether treatment with alpelisib in combination with nab-paclitaxel prolongs Progression Free Survival (PFS) compared to placebo in combination with nab-paclitaxel
Part B1
•to assess the antitumour activity of alpelisib in combination with nab-paclitaxel based on the Overall Response Rate (ORR) with confirmed response at 6 months via local radiology assessments

E.2.2

Secondary objectives of the trial

Part A and Part B2 key secondary objective:
•to determine whether treatment with alpelisib in combination with nab-paclitaxel prolongs OS
Part A and Part B2 secondary objectives:
•To evaluate safety and tolerability
•To further evaluate the efficacy of alpelisib in combination with nab-paclitaxel measuring the ORR, CBR, DOR and TTR based on local radiological assessments•To characterize exposure of alpelisib and nab-paclitaxel •To evaluate PROs •To evaluate the association between PIK3CA mutation status as measured in ctDNA at baseline with PFS upon treatment with alpelisib
•To evaluate the time to definitive deterioration of the ECOG performance status from baseline
Part B1 secondary objectives:
•To evaluate safety and tolerability•To further evaluate the efficacy measuring the CBR with confirmed response, DOR with confirmed response and TTR based on local radiological assessments
•To characterize exposure of alpelisib and nab-paclitaxel when administered in combination

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

- Subject has histologically confirmed diagnosis of advanced (loco-regionally recurrent and not amenable to curative therapy, or metastatic (stage IV)) TNBC - Subject has either a measurable disease per RECIST 1.1 criteria or, if no measurable disease is present, then at least one predominantly lytic bone lesion or mixed lytic-blastic bone lesion with identifiable soft tissue component (that can be evaluated by CT/MRI) must be present Part B1: patients must have measurable disease - Subject has adequate tumor tissue to identify the PIK3CA mutation status (either carrying a mutation or without a mutation) and the PTEN loss status; both of which will determine whether the subject can be allocated to Part A - PIK3CA mutation regardless of PTEN status; or to Part B - PTEN loss without a PIK3CA mutation - Subject has an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1 - Subject has received no more than one line of therapy for metastatic disease. - Subject has adequate bone marrow and organ function

E.4

Principal exclusion criteria

- Subject has received prior treatment with any PI3K, mTOR or AKT inhibitor - Subject has a known hypersensitivity to alpelisib, nab-paclitaxel or to any of their excipients - Subject has not recovered from all toxicities related to prior anticancer therapies to NCI CTCAE version 4.03 Grade ≤1; with the exception of alopecia - Subject has central nervous system (CNS) involvement - Subject with an established diagnosis of diabetes mellitus type I or uncontrolled type II based on Fasting Plasma Glucose and HbA1c - Subject has impairment of gastrointestinal (GI) function or GI disease that may significantly alter the absorption of the study drugs (e.g., ulcerative diseases, uncontrolled nausea, vomiting, diarrhea, malabsorption syndrome, or small bowel resection) based on investigator discretion - Subject has a history of acute pancreatitis within 1 year of screening or past medical history of chronic pancreatitis - Subject has currently documented pneumonitis/interstitial lung disease - Subject has a history of severe cutaneous reactions, such as Steven-Johnson Syndrome (SJS), erythema multiforme (EM),Toxic Epidermal Necrolysis (TEN) or Drug Reaction with Eosinophilia and Systemic Syndrome (DRESS) - Subject with unresolved osteonecrosis of the jaw Other protocol-defined inclusion/exclusion criteria apply

E.5 End points

E.5.1

Primary end point(s)

Progression-free Survival (PFS) Per Investigator Assessment in Study part A
Progression-free Survival (PFS) Per Investigator Assessment in Study part B2
Overall Response Rate (ORR) based on local radiology assessments in subjects with measurable disease at baseline in study Part B1

E.5.1.1

Timepoint(s) of evaluation of this end point

Part A : Once approximately 192 PFS events in Study Part A had been observed, up to 35 months

PartB2 : Once approximately 192 PFS events in Study Part A had been observed, up to 22 months

Part B1 up to 6 months

E.5.2

Secondary end point(s)

Overall Survival (OS) in Study Part A
Overall Survival (OS) in Study Part B2
Overall response rate (ORR) with confirmed response in Study Part A and B2
Clinical benefit rate (CBR) with confirmed response, in Study Parts A, B1 and B2
Time to response (TTR), in Study Parts A, B1 and B2
Duration of Response (DOR) with confirmed response, in Study Parts A, B1 and B2
Time to definitive deterioration of the ECOG performance status from baseline, in Study Parts A and B2
Overall Survival (OS) in Study Part B2
Progression-free Survival (PFS) Per Investigator Assessment in Study part B1
Safety and Tolerability of alpelisib in Combination With nab-paclitaxel in study Parts A, B1 and B2
Summary statistics of plasma alpelisib concentrations by time point in study Parts A, B1 and B2 Day 8 and Day 15 of Cycle 1, then Day 1 of Cycles 2, 4 and 6
Summary statistics of plasma paclitaxel concentrations by time point in study Parts A and B1 Day 8 of Cycle 1, then Day 1 of Cycles 2 and 4
Change from baseline in the global health status/QoL scale score of the EORTC QLQ-C30 in study Parts A and B1
Time to 10% definitive deterioration in the global health status/QOL scale score of the EORTC QLQ-C30 in study Parts A and B1
PFS based on local radiology assessments using RECIST 1.1 criteria for subjects by PIK3CA mutation status measured in baseline ctDNA in study Parts A and B2

E.5.2.1

Timepoint(s) of evaluation of this end point

Part A up to 66 months
Part B2 up to 41 months

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

Yes

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

E.8.1.3

Single blind

E.8.1.4

Double blind

Yes

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)

E.8.2.2

Placebo

Yes

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

Yes

E.8.5.1

Number of sites anticipated in the EEA

105

E.8.6 Trial involving sites outside the EEA

E.8.6.1

Trial being conducted both within and outside the EEA

Yes

E.8.6.2

Trial being conducted completely outside of the EEA

E.8.6.3

If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned

Argentina

Australia

Austria

Brazil

Bulgaria

Canada

China

Colombia

Croatia

France

Germany

Hungary

India

Israel

Italy

Kenya

Korea, Republic of

Lebanon

Malaysia

Mexico

Norway

Peru

Poland

Romania

Russian Federation

Saudi Arabia

Serbia

Slovakia

Slovenia

South Africa

Spain

Switzerland

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

Study completion is defined as when the last subject, regardless of Study Part, finishes their safety and efficacy follow-up periods (as applicable) and any repeat assessments associated with these visits have been documented and followed-up appropriately by the Investigator or, in the event of an early study termination decision, the date of that decision.

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

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:

495

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.4.2

For a multinational trial

F.4.2.1

In the EEA

247

F.4.2.2

In the whole clinical trial

566

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)

At the end of the study, every effort will be made to continue provision of study treatment outside this study through an alternative setting to subjects who in the opinion of the Investigator are still deriving clinical benefit.

G. Investigator Networks to be involved in the Trial

N. Review by the Competent Authority or Ethics Committee in the country concerned

Competent Authority Decision

Authorised

Date of Competent Authority Decision

2020-04-24

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2020-04-17

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

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