Clinical Trials Register

Summary
EudraCT Number:	2019-001559-38
Sponsor's Protocol Code Number:	GEICAM/2018-06
National Competent Authority:	France - ANSM
Clinical Trial Type:	EEA CTA
Trial Status:	Trial now transitioned
Date on which this record was first entered in the EudraCT database:	2023-01-30
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

France - ANSM

A.2

EudraCT number

2019-001559-38

A.3

Full title of the trial

A Randomized Phase II Study to Evaluate the Incidence of Discontinuations due to Diarrhoea at 3 Cycles in patients with Early-stage HER2-positive (HER2+), Hormone Receptor-positive (HR+) Breast Cancer treated with Neratinib plus Loperamide prophylaxis versus Neratinib with Initial Dose Escalation plus PRN Loperamide prophylaxis versus Neratinib plus Loperamide plus Colesevelam prophylaxis. “DIANER Study”

A.3.1

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

Phase II study to evaluate diarrhoea discontinuations at 3 cycles in patients with early-stage HER2 positive, hormone receptor positive breast cancer treated with neratinib plus loperamide versus neratinib dose escalation plus loperamide administered as needed versus neratinib plus loperamide plus colesevelam

A.3.2

Name or abbreviated title of the trial where available

DIANER

A.4.1

Sponsor's protocol code number

GEICAM/2018-06

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	GEICAM (Fundación Grupo Español de Investigación en Cáncer de Mama)
B.1.3.4	Country	Spain
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	PUMA BIOTECHNOLOGY, INC
B.4.2	Country	United States
B.5 Contact point designated by the sponsor for further information on the trial
B.5.1	Name of organisation	GEICAM (Fundación Grupo Español de Investigación en Cáncer de Mama)
B.5.2	Functional name of contact point	Clinical Operations Department
B.5.3	Address:
B.5.3.1	Street Address	Avenida de los Pirineos nº 7, 1ª Planta, oficina 1-14
B.5.3.2	Town/ city	San Sebastián de los Reyes (Madrid)
B.5.3.3	Post code	28703
B.5.3.4	Country	Spain
B.5.4	Telephone number	+34916592870
B.5.5	Fax number	+34916510406
B.5.6	E-mail	geicam@geicam.org

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	Nerlynx
D.2.1.1.2	Name of the Marketing Authorisation holder	Pierre Fabre Médicament
D.2.1.2	Country which granted the Marketing Authorisation	Spain
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	Neratinib
D.3.2	Product code	PB-272; HKI-272
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	Neratinib
D.3.9.1	CAS number	698387-09-6
D.3.9.3	Other descriptive name	Neratinib
D.3.9.4	EV Substance Code	SUB32232
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	40
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	Sindiar
D.2.1.1.2	Name of the Marketing Authorisation holder	Teva Pharma, S.L.U
D.2.1.2	Country which granted the Marketing Authorisation	Spain
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	Loperamide
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	LOPERAMIDE
D.3.9.1	CAS number	53179-11-6
D.3.9.3	Other descriptive name	Loperamide
D.3.9.4	EV Substance Code	SUB08572MIG
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	2
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	Yes
D.2.1.1.1	Trade name	Cholestagel
D.2.1.1.2	Name of the Marketing Authorisation holder	Genzyme Europe B.V.
D.2.1.2	Country which granted the Marketing Authorisation	Spain
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	Colesevelam
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	Colesevelam
D.3.9.1	CAS number	182815-43-6
D.3.9.3	Other descriptive name	Colesevelam
D.3.9.4	EV Substance Code	SUB01423MIG
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	625
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

HER2+, HR+ Early stage Breast Cancer

E.1.1.1

Medical condition in easily understood language

HER2 positive, Hormone Receptor positive Early-stage Breast Cancer

E.1.1.2

Therapeutic area

Diseases [C] - Cancer [C04]

MedDRA Classification

E.1.2 Medical condition or disease under investigation

E.1.2	Version	23.0
E.1.2	Level	PT
E.1.2	Classification code	10065430
E.1.2	Term	HER2 positive 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	23.0
E.1.2	Level	PT
E.1.2	Classification code	10083234
E.1.2	Term	Hormone receptor positive breast cancer
E.1.2	System Organ Class	10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps)

E.1.3

Condition being studied is a rare disease

E.2 Objective of the trial

E.2.1

Main objective of the trial

To evaluate the incidence of neratinib discontinuations due to diarrhoea within the first 3C (1C = 28 days) in patients with early-stage HER2 overexpressed/amplified (HER2+), hormone receptor-positive (HR+) breast cancer who have completed neoadjuvant/adjuvant trastuzumab-based therapy.

E.2.2

Secondary objectives of the trial

- Incidence and time of neratinib discontinuations due to any treatment-emergent adverse event (TEAE).
- Diarrhoea due to neratinib: incidence, duration, severity, and treatment interventions.
- Incidence of neratinib discontinuation due to any reason.
- Incidence of hospitalisations (overall and for diarrhoea).
- Incidence of TEAEs and serious adverse events (SAEs) and adverse events of special interest (AESIs, ie, hepatic, cardiac, pulmonary, reproductive and developmental).
- Neratinib exposure assessment.
- Determine the effect of study treatment on quality of life, as measured by patient reported outcomes, in all treatment arms.

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

1. Male or female patient > or = 18 years of age at signing of informed consent.
2. Histologically confirmed Stage IB through Stage IIIC primary adenocarcinoma of the breast according to the 8th edition of the TNM Classification of Breast Cancer, by the UICC (Union for International Cancer Control).
3. Documented HER2-positive disease based on local laboratory determination according to ASCO/CAP 2018 criteria.
4. Documented hormone receptor-positive (HR+) disease, defined as oestrogen receptor (ER) and/or progesterone receptor (PR) > or = 1% based on local laboratory determination.
5. Patients must have completed prior neoadjuvant/adjuvant trastuzumab-based therapy (eg, trastuzumab-based treatments including trastuzumab-emtansine [T-DM1]) or experienced side effects that resulted in early discontinuation of trastuzumab-based therapy that have since resolved (pertuzumab therapy is accepted but not mandatory).
6. The last dose of trastuzumab-based therapy must have been given to the patient >2 weeks and ≤1 year (365 days) before first dose of neratinib.
7. Left ventricular ejection fraction (LVEF) > or = 50% measured by multiple-gated acquisition scan (MUGA) or echocardiogram (ECHO).
8. Eastern Cooperative Oncology Group (ECOG) status of 0 or 1.
9. Negative β-human chorionic gonadotropin (hCG) pregnancy test for premenopausal women of reproductive capacity (those who are biologically capable of having children) and for women less than 12 months after menopause. [Women are considered postmenopausal if they are > or = 12 months without menses, in the absence of endocrine or anti-endocrine therapies].
10. Women of childbearing potential must agree and commit to the use of a highly effective non-hormonal method of contraception, ie, intrauterine device, bilateral tubal ligation, vasectomized male partner, or abstinence (only when it is the preferred lifestyle of the patient), from the time of informed consent until 30 days after the last dose of the medicinal products. Male patient with female partner of childbearing potential must agree and commit with this female partner to use a highly effective method of contraception (ie, any of the above methods, or for females, hormonal contraception associated with inhibition of ovulation) while on treatment and for 3 months after last dose of medicinal products.
11. Recovery (ie, to Grade 1 or baseline) from all clinically significant adverse events (AEs) related to prior therapies (excluding alopecia, neuropathy, and nail changes).
12. Provide written, informed consent to participate in the study and follow the study procedures.

E.4

Principal exclusion criteria

1. Clinical or radiologic evidence of local or regional recurrence of disease or metastatic disease prior to or at the time of study entry.
2. Currently receiving chemotherapy, radiation therapy, immunotherapy, or biological therapy for breast cancer (adjuvant endocrine therapy is allowed).
3. Major surgery within <30 days of starting treatment or received chemotherapy, investigational agents, or other cancer therapy <14 days prior to the initiation of investigational products.
4. Active uncontrolled cardiac disease, including cardiomyopathy, congestive heart failure (New York Heart Association functional classification of > or = 2), unstable angina, myocardial infarction within 12 months of enrolment, or ventricular arrhythmia.
5. QTc interval >0.450 seconds (males) or >0.470 (females), or known history of QTc prolongation or Torsade de Pointes (TdP).
6. Screening laboratory assessments outside the following limits:
Laboratory Parameters: Required Limit for Exclusion
Absolute neutrophil count (ANC): <1,000/µl (<1.0 x 109/L).
Platelet count: <100,000/µl (<100 x 109/L).
Hemoglobin: <9 g/dL.
Total bilirubin: >1.5 x institutional upper limit of normal (ULN) (in case of known Gilbert’s syndrome, <2 x ULN is allowed).
Aspartate aminotransferase (AST) and/or alanine aminotransferase (ALT): >2.5 x institutional ULN.
Creatinine: Creatinine clearance <30 mL/min (as calculated by Cockcroft-Gault formula a or Modification of Diet in Renal Disease [MDRD] formula b).
a Cockcroft and Gault, 1976
b Levey et al, 1999

7. Active, unresolved infections.
8. Patients with a second malignancy, other than adequately treated non-melanoma skin cancers, in situ melanoma or in situ cervical cancer. Patients with other non-mammary malignancies must have been disease free for at least 5 years.
9. Currently pregnant or breast-feeding.
10. Significant chronic gastrointestinal disorder with diarrhoea as a major symptom (eg, Crohn’s disease, malabsorption, or Grade > or = 2 National Cancer Institute [NCI] Common Terminology Criteria for Adverse Events Version 5.0 [CTCAE v.5.0] diarrhoea of any etiology at baseline); or gastroparesis, dysphagia, or swallowing disorder.
11. Clinically active infection with hepatitis B or hepatitis C virus.
12. Evidence of significant medical illness, abnormal laboratory finding, or psychiatric illness/social situations that could, in the Investigator’s judgment, make the patient inappropriate for this study.
13. Known hypersensitivity to any component of the investigational products; known allergies to any of the medications or components of medications used in the trial.
14. Unable or unwilling to swallow tablets.

E.5 End points

E.5.1

Primary end point(s)

Incidence of neratinib discontinuations due to diarrhoea at the end of 3 cycles of neratinib treatment.

E.5.1.1

Timepoint(s) of evaluation of this end point

When all patients have finished the first 3 months of treatment (July 2024).

E.5.2

Secondary end point(s)

- Incidence and time to neratinib discontinuations due to any TEAE.
- Incidence, cumulative duration and time to first episode of any diarrhoea and grade 3 or higher diarrhoea.
- Incidence and time to neratinib discontinuation due to any reason.
- Incidence of hospitalisations due to any reason and diarrhoea.
- Incidence of TEAEs and SAEs that included AESIs (i.e. hepatic, cardiac, pulmonary, reproductive and developmental).
- Incidence of Neratinib dose modifications (reductions and dose holds), and dose intensity.
- FACT B and EQ5D-5L questionnaires.

E.5.2.1

Timepoint(s) of evaluation of this end point

When all patients have finished all treatment (May 2025).

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

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

Yes

E.8.1.1

Randomised

Yes

E.8.1.2

Open

E.8.1.3

Single blind

E.8.1.4

Double blind

E.8.1.5

Parallel group

Yes

E.8.1.6

Cross over

E.8.1.7

Other

E.8.2

Comparator of controlled trial

E.8.2.1

Other medicinal product(s)

Yes

E.8.2.2

Placebo

E.8.2.3

Other

E.8.2.4

Number of treatment arms in the trial

E.8.3

The trial involves single site in the Member State concerned

E.8.4

The trial involves multiple sites in the Member State concerned

Yes

E.8.4.1

Number of sites anticipated in Member State concerned

E.8.5

The trial involves multiple Member States

Yes

E.8.5.1

Number of sites anticipated in the EEA

110

E.8.6 Trial involving sites outside the EEA

E.8.6.1

Trial being conducted both within and outside the EEA

E.8.6.2

Trial being conducted completely outside of the EEA

E.8.7

Trial has a data monitoring committee

Yes

E.8.8

Definition of the end of the trial and justification where it is not the last visit of the last subject undergoing the trial

LVLS

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:

315

F.1.3

Elderly (>=65 years)

Yes

F.1.3.1

Number of subjects for this age range:

315

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

F.3.3.1

Women of childbearing potential not using contraception

F.3.3.2

Women of child-bearing potential using contraception

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

315

F.4.2.2

In the whole clinical trial

315

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)

None

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

2023-02-28

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2023-03-09

P. End of Trial
P.	End of Trial Status	Trial now transitioned

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