Clinical Trials Register

Summary
EudraCT Number:	2015-004374-15
Sponsor's Protocol Code Number:	PUMA-NER-6201
National Competent Authority:	Austria - BASG
Clinical Trial Type:	EEA CTA
Trial Status:	Completed
Date on which this record was first entered in the EudraCT database:	2018-06-20
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

Austria - BASG

A.2

EudraCT number

2015-004374-15

A.3

Full title of the trial

An Open Label Study to Characterize the Incidence and Severity of Diarrhea in Patients with Early Stage HER2+ Breast Cancer Treated with Neratinib and Loperamide

A.3.1

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

A clinical study to examine the occurrence and severity of diarrhea in breast cancer patients receiving Neratinib (an investigational medicine for cancer) and Loperamide (used to treat diarrhea)

A.4.1

Sponsor's protocol code number

PUMA-NER-6201

A.5.2

US NCT (ClinicalTrials.gov registry) number

NCT02400476

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	Puma Biotechnology, Inc.
B.1.3.4	Country	United States
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	Puma Biotechnology, Inc
B.5.2	Functional name of contact point	Clinical Trials Information Desk
B.5.3	Address:
B.5.3.1	Street Address	10880 Wilshire Boulevard, Suite 2150
B.5.3.2	Town/ city	Los Angeles
B.5.3.3	Post code	CA 90024
B.5.3.4	Country	United States
B.5.4	Telephone number	+14242486500
B.5.5	Fax number	+14242486501
B.5.6	E-mail	ClinicalTrials@PumaBiotechnology.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	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	Loperamide 2 mg Capsules
D.2.1.1.2	Name of the Marketing Authorisation holder	TEVA UK Limited
D.2.1.2	Country which granted the Marketing Authorisation	United Kingdom
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
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.3.9.4	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.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

Early Stage HER2+ Breast Cancer

E.1.1.1

Medical condition in easily understood language

Breast cancer with a specific mutation (HER2)

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.1.3

Condition being studied is a rare disease

E.2 Objective of the trial

E.2.1

Main objective of the trial

To characterize the incidence and severity of diarrhea in patients with early stage HER2 overexpressed/amplified (HER2+) breast cancer treated with neratinib when administered with intensive loperamide prophylaxis, after prior treatment with trastuzumab.

E.2.2

Secondary objectives of the trial

•To assess the incidence of serious adverse events (SAEs) and other adverse events of special interest (AESI).
•To assess the incidence and severity of diarrhea following a dose-escalation regimen of neratinib

Exploratory objectives include:
• To assess patient-reported health outcomes using the EuroQol 5D-5L (EQ-5D-5L), Functional Assessment of Cancer Therapy Breast (FACT-B) and the Rotterdam Symptom Checklist (RSCL)questionnaires
• To collect biomarkers of disease from cell-free DNA (cfDNA) to evaluate their relationship to clinical recurrence of disease.
•Evaluation of stool bacterial diversity (microbiome); (currently US only)

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

1. Aged ≥18 years at signing of informed consent.
2. Histologically confirmed stage 1 through stage 3c primary adenocarcinoma of the breast.
3.Documented HER2 overexpression or gene-amplified tumor by a validated approved method.
4.Patients must have completed a course of prior adjuvant trastuzumab or experienced side effects that resulted in early discontinuation of trastuzumab that have since resolved.
5. The last dose of trastuzumab must have been given >2 weeks and ≤1 year (365 days) from enrollment.
6. Physician assessment confirming that the patient is negative for local or regional recurrence of disease or metastatic disease at the time of study entry, including:
- Per standard of care, bone scan or positron emission tomography (PET) scan; required only if alkaline phosphatase (ALP) is ≥2 x upper limit of normal (ULN) and/or there are symptoms of metastatic bone disease. A confirmatory imaging study is required if the results from the bone scan are questionable.
- Per standard of care, computed tomography (CT), magnetic resonance imaging (MRI) or ultrasound of the abdomen and chest; required only if aspartate aminotransferase (AST)/alanine aminotransferase (ALT) or ALP is ≥2 x ULN.
- Other radiologic assessments may be performed to rule out underlying breast cancer recurrence if indicated and as per standard of care.
7.Left ventricular ejection fraction (LVEF) ≥50% measured by multiple-gated acquisition scan (MUGA) or echocardiogram (ECHO).
8. Eastern Cooperative Oncology Group (ECOG) status of 0 to 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 ≥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 partner, or abstinence (only when it is the preferred lifestyle of the patient), from the time of informed consent until 28 days after the last dose of the investigational products. A man (male patient) with a female partner of childbearing potential must agree and commit to use a condom and the female partner must agree and commit 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 investigational products.
11. Recovery (ie, to Grade 1 or baseline) from all clinically significant 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.
13. Documented hormone receptor (HR)-positive disease, defined as estrogen receptor (ER)-positive and/or progesterone receptor (PR)- positive.

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 biotherapy for breast cancer.
3.Major surgery within <30 days of starting treatment or received chemotherapy, investigational agents, or other cancer therapy, except hormonal therapy (eg, tamoxifen, aromatase inhibitors), <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 ≥2; including individuals who currently use digitalis, beta-blockers, or calcium channel blockers specifically for congestive heart failure), unstable angina, myocardial infarction within 12 months of enrollment, 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:
-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 or Modification of Diet in Renal Disease [MDRD] formula)
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 diarrhea as a major symptom (eg, Crohn’s disease, malabsorption, or Grade ≥2 National Cancer Institute [NCI] CTCAE v.4.0 diarrhea of any etiology at baseline).
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 hypersensitivity to salicylates; 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 Grade 3 or higher diarrhea in patients with early stage HER2+ breast cancer.

E.5.1.1

Timepoint(s) of evaluation of this end point

At the end of each 28 day treatment cycle and at 28 days after the last dose.

E.5.2

Secondary end point(s)

The frequency distribution of the maximum grade incidence of diarrhea, the incidence and severity of diarrhea by loperamide exposure, and the incidence of SAEs and AESIs

Exploratory endpoints include
- Patient-related outcomes data (scores from the EQ-5D-5L, and FACT-B, and RSCL questionnaires)
- the relationship between disease biomarkers identified from molecular profiling and indications of clinical disease recurrence
- evaluation of stool bacterial diversity to assess the effect of neratinib on the microbiome (selected sites)

E.5.2.1

Timepoint(s) of evaluation of this end point

Secondary endpoints:
At the end of each 28 day treatment cycle and at 28 days after the last dose.
Exploratory endpoints:
QoL at start of cycles 1, 2, 4, 7, 10 and end of cycle 13/EOT;
Biomarkers at start of cycle 7 and end of cycle 13/EOT and at disease recurrence.
Stool swab for microbiome evaluation at Screening, start of cycles 2 and 4/EOT.

E.6 and E.7 Scope of the trial

E.6

Scope of the trial

E.6.1

Diagnosis

E.6.2

Prophylaxis

Yes

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

E.8.1.1

Randomised

E.8.1.2

Open

Yes

E.8.1.3

Single blind

E.8.1.4

Double blind

E.8.1.5

Parallel group

E.8.1.6

Cross over

E.8.1.7

Other

E.8.2

Comparator of controlled trial

E.8.2.1

Other medicinal product(s)

E.8.2.2

Placebo

E.8.2.3

Other

E.8.3

The trial involves single site in the Member State concerned

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

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

Australia

Austria

Canada

France

Germany

Spain

United Kingdom

United States

E.8.7

Trial has a data monitoring committee

E.8.8

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

LVLS

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:

375

F.1.3

Elderly (>=65 years)

Yes

F.1.3.1

Number of subjects for this age range:

375

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

F.4.2.2

In the whole clinical trial

750

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
G.4 Investigator Network to be involved in the Trial: 1

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

Competent Authority Decision

Authorised

Date of Competent Authority Decision

2018-08-20

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2018-10-29

P. End of Trial
P.	End of Trial Status	Completed
P.	Date of the global end of the trial	2021-04-22

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