Clinical Trials Register

Summary
EudraCT Number:	2007-007885-39
Sponsor's Protocol Code Number:	3144A1-2204-WW/B1891015
National Competent Authority:	UK - MHRA
Clinical Trial Type:	EEA CTA
Trial Status:	Completed
Date on which this record was first entered in the EudraCT database:	2008-09-02
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

UK - MHRA

A.2

EudraCT number

2007-007885-39

A.3

Full title of the trial

A Phase I/II Study of HKI-272 in Combination With Vinorelbine in Subjects With Solid Tumors and Metastatic Breast Cancer.

A.3.1

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

Neratinib in combination with vinorelbine in metastatic breast cancer patients

A.4.1

Sponsor's protocol code number

3144A1-2204-WW/B1891015

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	Richard B. Phillips
B.5.3	Address:
B.5.3.1	Street Address	10880 Wilshire Blvd, Suite 2150
B.5.3.2	Town/ city	Los Angeles
B.5.3.3	Post code	CA 91320
B.5.3.4	Country	United States
B.5.4	Telephone number	0014242486550
B.5.5	Fax number	0014242486501
B.5.6	E-mail	rphillips@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	HKI-272
D.3.4	Pharmaceutical form	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	WAY-179272-B
D.3.9.3	Other descriptive name	HKI-272 Maleate
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	Navelbine 10mg/ml Concentrate for Solution for Infusion
D.2.1.1.2	Name of the Marketing Authorisation holder	Pierre Fabre Ltd
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	VINORELBINE 10MG/ML CONCENTRATE FOR SOLUTION FOR INFUSION
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.3.9.1	CAS number	125317-39-7
D.3.9.3	Other descriptive name	VINORELBINE TARTRATE
D.3.9.4	EV Substance Code	SUB20777
D.3.10	Strength
D.3.10.1	Concentration unit	mg/m2 milligram(s)/square meter
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	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.3.1	Product name	NERATINIB
D.3.2	Product code	HKI-272
D.3.4	Pharmaceutical form	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	WAY-179272-B
D.3.9.3	Other descriptive name	HKI-272 Maleate
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	240
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

Solid tumors (part 1) and metastatic breast cancer (part 2).

E.1.1.1

Medical condition in easily understood language

Metastatic 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	14.1
E.1.2	Level	LLT
E.1.2	Classification code	10027475
E.1.2	Term	Metastatic breast cancer
E.1.2	System Organ Class	100000004864

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 1: The primary objectives of part 1 of the study are to assess the safety and tolerability and to define the maximum tolerated dose (MTD) of HKI-272 in combination with vinorelbine in subjects with advanced solid tumors.

Part 2: The primary objective of part 2 of the study is to estimate the ORR for subjects with ErbB-2-positive breast cancer treated at the MTD of HKI-272 in combination with vinorelbine.

E.2.2

Secondary objectives of the trial

Part 1: The secondary objectives of part 1 are to obtain preliminary data describing antitumor activity for the combination of HKI-272 with vinorelbine.

Part 2: The secondary objectives of part 2 are to confirm the MTD identified in part 1 of the study, to obtain safety and PK information, and to assess additional efficacy parameters including clinical benefit (complete response [CR]+partial response [PR]+stable disease [SD] >=24 weeks), PFS rate, and duration of response to HKI-272 in combination with vinorelbine.

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

1. Aged ≥18 years.

2. Confirmed pathologic diagnosis of a solid tumor that is not curable with available therapies for which HKI-272 plus vinorelbine is a reasonable treatment option (part 1 only).

3. Confirmed pathologic diagnosis of ErbB-2-positive breast cancer (current stage IV) in female subjects for which vinorelbine plus HKI-272 is a reasonable treatment option (part 2 only).

4. At least 1 prior antineoplasic chemotherapy treatment regimen for metastatic disease or subject relapsing under adjuvant treatment (part 2 only).

5. At least 1 prior treatment with a trastuzumab-containing regimen for at least 6 weeks [receiving no more than 6 weeks (weekly or tri weekly schedule equivalents) for economical reason is acceptable] , for metastatic disease or subject relapsing under adjuvant treatment (part 2 only) [“relapsing under adjuvant treatment” should be understood as patients still taking trastuzumab treatment or being off trastruzumab treatment for a maximal period of 6 months after the last dose of trastuzumab at the time of disease recurrence].

6. erbB-2 gene amplified tumor detected by fluorescence in situ hybridization (FISH) or chromogenic in situ hybridization (CISH) (part 2 only). Documentation of erbB-2 status by FISH or CISH performed by a local laboratory is accepted. Otherwise, tumor tissue must be available and adequate for centralised FISH testing prior to study day 1. In case of more than 1 result, the status retrieved on the most recent biopsy should be used.

7. At least 1 measurable lesion as defined by Response Evaluation Criteria in Solid Tumors (RECIST).

8. Eastern Cooperative Oncology Group (ECOG) status of 0 to 2 (not declining within 2 weeks before signing the informed consent form (ICF)).

9. Recovery from all clinically significant AEs related to prior therapies (excluding alopecia).

10. Left ventricular ejection fraction (LVEF) within the study site’s limits of normal.

11. Screening laboratory values within the following parameters:
Absolute neutrophil count (ANC): >=1.5×109/L (1500/mm3)
Platelet count: >=100×109/L (100,000/mm3)
Hemoglobin: >=9.0 g/dL (90 g/L)
Serum creatinine: ≤1.5×upper limit of normal (ULN)
Total bilirubin: ≤1.5×ULN
Aspartate aminotransferase (AST) and alanine aminotransferase (ALT): ≤2.5 ×
ULN (≤5×ULN if liver metastases are present)

12. For women of childbearing potential, a negative urine or serum pregnancy test result before study entry.

13. All subjects who are not surgically sterile or postmenopausal must agree and commit to the use of a reliable method of birth control for the duration of the study and for 28 days after the last dose of test article.

E.4

Principal exclusion criteria

1. More than 2 prior antineoplasic treatment regimens ( excluding hormonotherapy) for metastatic disease. Subjects who relapsed under adjuvant therapy should not have received more than one line of antineoplasic treatment for metastatic disease (part 2 only).

2. Prior treatment with vinorelbine for metastatic setting, or prior treatment with any ErbB-2 targeted agents except trastuzumab (part 2 only). Up to 20 subjects with ErbB-2-overexpressing metastatic breast cancer who have been previously exposed to lapatinib but are not refractory to lapatinib may be enrolled in part 2.

3. Prior treatment with anthracyclines with a cumulative dose of doxorubicin of >400 mg/m2, or of epirubicin dose of >800 mg/m2, or the equivalent dose for other anthracyclines or derivatives (part 2 only).

4. Major surgery, chemotherapy, radical (curative intent) radiotherapy, investigational agents, or other cancer therapy within at least 2 weeks before treatment day 1.

5. Subjects with bone only disease or skin lesions that are not measurable by CT or MRI as the only site of disease.

6. Subject with history of inflammatory breast cancer

7. Active central nervous system (CNS) metastases, as indicated by clinical symptoms, cerebral edema, and/or progressive growth.

8. QT (QTc) interval >0.47 second or known history of QTc prolongation or torsades de pointes (TdP).

9. Presence of clinically significant or uncontrolled cardiac disease, including congestive heart failure (New York Heart Association [NYHA] functional classification of ≥2), angina requiring treatment, myocardial infarction within the past 12 months, or any clinically significant supraventricular arrhythmia or ventricular arrhythmia requiring treatment or intervention.

10. Pregnant or breastfeeding women.

11. Significant chronic or recent acute gastrointestinal disorder with diarrhea as a major symptom (eg, Crohn disease, malabsorption, or grade >=2 diarrhea of any etiology at baseline).

12. Inability or unwillingness to swallow tablets (HKI-272).

13. Preexisting grade 2 or greater motor or sensory neuropathy.

14. Subject known to be human immunodeficiency virus (HIV) seropositive and/or acute chronic hepatitis B (HBsAg positive) or hepatitis C (anti-HCV positive).

15. History of known hypersensitivity to vinorelbine and any of its components.

16. Any other cancer within 5 years prior to screening with the exception of contralateral breast carcinoma, adequately treated cervical carcinoma in situ, or adequately treated basal or squamous cell carcinoma of the skin.

17. Clinically significant ongoing or recent infection within 2 weeks before treatment day 1.

18. Evidence of significant medical illness or abnormal laboratory finding that would, in the investigator’s judgment, make the subject inappropriate for this study.

E.5 End points

E.5.1

Primary end point(s)

The primary end-point of this study is to assess the safety and define the maximum tolerated dose of the combination of HKI-272 with vinorelbine in subjects with solid tumors, and to assess the efficacy of the optimal safe dose for the drug combination in subjects with metastatic breast cancer

E.5.1.1

Timepoint(s) of evaluation of this end point

Every 6 weeks

E.5.2

Secondary end point(s)

Safety data collection

E.5.2.1

Timepoint(s) of evaluation of this end point

Every 6 weeks

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

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

First use in human for HKI 272 + Vinorelbine

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

Information not present in EudraCT

E.8.1.2

Open

Information not present in EudraCT

E.8.1.3

Single blind

Information not present in EudraCT

E.8.1.4

Double blind

Information not present in EudraCT

E.8.1.5

Parallel group

Information not present in EudraCT

E.8.1.6

Cross over

Information not present in EudraCT

E.8.1.7

Other

Information not present in EudraCT

E.8.2

Comparator of controlled trial

E.8.2.1

Other medicinal product(s)

Information not present in EudraCT

E.8.2.2

Placebo

Information not present in EudraCT

E.8.2.3

Other

Information not present in EudraCT

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.8.5

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

Information not present in EudraCT

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

Belgium

China

France

Hong Kong

Netherlands

Spain

Sweden

Taiwan

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

Last visit of the last subject.

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.4.2

For a multinational trial

F.4.2.1

In the EEA

F.4.2.2

In the whole clinical trial

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)

As applicable under country-specific standard of care

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

2008-09-10

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2009-02-09

P. End of Trial
P.	End of Trial Status	Completed
P.	Date of the global end of the trial	2018-06-07

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