Clinical Trials Register

Summary
EudraCT Number:	2012-004743-68
Sponsor's Protocol Code Number:	PUMA-NER-4201
National Competent Authority:	France - ANSM
Clinical Trial Type:	EEA CTA
Trial Status:	Completed
Date on which this record was first entered in the EudraCT database:	2013-04-19
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

France - ANSM

A.2

EudraCT number

2012-004743-68

A.3

Full title of the trial

A Phase 2 Study of Neratinib and Neratinib Plus Temsirolimus in Patients with Non-Small Cell Lung Cancer Carrying Known HER2 Activating Mutations

A.3.1

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

A clinical study of Neratinib, with or without Temsirolimus, in patients with lung cancer and who have a specific mutation (HER2).

A.4.1

Sponsor's protocol code number

PUMA-NER-4201

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 Blvd, 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	+1424248 6500
B.5.5	Fax number	+1424248 6501
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	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.3.8	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	Torisel®
D.2.1.1.2	Name of the Marketing Authorisation holder	Pfizer Limited
D.2.1.2	Country which granted the Marketing Authorisation	France
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	Concentrate and diluent 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.3.8	INN - Proposed INN	TEMSIROLIMUS
D.3.9.1	CAS number	162635-04-3
D.3.9.4	EV Substance Code	SUB21308
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	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.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

Non-Small Cell Lung Cancer Carrying Known HER2 Activating Mutations

E.1.1.1

Medical condition in easily understood language

Lung 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	14.1
E.1.2	Level	LLT
E.1.2	Classification code	10029514
E.1.2	Term	Non-small cell lung cancer NOS
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

to determine the confirmed best overall response rate (ORR = complete response [CR] + partial response [PR]) following treatment with neratinib and neratinib plus temsirolimus in patients with NSCLC carrying known human epidermal growth factor receptor 2 (HER2) activating mutations who have received at least one prior regimen of chemotherapy

E.2.2

Secondary objectives of the trial

• to determine the clinical benefit rate (CBR) with respect to neratinib monotherapy and neratinib plus temsirolimus combination therapy, defined as the percentage of patients with CR + PR + stable disease (SD) ≥12 weeks;
• to determine the duration of response (DOR) with respect to neratinib monotherapy and neratinib plus temsirolimus combination therapy, defined as the date when criterion of CR or PR is first met and subsequently confirmed (whichever status is recorded first) to the first date of documented disease progression;
• to determine progression-free survival (PFS), defined as the interval from date of randomization to date of first documented disease progression or death due to any cause, whichever comes first, following treatment with neratinib and neratinib plus temsirolimus;
• to determine median overall survival (OS);
• to assess the safety profile and tolerability of neratinib and neratinib plus temsirolimus;
• health outcome assessments.

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

1. Aged ≥18 years at the time of signing the informed consent.
2. Histologically confirmed diagnosis of NSCLC, advanced (stage IIIB) or metastatic (stage IV).
3. Documented somatic ErbB2 (HER2) activating mutation.
4. Patients with anaplastic lymphoma kinase (ALK) translocations must have received crizotinib, except for cases of intolerable toxicity to crizotinib.
5. Documented progressive disease by radiographic study following at least one prior cytotoxic chemotherapy regimen, or withdrawal from prior treatment due to documented toxicity.
6. At least one measurable lesion as defined by Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST v1.1).
7. Eastern Cooperative Oncology Group (ECOG) status <2.
8. Left ventricular ejection fraction (LVEF) ≥50% measured by multiple-gated acquisition scan (MUGA) or echocardiogram (ECHO).
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.
10. Men and women of childbearing potential must agree and commit to the use of a highly effective method of contraception, as determined to be acceptable by the Investigator, from the time of informed consent until 3 months after the last dose of the investigational products.
11. Provide written, informed consent to participate in the study and follow the study procedures.

E.4

Principal exclusion criteria

1. Previous treatment with any investigational agent ≤30 days prior to the initiation of investigational products.
2. Previous treatment with any strong inhibitor and/or inducer of CYP3A4 enzyme or sensitive P-glycoprotein (P gp) substrates ≤30 days prior to the initiation of investigational products.
3. Active uncontrolled cardiac disease, including cardiomyopathy, congestive heart failure (New York Heart Association functional classification of ≥2), unstable angina, myocardial infarction within 12 months of enrollment, or ventricular arrhythmia.
4. Major surgery <30 days of starting treatment.
5. Chronic steroid use (prednisone >12.5 mg/day or dexamethasone >2 mg/day, excluding inhaled steroids).
6. Currently breast feeding.
7. Symptomatic or unstable brain metastases.
8. QTc interval >0.450 seconds or known history of QTc prolongation or Torsades de Pointes (TdP).
9. Significant chronic gastrointestinal disorder with diarrhea as a major symptom (e.g., Crohn’s disease, malabsorption, or Grade ≥2 (National Cancer Institute [NCI] Common Terminology Criteria for Adverse Events Version 4.0 [CTCAE v.4.0] diarrhea of any etiology at baseline).
10. Prior exposure to tyrosine kinase inhibitor including neratinib, lapatinib, and afatinib (excluding dacomitinib), or mTOR inhibitor.
11. Active infection or unexplained fever >38.5°C (101.3°F).
12. Unable or unwilling to swallow tablets.
13. Evidence of significant medical illness, abnormal laboratory finding, or psychiatric illness/social situations that would, in the Investigator’s judgment, make the patient inappropriate for this study.
14. Known hypersensitivity to any component of the investigational products.
15. Unstable or uncontrolled diabetes mellitus (glycosylated hemoglobin [HbA1c] >6.5%).
16. Screening laboratory assessments outside the following limits:

Laboratory endpoint : Required limit for exclusion
Absolute neutrophil count (ANC) : <1500/mL (1.5 x 10e9/L)
Platelet count : <75,000/mL
Hemoglobin (Hb) : <8 g/dL (transfusions allowed) Transfusions must be at least 14 days prior to baseline.
Total bilirubin : >1.5 x institutional upper limit of normal (ULN)
Aspartate aminotransferase (AST)
and/or Alanine aminotransferase (ALT) : >2.5 x institutional ULN (>5 x ULN if liver metastases are present)
Creatinine clearance : <50 mL/min (as calculated by Cockroft-Gault formula or Modification of Diet in Renal Disease [MDRD] formula)
Serum lipids : Fasting serum cholesterol >9.0 mmol/L (>350 mg/dL), fasting triglycerides >4.56 mmol/L (>400 mg/dL)
Serum calcium (corrected for albumin level) : >1.0 x ULN.

E.5 End points

E.5.1

Primary end point(s)

confirmed best ORR per RECIST v1.1 on treatment with neratinib monotherapy (Arm A) and the combination of neratinib plus temsirolimus (Arm B).

E.5.1.1

Timepoint(s) of evaluation of this end point

Responses must be re-evaluated no sooner than 4 weeks after first response is observed for confirmation of response.

E.5.2

Secondary end point(s)

• CBR, with respect to neratinib monotherapy (Arm A) and neratinib plus temsirolimus combination therapy (Arm B), defined as the percentage of patients with PR + CR + SD ≥12 weeks.
• DOR, with respect to neratinib monotherapy (Arm A) and neratinib plus temsirolimus combination therapy (Arm B), defined as the date when criterion of CR or PR is first met and subsequently confirmed (whichever status is recorded first) to the first date of documented disease progression.
• PFS, defined as the interval from the date of randomization to date of first documented disease progression or death due to any cause, whichever comes first, following treatment with neratinib and neratinib plus temsirolimus
• OS, defined as time from randomization to death due to any cause for all patients aggregated and for each randomized arm of treatment. Patients will be followed-up until death or censored at the last date of contact.

E.5.2.1

Timepoint(s) of evaluation of this end point

Time points for secondary end points are included in section E.5.2 above

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

Yes

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

Yes

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)

E.8.2.2

Placebo

E.8.2.3

Other

Yes

E.8.2.3.1

Comparator description

test IMP in combination with other medicinal product

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

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

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

End of study (EOS) will occur when all patients in the study have been followed for OS to death, withdrawal of consent, or are lost to follow-up.

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

104

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)

In the event that EOS is declared earlier for any reason, patients who continue to receive clinical benefit from neratinib plus temsirolimus will be offered the opportunity to continue to receive this combination via a treatment extension study or expanded access protocol.

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

2014-05-06

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2013-05-06

P. End of Trial
P.	End of Trial Status	Completed
P.	Date of the global end of the trial	2017-10-06

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