Clinical Trials Register

Summary
EudraCT Number:	2012-005037-37
Sponsor's Protocol Code Number:	10-005
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:	2013-05-10
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

Expand All Collapse All

A. Protocol Information

A.1

Member State Concerned

UK - MHRA

A.2

EudraCT number

2012-005037-37

A.3

Full title of the trial

A Phase I/II Trial of Temsirolimus Plus Neratinib for Patients with Metastatic HER2-Amplified or Triple-Negative Breast Cancer

A.3.1

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

A clinical study of Temsirolimus and Neratinib in patients with breast cancer who have a specific genetic make up.

A.4.1

Sponsor's protocol code number

10-005

A.5.2

US NCT (ClinicalTrials.gov registry) number

NCT01111825

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	PB-272 ; HKI-272
D.3.4	Pharmaceutical form	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	Torisel®
D.2.1.1.2	Name of the Marketing Authorisation holder	Pfizer Inc
D.2.1.2	Country which granted the Marketing Authorisation	United States
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 solvent 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

advanced breast carcinoma in patients with trastuzumab-refractory HER2-amplified disease

E.1.1.1

Medical condition in easily understood language

breast cancer which has grown in spite of standard treatment

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	PT
E.1.2	Classification code	10065430
E.1.2	Term	HER-2 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	14.1
E.1.2	Level	LLT
E.1.2	Classification code	10072737
E.1.2	Term	Advanced 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	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	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

Phase 1
To determine the maximum tolerated dose (MTD) of weekly intravenous (IV) temsirolimus when administered in combination with a fixed dose of daily oral neratinib therapy.

Phase 2
To estimate the efficacy [overall response rate (ORR) = complete response (CR) and partial response (PR)] by RECIST criteria of temsirolimus when administered in combination with neratinib at the established maximum tolerated dose (MTD) for both HER2-amplified trastuzumab-refractory and triple-negative patients.

E.2.2

Secondary objectives of the trial

Phase 1:
• To determine if the addition of neratinib affects the exposure and half-life of temsirolimus and its active metabolite, sirolimus.

Phase 2 :
• To determine the safety and tolerability of temsirolimus when administered in combination with neratinib.
• To determine progression-free survival (PFS), duration of response (DoR), clinical benefit rate (CBR, i.e., CR + PR + SD ≥24) weeks for the combination at the MDT, and overall survival (OS).
• To estimate the efficacy (ORR) and safety assessment of dose escalation to 240 mg neratinib plus 15 mg temsirolimus with revised prophylactic diarrhea management regimen in pretreated HER2+ metastatic breast cancer (MBC) patients.

Exploratory:
• Exploratory end points are detailed in the protocol.

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

Phase 1 HER2-Amplified (HER2-Positive) Cohort – Closed to accrual

Phase 1 Triple-Negative Cohort – Closed to accrual

Phase 2 Triple-Negative Cohort – Closed to accrual

Phase 2 HER2-Positive Cohort with dose escalation
• HER2 overexpression and/or amplification as determined by IHC (3+) or FISH (≥2.0).
• Previously received trastuzumab as part of a regimen in the adjuvant or metastatic setting with evidence of progression. Washout period for trastuzumab of 14 days.
• May have previously received lapatinib as part of a regimen in the adjuvant or metastatic setting with evidence of progression of disease. Washout period for lapatinib of 14 days.
• Radiographic progression of disease while on treatment with trastuzumab as defined by RECIST 1.1 criteria.
• Prior therapy inclusion:
o No restriction on prior chemotherapy regimens for advanced stage disease. No restriction for prior hormonal therapy. No concurrent use of endocrine therapy is permitted.

Inclusion Criteria for ALL patients
• Patients with a diagnosis of invasive adenocarcinoma of the breast confirmed by histology or cytology.
• Metastatic disease that is or has been pathologically documented.
• At least one measurable metastatic lesion according to RECIST 1.1 criteria. Ascites, pleural effusions, and bone metastases are not considered measurable. Minimum indicator lesion size ≥10 mm by helical computerized tomography (CT) or ≥20 mm by conventional techniques.
o Pathological nodes must be ≥15 mm by the short axis to be considered measurable.
• Age ≥18, as no dosing or adverse event data are currently available on the use of neratinib or temsirolimus in patients <18 years of age.
• Patients must be willing to discontinue sex hormonal therapy, e.g., birth control pills, hormonal replacement therapy, prior to enrollment. Women of childbearing potential must consent to use effective contraception while on treatment and for 28 days thereafter. Men must consent to use a barrier method of contraception while on treatment and for 3 months thereafter.
• Negative serum human chorionic gonadotropin (HCG) pregnancy test for premenopausal women of reproductive capacity and for women less than 12 months after menopause.
• Asymptomatic, central nervous system metastases are permitted if patients remain clinically stable after discontinuation of steroids and anticonvulsants for 3 months.
• Eastern Cooperative Oncology Group (ECOG) performance status score of ≤2.
• Patients must have normal organ and marrow function: AST/ALT ≤2.5x institutional upper limit of normal except for patients with liver metastases. For patients with liver metastases, AST/ALT/alkaline phosphatase ≤5.0 x institutional upper limit of normal. Total bilirubin within institutional limits except for patients with liver metastases. For patients with liver metastases, total bilirubin ≤1.5x institutional upper limit of normal. Creatinine clearance within normal limits or ≥60 mL/min, PT and PTT ≤1.5x institutional upper limit of normal except for patients on Coumadin or low molecular weight heparin, leukocytes ≥3,000/µL, absolute neutrophil count ≥1,000/µL, and platelets ≥75,000/µL.
• Able to swallow and retain oral medication.

E.4

Principal exclusion criteria

• Patients receiving any concurrent anticancer therapy or investigational agents with the intention of treating breast cancer.
• Previous treatment with any strong inhibitor and/or inducer of CYP3A4 enzyme or sensitive P glycoprotein (P gp) substrates ≤30 days prior to initiation of investigational products.
• History of allergic reactions attributed to compounds of similar chemical or biologic composition to neratinib or temsirolimus.
• Women who are pregnant or breast feeding.
• Life expectancy <3 months.
• Completion of previous chemotherapy regimen <3 weeks prior to the start of study treatment. Prior hormonal therapy must be discontinued prior to treatment start. Biologic therapy with bevacizumab for the treatment of metastatic disease must be discontinued ≥3 weeks from the start of protocol treatment.
• Concurrent radiotherapy is not permitted for disease progression on treatment on protocol, but might be allowed for pre-existing non-target lesions with approval from the Sponsor.
• Concurrent medical conditions which may increase the risk of toxicity, including ongoing or active infection, history of significant bleeding disorder unrelated to cancer (congenital bleeding disorders, acquired bleeding disorders within one year), human immunodeficiency virus (HIV)-positive or active hepatitis.
• History of clinically significant or uncontrolled cardiac disease, including congestive heart failure, angina, myocardial infarction, arrhythmia, and left ventricular ejection fraction less than 50% measured by a multigated acquisition imaging (MUGA scan) of the heart or an echocardiogram (ECHO).
• QTc interval >0.47 seconds.
• Patients with GI tract disease resulting in an inability to take oral medication, malabsorption syndrome, a requirement for IV alimentation, prior surgical procedures affecting absorption, or uncontrolled inflammatory GI disease.
• History of an invasive second primary malignancy diagnosed within the previous 3 years, except for stage I endometrial or cervical carcinoma or prostate carcinoma treated surgically, and non-melanoma skin cancer.
• History of uncontrolled seizures, central nervous system disorders or psychiatric disability judged by the investigator to be clinically significant, precluding informed consent, or interfering with compliance of oral drug intake.
• Unwillingness to give written informed consent, unwillingness to participate, or inability to comply with the protocol for the duration of the study. Willingness and ability to comply with scheduled visits, treatment plan, laboratory tests and other study procedures are necessary to participation in this clinical trial.

E.5 End points

E.5.1

Primary end point(s)

The primary endpoint in the Phase 2 portion of the trial is the ORR (CR + PR) by RECIST 1.1.

E.5.1.1

Timepoint(s) of evaluation of this end point

Patients are evaluable for response if they complete at least one week of treatment.
Baseline extent of disease evaluation will usually be measured including CT scan of chest, abdomen, and pelvis with oral and intravenous contrast (if not contraindicated) and a bone or positron emission tomography (PET) scan. Target lesions will be identified at this time according to RECIST 1.1. Radiographic tumor assessments will be performed after every 8 weeks of treatment for the first 6 cycles and subsequently every 12 weeks after 6 cycles of treatment.

E.5.2

Secondary end point(s)

The secondary efficacy endpoints include:
• PFS
• DoR
• CBR (CR + PR + SD ≥24 weeks)
• OS

E.5.2.1

Timepoint(s) of evaluation of this end point

Baseline extent of disease evaluation will usually be measured including CT scan of chest, abdomen, and pelvis with oral and intravenous contrast (if not contraindicated) and a bone or positron emission tomography (PET) scan. Target lesions will be identified at this time according to RECIST 1.1. Radiographic tumor assessments will be performed after every 8 weeks of treatment for the first 6 cycles and subsequently every 12 weeks after 6 cycles of treatment.

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

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)

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

to identify a maximum tolerated dose

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

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

Yes

E.8.1.7.1

Other trial design description

open-label, single arm, adaptive design, dose-escalation Phase 1/2 study

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

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

The end of study (EOS) will occur once disease progression is reported for all patients on study. In the event that EOS is declared earlier (i.e., primary endpoint is met), 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.

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)

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

2013-06-21

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2013-10-02

P. End of Trial
P.	End of Trial Status	Completed
P.	Date of the global end of the trial	2016-07-04

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