Clinical Trials Register

Summary
EudraCT Number:	2015-002801-12
Sponsor's Protocol Code Number:	ONT-380-206
National Competent Authority:	Germany - BfArM
Clinical Trial Type:	EEA CTA
Trial Status:	Completed
Date on which this record was first entered in the EudraCT database:	2017-03-09
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

Germany - BfArM

A.2

EudraCT number

2015-002801-12

A.3

Full title of the trial

Phase 2 Randomized, Double-Blinded, Controlled Study of Tucatinib vs. Placebo in Combination with Capecitabine and Trastuzumab in
Patients with Pretreated Unresectable Locally Advanced or Metastatic HER2+ Breast Carcinoma (HER2CLIMB)

A.3.1

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

A clinical trial comparing tucatinib against placebo in patients who have advanced breast cancer and are being treated with capecitabine and trastuzamab

A.4.1

Sponsor's protocol code number

ONT-380-206

A.5.2

US NCT (ClinicalTrials.gov registry) number

NCT02614794

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	Seagen 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	Seagen 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	Seagen Trial Information Support
B.5.2	Functional name of contact point	Seagen Trial Information
B.5.3	Address:
B.5.3.1	Street Address	21823 30th Drive SE
B.5.3.2	Town/ city	Bothell
B.5.3.3	Post code	WA 98021
B.5.3.4	Country	United States
B.5.4	Telephone number	+1866333 7436
B.5.6	E-mail	clinicaltrials@seagen.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	Tucatinib
D.3.2	Product code	ONT-380
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	Tucatinib
D.3.9.1	CAS number	937263-43-9
D.3.9.2	Current sponsor code	ONT-380
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	150
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	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	Tucatinib
D.3.2	Product code	ONT-380
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	Tucatinib
D.3.9.1	CAS number	937263-43-9
D.3.9.2	Current sponsor code	ONT-380
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	50
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
D.8 Placebo: 1
D.8.1	Is a Placebo used in this Trial?	Yes
D.8.3	Pharmaceutical form of the placebo	Tablet
D.8.4	Route of administration of the placebo	Oral use
D.8 Placebo: 2
D.8.1	Is a Placebo used in this Trial?	Yes
D.8.3	Pharmaceutical form of the placebo	Tablet
D.8.4	Route of administration of the placebo	Oral use

E. General Information on the Trial

E.1 Medical condition or disease under investigation

E.1.1

Medical condition(s) being investigated

Pretreated Unresectable Locally Advanced or Metastatic HER2+ Breast Carcinoma

E.1.1.1

Medical condition in easily understood language

Breast cancer which may have spread

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 assess the effect of tucatinib vs. placebo in combination with capecitabine and trastuzumab on progression-free survival (PFS) per RECIST 1.1 based on blinded independent central review (BICR)

E.2.2

Secondary objectives of the trial

Double-Blinded Phase:
To assess the effect of tucatinib vs. placebo in combination with capecitabine and trastuzumab in patients with brain metastases at baseline using RECIST 1.1 based on BICR
To assess the effects of tucatinib vs. placebo in combination with capecitabine and trastuzumab on OS
To assess the health-related quality of life and health economics associated with tucatinib vs. placebo in combination with capecitabine and trastuzumab

Safety Objective
To assess the safety and tolerability of tucatinib in combination with capecitabine and trastuzumab

Pharmacokinetic Objective
To evaluate the pharmacokinetics of tucatinib and metabolite ONT-993 when administered in combination with capecitabine and trastuzumab

Unblinded Phase:
To assess the safety and tolerability of tucatinib in combination with capecitabine and trastuzumab
To assess PFS per RECIST 1.1 by investigator
To assess OS

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

Double-Blinded Phase:
Have histologically confirmed HER2+ breast carcinoma, with HER2+ defined by in situ hybridization (ISH) or fluorescence in situ hybridization (FISH) or immunohistochemistry (IHC) methodology

Have received previous treatment with a taxane, trastuzumab, pertuzumab, and T-DM1

Have progression of unresectable locally advanced or metastatic breast cancer after last systemic therapy (as confirmed by investigator), or be intolerant of last systemic therapy

Have measurable or non-measureable disease assessable by RECIST 1.1

At least 18 years of age at time of consent

Have Eastern Cooperative Oncology Group Performance Status (ECOG PS) 0 or 1

Have adequate hepatic function

Have adequate baseline hematologic parameters

Have creatinine clearance ≥ 50 mL/min or, in patients ≤ 45 kg in weight, a serum creatinine within institutional normal limits

Have left ventricular ejection fraction (LVEF) ≥ 50%

If female of childbearing potential, must have a negative result of serum or urine pregnancy test.

Women of childbearing potential and men with partners of childbearing potential must agree to use a highly effective birth control methods.

CNS Inclusion – Based on screening contrast brain magnetic resonance imaging (MRI), patients must have one of the following:
- No evidence of brain metastases
- Untreated brain metastases not needing immediate local therapy.
- Previously treated brain metastases
a. Brain metastases previously treated with local therapy my either be stable since treatment or may have progressed since prior local CNS
therapy.
b. Patients treated with CNS local therapy for newly identified lesions found on contrast brain MRI performed during screening for this study may be eligible to enrol if all of the following criteria are met:
i. Time since whole brain radiation therapy (WBRT) is ≥ 21 days prior to first dose of treatment, time since stereotactic radiosurgery (SRS) is ≥ 7 days prior to first dose of treatment, or time since surgical resection is ≥ 28 days
ii. Other sites of disease assessable by RECIST 1.1 are present
c. Relevant records of any CNS treatment must be available to allow for classification of target and non-target lesions

Unblinded Phase:
For patients who were randomized to the control arm and on the longterm follow-up period at the time of the crossover screening: have
progression of unresectable locally advanced or metastatic breast cancer after last systemic therapy (as confirmed by investigator), or be intolerant of last systemic therapy.

Have measurable or non-measurable disease assessable by RECIST 1.1

Have ECOG PS 0 or 1

Adequate hepatic function

Adequate hematologic parameters

Have creatinine clearance ≥ 50 mL/min as calculated per institutional guidelines or, in patients ≤ 45 kg in weight, serum creatinine within
institutional normal limits

Have LVEF ≥ 50% as assessed by ECHO or MUGA scan documented within 6 weeks prior to the time of crossover consent

If female of childbearing potential, must have a negative result of serum or urine pregnancy test.

Women of childbearing potential and men with partners of childbearing potential must agree to use a highly effective birth control methods

CNS Inclusion – Based on screening contrast brain magnetic resonance imaging (MRI), patients must have one of the following:
- No evidence of brain metastases
- Untreated brain metastases not needing immediate local therapy.
- Previously treated brain metastases
a. Brain metastases previously treated with local therapy may either be stable since treatment or may have progressed since prior local CNS therapy.
b. Patients treated with CNS local therapy for newly identified lesions found on contrast brain MRI performed during screening for this study may be eligible to enroll if all of the following criteria are met:
i. Time since whole brain radiation therapy (WBRT) is ≥ 21 days prior to first dose of treatment, time since stereotactic radiosurgery (SRS) is ≥ 7 days prior to first dose of treatment, or time since surgical resection is ≥ 28 days
ii. Other sites of disease assessable by RECIST 1.1 are present

E.4

Principal exclusion criteria

Double-Blinded Phase:
Have previously been treated with:
a. lapatinib within 12 months of starting study treatment (except in cases where lapatinib was given for ≤ 21 days and was discontinued for reasons other than disease progression or severe toxicity)
b. neratinib, afatinib, or other investigational HER2/epidermal growth factor receptor (EGFR) or HER2 tyrosine kinase inhibitor (TKI) at any time previously.

Have previously been treated with capecitabine (or other fluoropyrimidine [e.g., 5-fluorouracil]) for metastatic disease (except in cases where capecitabine was given for ≤ 21 days and was discontinued for reasons other than disease progression or severe toxicity). Note patients who have received capecitabine for adjuvant or neoadjuvant treatment at least 12 months prior to starting study treatment are eligible.

Have previously been treated with capecitabine for metastatic disease. Note patients who have received capecitabine for adjuvant or neoadjuvant treatment at least 12 months prior to starting study treatment are eligible.

Have any toxicity related to prior cancer therapies that has not resolved to ≤ Grade 1.

Have clinically significant cardiopulmonary disease.

Are known carriers of Hepatitis B or Hepatitis C or have other known chronic liver disease

Are known to be positive for human immunodeficiency virus (HIV)

Require therapy with warfarin or other coumarin derviatives

Unable for any reason to undergo MRI of the brain

CNS Exclusion – Based on screening brain MRI, patients must not have any of the following:
Any untreated brain lesions > 2.0 cm in size unless discussed with medical monitor and approval for enrolment is given

Ongoing use of systemic corticosteroids for control of symptoms of brain metastases at a total dose of > 2mg dexamethasone.

Any brain lesion thought to require immediate local therapy. Patients who undergo local treatment for such lesions identified by screening contrast brain MRI may still be eligible for the study based on criteria described under CNS inclusion criteria 19b

Known or suspected leptomeningeal disease (LMD)

Unblinded Phase:
Discontinuation of study treatment due to an adverse event while on the double-blind phase of the study

Have any toxicity related to prior cancer therapies that has not resolved to ≤ Grade 1

Have clinically significant cardiopulmonary disease

Are known carriers of Hepatitis B or Hepatitis C or have other known chronic liver disease

Are known to be positive for HIV

Require therapy with warfarin or other coumarin derivatives

Unable for any reason to undergo contrast MRI of the brain

CNS Exclusion – Based on crossover screening brain MRI, patients must not have any of the following:
Any untreated brain lesions > 2.0 cm in size unless discussed with medical monitor and approval for enrolment is given
Ongoing use of systemic corticosteroids for control of symptoms of brain metastases at a total dose of > 2mg dexamethasone.
Any brain lesion thought to require immediate local therapy. Patients who undergo local treatment for such lesions identified by screening contrast brain MRI may still be eligible for the study based on criteria

E.5 End points

E.5.1

Primary end point(s)

Progression Free Survival

E.5.1.1

Timepoint(s) of evaluation of this end point

Time from randomization to documented disease progression (as determined by BICR per RECIST 1.1), or death from any cause, whichever occurs first

E.5.2

Secondary end point(s)

Efficacy
- PFS in patients with brain metastases at baseline using RECIST 1.1, as determined by BICR
- OS
- Comparative health economics

Safety
- Adverse events (AEs)

Pharmacokinetics
- Plasma concentrations of tucatinib and metabolites

E.5.2.1

Timepoint(s) of evaluation of this end point

Efficacy - Time from randomization to documented disease progression (as documented by BICR per RECIST 1.1), or death from any cause, whichever occurs first

OS - End of the study

Safety - Time from randomization to 30 days of last dose.

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

E.6.11

Pharmacogenomic

E.6.12

Pharmacoeconomic

Yes

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

Yes

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

Yes

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

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

Canada

Israel

United States

Switzerland

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 months

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:

468

F.1.3

Elderly (>=65 years)

Yes

F.1.3.1

Number of subjects for this age range:

132

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

252

F.4.2.2

In the whole clinical trial

600

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)

At the time of study closure, patients will revert to physician care.
When applicable, the Sponsor will assist with post-trial access to tucatinib.

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

2017-06-06

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2017-08-07

P. End of Trial
P.	End of Trial Status	Completed
P.	Date of the global end of the trial	2022-08-11

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