Clinical Trials Register

Summary
EudraCT Number:	2013-003947-51
Sponsor's Protocol Code Number:	M14POS
National Competent Authority:	UK - MHRA
Clinical Trial Type:	EEA CTA
Trial Status:	Temporarily Halted
Date on which this record was first entered in the EudraCT database:	2014-07-21
Trial 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

2013-003947-51

A.3

Full title of the trial

Phase I/prospective randomized phase II trial Of the Safety and Efficacy of tamoxifen in combination with the Isoform selective Pi3K inhibitor GDC-0032 compared with tamoxifen alONe in hormone receptor positive, HER2 negative, metastatic breast cancer patients with prior exposure to endocrine treatment (POSEIDON trial)

A.3.1

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

An early-stage clinical trial to evaluate the safety and effectiveness of GDC-0032 when given alongside Tamoxifen to patients with HER2 negative advanced breast cancer, who have previously received hormone treatment

A.3.2

Name or abbreviated title of the trial where available

Poseidon

A.4.1

Sponsor's protocol code number

M14POS

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	NKI-AVL
B.1.3.4	Country	Netherlands
B.3.1 and B.3.2	Status of the sponsor	Non-Commercial
B.4 Source(s) of Monetary or Material Support for the clinical trial:
B.4.1	Name of organisation providing support	Genentech
B.4.2	Country	Switzerland
B.4.1	Name of organisation providing support	Eurocan
B.4.2	Country	Sweden
B.4.1	Name of organisation providing support	Rather
B.4.2	Country	Ireland
B.5 Contact point designated by the sponsor for further information on the trial
B.5.1	Name of organisation	NKI-AVL
B.5.2	Functional name of contact point	Prof. Dr. S. Linn
B.5.3	Address:
B.5.3.1	Street Address	Plesmanlaan 121
B.5.3.2	Town/ city	Amsterdam
B.5.3.3	Post code	1066 CX
B.5.3.4	Country	Netherlands
B.5.4	Telephone number	31205122591
B.5.5	Fax number	31205122572
B.5.6	E-mail	s.linn@nki.nl

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	GDC-0032/ Taselisib ®/ RG 7604
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	Taselisib ®
D.3.9.1	CAS number	1282512484
D.3.9.2	Current sponsor code	GDC-0032
D.3.9.3	Other descriptive name	GDC-0032 (RO5537381)
D.3.9.4	EV Substance Code	SUB61505
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.IMP: 2
D.1.2 and D.1.3	IMP Role	Comparator
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	tamoxifen
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	tamoxifen
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	TAMOXIFEN
D.3.9.1	CAS number	10540-29-1
D.3.9.4	EV Substance Code	SUB10825MIG
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	20
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

E. General Information on the Trial

E.1 Medical condition or disease under investigation

E.1.1

Medical condition(s) being investigated

Hormone receptor positive metastatic breast cancer

E.1.1.1

Medical condition in easily understood language

Advanced staged breast cancer patients who previously received hormone 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	19.0
E.1.2	Level	LLT
E.1.2	Classification code	10072737
E.1.2	Term	Advanced 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

Dose escalation (phase Ib):
• To determine the recommended phase II dose (RPTD) of GDC-0032 in combination with tamoxifen in hormone receptor positive metastatic breast cancer patients who have progressed after prior endocrine treatment
Randomized phase II:
• To compare progression free survival (PFS) in hormone receptor positive, HER2 negative, metastatic breast cancer patients (both lobular and non-lobular) with prior exposure to endocrine therapy, randomized to treatment with (tamoxifen and placebo) versus (tamoxifen and GDC-0032) at the recommended phase II dose defined in the phase 1b study

E.2.2

Secondary objectives of the trial

phase Ib:
•safety and tolerability using CTCAE v. 4.03 criteria
•pharmacokinetics of GDC-0032 in combination with tamoxifen
•investigate the possibility of major drug-drug interactions (PK)
•obtain proof of target inhibition by selected pharmacodynamic measurements
•look for preliminary evidence of anti-tumour activity
•assess the status of potential biomarkers for drug response
•assess germline DNA sequence for pharmacogenetics studies
Randomized phase II:
•compare OS, ORR, CBR in both treatment arms
•compare PFS, ORR, CBR and OS in patients randomised to tamoxifen and placebo versus tamoxifen in combination with GDC-0032 in lobular breast cancer patients and in prespecified subgroups
•compare toxicity profiles in each treatment arm using CTCAE v. 4.03 criteria
•compare differences in tamoxifen and tamoxifen metabolite levels between treatment arms
•assess potential biomarkers of drug response
•assess germline DNA sequence for pharmacogenetic studies

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

Phase Ib (dose escalation)
• Minimum age for inclusion 18 years
• Breast cancer patients with ER and/or PR positive tumours, or patients with other cancer types whom the investigator considers might benefit from endocrine therapy combined with PI3K inhibition (for example ovarian cancer and cancer of the uterus).
• Patients with WHO performance status ≤ 2
• Adequate organ and marrow function
• Fasting glucose ≤ 120 mg/dL (=6.66 mmol/L) and HbA1c ≤ ULN.

Randomized phase II:
• Pre- and Postmenopausal patients with histology-/cytology- proven ER and/or PR positive*, HER2 negative breast cancer with recurrent or metastatic disease which has progressed on prior endocrine therapy
Premenopausal patients should also receive LHRH agonist.
• Patient with WHO performance status ≤ 2
• Adequate organ and marrow function
• Fasting glucose ≤ 120 mg/dL (=6.66 mmol/L) and HbA1c ≤ ULN.
• Patients must have either measurable or evaluable disease by RECIST criteria.
• Availability of a representative tumour tissue specimen

E.4

Principal exclusion criteria

Exclusion Criteria
• Patients with premenopausal follicle stimulating hormone (FSH) and/or plasma estradiol levels who are not treated with a LHRH agonist
• More than 5 prior chemotherapeutic regimens for metastatic breast cancer
• Endocrine therapies or small molecule targeted (non-cytotoxic) inhibitors (including investigational kinase inhibitors) within 5 half-lives of the compund or active metabolites with a maximum of 4 weeks..
• Cytotoxic chemotherapy within 3 weeks, or nitrosoureas or mitomycin C within 6 weeks before the first dose of the study treatment
• Antibody therapy within 4 weeks before the first dose of the study treatment
• Radiation therapy within 2 weeks before the first dose of study treatment
• Untreated, symptomatic, or progressive brain metastases.
• PT/ INR (PTT) test results at screening > 1.3 x the laboratory upper limit of normal.
• Corticosteroid use equivalent to more than 10mg prednisone daily
• Patients with a history of
- Thrombo-embolic disease or is currently receiving therapeutic doses of warfarin
- Crohn’s disease or ulcerative colitis or other forms of autoimmune colitis
- Clinically significant cardiac or pulmonary dysfunction
- Type 1 or 2 diabetes requiring daily anti-hyperglycaemic medication

E.5 End points

E.5.1

Primary end point(s)

Dose escalation (phase Ib):
• The recommended phase II dose of GDC-0032 in combination with tamoxifen

Randomized phase II:
• Progression free survival in hormone receptor positive, HER2 negative, metastatic breast cancer patients randomized to (tamoxifen and placebo) compared with (tamoxifen plus GDC-0032)

E.5.1.1

Timepoint(s) of evaluation of this end point

Dose escalation (phase Ib): • 28 days after treatment start of the last patient Randomized phase II: • to be assessed every 3 months after end of treatment, until death

E.5.2

Secondary end point(s)

Dose escalation (phase Ib):
• Toxicity profile, severity and frequency of adverse events (based on the CTCAE Version 4.03
• Pharmacokinetic measurements for GDC-0032 and tamoxifen
• Pharmacodynamic measurements of PI3K inhibition like: p-AKT, p-mTOR, p-p70S6K, p-S6RP, p-4EBP1; changes in markers of glucose metabolism; and treatment induced cellular responses such as inhibition of proliferation in tumour biopsies
• Assessment of objective response measured by RECIST criteria.
• Assessment of gene mutation status (like PIK3CA), the level of relevant proteins and phospho-proteins in PI3K pathway, serial circulating tumour DNA measurements and the association with therapy response
• Exploratory assessment of germline DNA sequence for pharmacogenetics studies (including CYP2D6 genotype)

Randomized phase II:
• Differences in ORR, CBR and OS between both treatment arms
• PFS, ORR, CBR and OS in patients randomized to (tamoxifen and placebo) compared with (tamoxifen plus GDC-0032) in the predefined subgroups.
• Toxicity profile, severity and frequency of adverse events (based on the CTCAE Version 4.03) in both treatment arms (including PRO-CTCAE criteria in a subgroup of patients)
• Differences in tamoxifen and tamoxifen metabolite levels between both arms
• Assessment of gene mutation status (like PIK3CA), the level of relevant proteins and phospho-proteins in PI3K pathway, serial circulating tumour DNA measurements and the association with therapy response
• Exploratory assessment of germline DNA sequence for pharmacogenetics studies (including CYP2D6 genotype) in relation to tamoxifen and GDC-0032 pharmacokinetics / toxicity

E.5.2.1

Timepoint(s) of evaluation of this end point

Dose escalation (phase Ib): • 6 months after end of treatment Randomized phase II: • to be assesses every 3 months after end of treatment, until death

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

Yes

E.6.8

Bioequivalence

E.6.9

Dose response

Yes

E.6.10

Pharmacogenetic

Yes

E.6.11

Pharmacogenomic

Yes

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 evaluate safety and tolerability of escalating doses of GDC-0032 in combination with tamoxifen

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

Yes

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

Yes

E.8.4

The trial involves multiple sites in the 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

E.8.6.2

Trial being conducted completely outside of the EEA

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 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:

300

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

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

322

F.4.2.2

In the whole clinical trial

322

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

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

Competent Authority Decision

Authorised

Date of Competent Authority Decision

2014-10-01

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2014-10-06

P. End of Trial
P.	End of Trial Status	Temporarily Halted

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