Clinical Trials Register

Summary
EudraCT Number:	2014-000887-16
Sponsor's Protocol Code Number:	ICR-CTSU/2014/10044
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:	2015-03-04
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

2014-000887-16

A.3

Full title of the trial

A phase II randomised study evaluating the biological and clinical effects of the combination of palbociclib with letrozole as neoadjuvant therapy in post-menopausal women with ER+ primary breast cancer.

A.3.1

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

A.3.2

Name or abbreviated title of the trial where available

PALLET

A.4.1

Sponsor's protocol code number

ICR-CTSU/2014/10044

A.5.1

ISRCTN (International Standard Randomised Controlled Trial) Number

ISRCTN31243262

A.5.2

US NCT (ClinicalTrials.gov registry) number

NCT01889680

A.5.4

Other Identifiers

Name:

CRUK reference number

Number:

CRUK/13/031

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	The Royal Marsden NHS Foundation Trust
B.1.3.4	Country	United Kingdom
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	Pfizer 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
B.5.2	Functional name of contact point
B.Sponsor: 2
B.1.1	Name of Sponsor	The Institute of Cancer Research
B.1.3.4	Country	United Kingdom
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	Pfizer 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	The Institute of Cancer Research
B.5.2	Functional name of contact point	Sophie Perry
B.5.3	Address:
B.5.3.1	Street Address	ICR-CTSU, 15 Cotswold Road
B.5.3.2	Town/ city	Sutton
B.5.3.3	Post code	SM2 5NG
B.5.3.4	Country	United Kingdom
B.5.4	Telephone number	02087224101
B.5.6	E-mail	pallet-icrctsu@icr.ac.uk

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	Palbociclib
D.3.2	Product code	PD-0332991
D.3.4	Pharmaceutical form	Capsule
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	Palbociclib
D.3.9.1	CAS number	571190-30-2
D.3.9.2	Current sponsor code	n/a
D.3.9.3	Other descriptive name	PD-0332991
D.3.9.4	EV Substance Code	AS1
D.3.10	Strength
D.3.10.1	Concentration unit	mg milligram(s)
D.3.10.2	Concentration type	up to
D.3.10.3	Concentration number	125
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	Information not present in EudraCT
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	Letrozole
D.3.2	Product code	n/a
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	Letrozole
D.3.9.1	CAS number	112809-51-5
D.3.9.2	Current sponsor code	N/A
D.3.9.3	Other descriptive name	N/A
D.3.9.4	EV Substance Code	AS2
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	2.5
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

E. General Information on the Trial

E.1 Medical condition or disease under investigation

E.1.1

Medical condition(s) being investigated

ER positive, HER2 negative early invasive breast cancer

E.1.1.1

Medical condition in easily understood language

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	18.1
E.1.2	Level	PT
E.1.2	Classification code	10057654
E.1.2	Term	Breast cancer female
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

PALLET has co-primary objectives:
1) To compare the changes in the proliferation (cell division) marker Ki67 after 14 weeks treatment with letrozole with or without palbociclib.
2) To compare clinical response (i.e. whether the tumour has responded to treatment) after 14 weeks treatment with letrozole with or without palbociclib.

E.2.2

Secondary objectives of the trial

Secondary objectives:
1) To determine the effect of palbociclib on Ki67 after 2 weeks and the added effect of subsequent treatment with palbociclib and letrozole from weeks 2-14
2) To determine the effect of letrozole on Ki67 after 2 weeks and the added effect of subsequent treatment with palbociclib and letrozole from weeks 2-14
3) To compare the pCR ('pathological complete response' - i.e. no invasive tumour left) rate after letrozole with and without 14 weeks of palbociclib
4) To compare the PEPI ('preoperative endocrine prognostic index' - i.e. the risk of recurrence after treatment) score after letrozole with and without 14 weeks of palbociclib
5) To assess safety and tolerability
6) To compare changes between surgical intent at baseline, surgical intent after 14 weeks and actual surgery received after treatment with letrozole with or without palbociclib.

Exploratory objectives:
1) To explore whether groups of people with greater or lesser Ki67 or clinical respon

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

1. Postmenopausal women defined as:
i. Age 56 or older with no spontaneous menses for at least 12 months prior to study entry; or
ii. Age 55 or younger with no menses for at least 12 months prior to study entry (e.g., spontaneous or after hysterectomy) and with a documented oestradiol level in the postmenopausal range according to local institutional/laboratory standard; or
iii. Age ≥16 with documented bilateral oophorectomy
2. Operable ER+ HER2- invasive early breast cancer suitable for neoadjuvant AI treatment. ER positivity is defined as an Allred score of 3 (or equivalent). HER2 negativity will be defined as per the 2013 ASCO/CAP guidelines as follows:
i. IHC 1+ as defined by incomplete membrane staining that is faint/barely perceptible and within >10% of the invasive tumour cells; or
ii. IHC 0 as defined by no staining observed or membrane staining that is incomplete and is faint/barely perceptible and within ≤10% of the invasive tumour cells; or
iii. ISH negative based on:
o Single-probe average HER2 copy number <4.0 signals/cell
o Dual-probe HER2/CEP17 ratio <2.0 with an average HER2 copy number <4.0 signals/cell
3. No medical contra-indication to palbociclib (as defined according to latest version of Investigator Brochure)
4. A tumour with an ultrasound size of at least 2.0cm
5. No evidence of metastatic spread by standard assessment according to local guidelines
6. ECOG performance status of 0 or 1
7. Adequate organ function including:
a) haemoglobin ≥10g/dL (100g/L)
b) ANC ≥ 1,500/mm³ (> 1.5 x 10^9/L)
c) platelets ≥100,000/mm³ (> 100 x 10^9/L)
d) AST and/or ALT <1.5 x x upper normal limits (ULN)
e) Alkaline phosphatase <1.5 x ULN
f) total serum bilirubin < ULN unless the patient has a bilirubin elevation > ULN to 1.5 x ULN due to Gilbert's disease or similar syndrome involving slow conjugation of bilirubin
g) serum creatinine ≤1.25 x ULN or estimated creatinine clearance > 60 mL/min (as calculated using the method standard for the institution)
h) no severe and relevant co-morbidity that would effect a patient’s participation in the study
i) INR must be within normal limits of the local laboratory ranges
8. Written informed consent to participate in the trial and to donation of tissue and blood samples
9. Patients must have the ability to swallow oral medication

E.4

Principal exclusion criteria

1. Premenopausal or perimenopausal women
2. Inflammatory/inoperable breast cancer
3. HER2 positive
4. Concurrent use (defined as use within 4 weeks prior to baseline tissue sample being taken) of HRT or any other oestrogen-containing medication (including vaginal oestrogens)
5. Prior endocrine therapy for breast cancer
6. Bilateral invasive disease
7. Any invasive malignancy within previous 5 years (other than basal cell carcinoma or cervical carcinoma in situ)
8. Any severe coincident medical disease, including seizure disorder requiring medication
9. Diagnosis by FNA alone or excisional biopsy or lumpectomy performed prior to study entry
10. Surgical axillary staging procedure prior to study procedure (with the exception of FNA or core biopsy)
11. Definitive clinical or radiologic evidence of metastatic disease
12. History of ipsilateral invasive breast cancer regardless of treatment or ipsilateral DCIS treated with radiotherapy or contralateral invasive breast cancer at any time
13. New York Heart Association classification of level III or IV heart disease
14. Any treatment, including radiotherapy, chemotherapy, and/or targeted therapy, administered for the currently diagnosed breast cancer prior to study entry
15. Patients on established CYP3A inhibitors/inducers
16. QTc > 480 msec or a family or personal history of long or short QT syndrome, Brugada syndrome or known history of QTc prolongation, or Torsade de Pointes (TdP).
17. Active Hepatitis B or Hepatitis C with abnormal liver function tests.
18. HIV positive patients receiving antivirals.

E.5 End points

E.5.1

Primary end point(s)

There are co-primary outcomes measures in PALLET:
1) Change in the proliferation marker Ki67 (% positive tumour cells) as tested by IHC from baseline to after 14 weeks treatment with letrozole with or without palbociclib
2) Clinical response as measured by ultrasound according to ECOG criteria after 14 weeks treatment with letrozole with or without palbociclib.

E.5.1.1

Timepoint(s) of evaluation of this end point

Biopsies will be obtained from patients at baseline, week 2 and at end of trial treatment and will be used for the biological endpoint.

Ultrasound measurements of tumour size will be carried out at baseline and at the end of trial treatment for assessment of the clinical endpoint.

E.5.2

Secondary end point(s)

- Effect of palbociclib on Ki67 after 2 weeks and the added effect of letrozole from weeks 2-14 (within group)
- Effect of letrozole on Ki67 after 2 weeks and the added effect of palbociclib from weeks 2-14 (within group)
- pCR rates after letrozole with or without 14 weeks palbociclib
- PEPI score after letrozole with or without 14 weeks palbociclib
- Assessment of safety and tolerability
- Changes between surgical intent at baseline, surgical intent after 14 weeks and actual surgery received after treatment with letrozole with or without palbociclib

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

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

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

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)

Yes

E.8.2.2

Placebo

E.8.2.3

Other

E.8.2.3.1

Comparator description

letrozole alone

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

Canada

United States

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

The trial end date is deemed to be the date of last data capture.

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

Yes

F.1.1