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.

• Register: EUCTR
• Last refreshed on: 8 June 2020
• Main ID: EUCTR2014-000887-16-GB
• Date of registration: 04/03/2015
• Prospective Registration: No
• Primary sponsor: The Royal Marsden NHS Foundation Trust
• Public title: 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.
• Scientific title: 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. - PALLET
• Date of first enrolment: 07/11/2014
• Target sample size: 306
• Recruitment status: Not Recruiting
• URL: https://www.clinicaltrialsregister.eu/ctr-search/search?query=eudract_number:2014-000887-16
• Study type: Interventional clinical trial of medicinal product
• Study design: Controlled: yes; Randomised: yes; Open: yes; Single blind: no; Double blind: no; Parallel group: no; Cross over: no; Other: no; If controlled, specify comparator, Other Medicinial Product: yes; Placebo: no; Other: no; Other specify the comparator: letrozole alone; Number of treatment arms in the trial: 4
• Phase: Human pharmacology (Phase I): no Therapeutic exploratory (Phase II): yes Therapeutic confirmatory - (Phase III): no Therapeutic use (Phase IV): no

Countries of recruitment

Canada, United Kingdom, United States

Key inclusion & exclusion criteria

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
Are the trial subjects under 18? yes
Number of subjects for this age range: 0
F.1.2 Adults (18-64 years) yes
F.1.2.1 Number of subjects for this age range 50
F.1.3 Elderly (>=65 years) yes
F.1.3.1 Number of subjects for this age range 100

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.



Age minimum:
Age maximum:
Gender:
Female: yes
Male: no

Health Condition(s) or Problem(s) studied

ER positive, HER2 negative early invasive breast cancer
MedDRA version: 18.1 Level: PT Classification code 10057654 Term: Breast cancer female System Organ Class: 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps)

Therapeutic area: Diseases [C] - Cancer [C04]

Intervention(s)

Product Name: Palbociclib
Product Code: PD-0332991
Pharmaceutical Form: Capsule
INN or Proposed INN: Palbociclib
CAS Number: 571190-30-2
Current Sponsor code: n/a
Other descriptive name: PD-0332991
Concentration unit: mg milligram(s)
Concentration type: up to
Concentration number: 125-

Product Name: Letrozole
Product Code: n/a
Pharmaceutical Form: Tablet
INN or Proposed INN: Letrozole
CAS Number: 112809-51-5
Current Sponsor code: N/A
Other descriptive name: N/A
Concentration unit: mg milligram(s)
Concentration type: equal
Concentration number: 2.5-

Primary Outcome(s)

Secondary Objective: 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

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.

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.

Main Objective: 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.

Secondary Outcome(s)

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

Secondary ID(s)

ISRCTN31243262

CRUK/13/031

ICR-CTSU/2014/10044

NCT01889680

Source(s) of Monetary Support

Pfizer Inc.

Secondary Sponsor(s)

The Institute of Cancer Research

Ethics review

Status: Approved
Approval date: 01/09/2014
Contact: