PALLAS - PALbociclib CoLlaborative Adjuvant Study: A randomized phase III trial of Palbociclib with standard adjuvant endocrine therapy versus standard adjuvant endocrine therapy alone for hormone receptor positive/HER2-negative early breast cancer

Overview

Sponsor-declared trial summary

Key facts

Sponsor

ABCSG GmbH, Alliance Foundation Trials LLC

Participant type

Patients

Age range

18-64 years, 65+ years

Gender

Male and Female

Therapeutic area

Diseases [C] - Neoplasms [C04]

Trial duration

27 Oct 2015 → ongoing

Decision date (initial)

2024-07-22

Transition trial

Yes

Low-intervention

No

Rare-disease indication

No

Vulnerable population

Yes

Funding sources

Pfizer Inc.

External identifiers

EU CT number

2024-514841-12-00

EudraCT number

2014-005181-30

ClinicalTrials.gov

NCT02513394

Trial design

CTIS Part I — objectives, methods, condition coding

Main objective

Scope: Efficacy, Therapy, Pharmacogenetic, Pharmacogenomic, Pharmacokinetic, Safety

To compare invasive disease-free survival (iDFS) for the combination of at least 5 years endocrine therapy and 2-year palbociclib treatment versus at least 5 years endocrine therapy alone in patients with histologically confirmed HR+/HER2- invasive early breast cancer (EBC).

Secondary objectives 2

1. To compare the following endpoints: iDFS excluding second primary invasive cancers of non-breast origin, distant recurrence-free survival (DRFS), locoregional recurrences-free survival (LRRFS), and overall survival (OS). To compare the safety of 2 years of palbociclib with adjuvant endocrine therapy versus adjuvant endocrine therapy alone.
2. To compare the safety of 2 years of palbociclib with adjuvant endocrine therapy versus adjuvant endocrine therapy alone.

Conditions and MedDRA coding

To determine whether the addition of palbociclib to adjuvant endocrine therapy will improve outcomes over endocrine therapy alone for HR+/HER2-early breast cancer.

Eligibility criteria

Principal inclusion / exclusion criteria as submitted by sponsor

Inclusion criteria 20

1. (1) Signed informed consent obtained prior to any study specific assessments and procedures.
2. (2) Age ≥18 years (or per national guidelines).
3. (3) Premenopausal and postmenopausal women or men with Stage II (Stage IIA limited to a max. of 1000 patients) or Stage III early invasive breast cancer per AJCC Breast Cancer Staging version 7 /UICC . Baseline staging to document absence of metastatic disease is not required, however is recommended as determined by institutional practice.
4. (4) Patients with multicentric and/or multifocal and/or bilateral early invasive breast cancer whose histopathologically examined tumors all meet pathologic criteria for ER+ and/or PR+ and HER2-.
5. (5) Patients must have histologically confirmed hormone receptor positive (ER+ and/or PR+), HER2-, early invasive breast cancer. ER, PR and HER2 measurements should be performed acc. to institutional guidelines, in a CLIA-approved setting in the US or certified laboratories for Non-US regions. Cut-off values for positive/negative staining should be in accordance with current ASCO/CAP guidelines. Patients with equivocal HER2 in situ hybridization results according to current ASCO/CAP guidelines are eligible, as long as they have not received and are not scheduled to receive anti-HER2 treatment. Testing may occur on diagnostic core or surgical tumor tissue.
6. (6) Patients must have undergone adequate (definitive) breast surgery for the current malignancy.
7. (7) A formalin-fixed paraffin-embedded (FFPE) tumor tissue block must be transmitted to a central sample repository and confirmation of receipt must be available prior to randomization.
8. (8) ECOG performance status 0-1.
9. (9) Patients must be able and willing to swallow and retain oral medication without a condition that would interfere with enteric absorption.
10. (10) Serum or urine pregnancy test must be negative within 7 days of randomization in women of childbearing potential. Pregnancy testing does not need to be pursued in patients who are judged as postmenopausal before randomization, as determined by local practice, or who have undergone bilateral oophorectomy, total hysterectomy, or bilateral tubal ligation. Women of childbearing potential and male patients randomized into treatment Arm A or B must use adequate contraception for the duration of protocol treatment and for 6 months after the last treatment with palbociclib if they are in arm A. In addition, patients receiving standard adjuvant endocrine therapy (Arm A and Arm B) should use adequate contraception in accordance with the specific medication requirements (e.g. SmPC).
11. (11) Patients may or may not have received neo/adjuvant therapy, but must be after last dose of chemotherapy and/or biologic therapy and must have sufficient resolution of side effects per physician assessment at the time of randomization.
12. (12) Patients may or may not have received breast/axilla/postmastectomy chest wall radiotherapy, but must be after last dose of radiotherapy and must have sufficient resolution of side effects per physician assessment at the time of randomization.
13. (13) Patients must have sufficient resolution of any surgical side effects from the last surgery per physician assessment with no active wound healing complications at the time of randomization.
14. (14) Patients must either be initiating or have already started adjuvant hormonal treatment. Patients may already have initiated endocrine therapy at the time of randomization, but randomization must take place within 12 months of date of histological diagnosis and within 6 months of initiating standard adjuvant endocrine therapy. Patients who received neoadjuvant endocrine therapy are eligible as long as they are randomized within 12 months of initial histological diagnosis and after completing no more than 6 months of adjuvant endocrine therapy. Patients may be receiving either tamoxifen or aromatase inhibitor (AI: letrozole, anastrozole, or exemestane). For premenopausal patients and men, concurrent LHRH agonist use is allowable and may also be ongoing at the time of randomization. If a LHRH agonist was used for ovarian protection during neo/adjuvant chemotherapy it is allowable and shall not be taken into account for calculations regarding the 6 months standard adjuvant endocrine therapy.
15. (15) Absolute neutrophil count ≥ 1,500/mm3
16. (16) Platelets ≥ 100,000/ mm3
17. (17) Hemoglobin ≥ 10g/dL
18. (18) Total serum bilirubin ≤ ULN; or total bilirubin ≤ 3.0 × ULN with direct bilirubin within normal range in patients with documented Gilbert's Syndrome.
19. (19) Aspartate amino transferase (AST or SGOT) and alanine amino transferase (ALT or SGPT) ≤ 1.5 × institutional ULN.
20. (20) Serum creatinine below the upper limit of the institutional normal range (ULN) or creatinine clearance (or glomerular filtration rate [GFR]) ≥ 60 mL/min/1.73 m2 for patients with serum creatinine levels above institutional ULN.

Exclusion criteria 12

1. (1) Concurrent therapy with other Investigational Products.
2. (2) Prior therapy with any CDK inhibitor.
3. (3) Patients with Stage I or IV breast cancer are not eligible. Baseline staging to document absence of metastatic disease is not required, however is recommended as determined by institutional practice.
4. (4) History of allergic reactions attributed to compounds of chemical or biologic composition similar to palbociclib.
5. (5) Patients receiving any medications or substances that are potent inhibitors or inducers of CYP3A isoenzymes within 7 days of randomization.
6. (6) Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, diabetes, or psychiatric illness/social situations that would limit compliance with study requirements. Ability to comply with study requirements is to be assessed by each investigator at the time of screening for study participation.
7. (7) Pregnant women, or women of childbearing potential without a negative pregnancy test (serum or urine) within 7 days prior to randomization, irrespective of the method of contraception used, are excluded from this study because the effect of palbociclib on a developing fetus is unknown. Breastfeeding must be discontinued prior to study entry.
8. (8) Patients with a history of any malignancy are ineligible except for the following circumstances: • Patients with a malignancy history other than invasive breast cancer are eligible if they have been disease-free for at least 5 years and are deemed by the investigator to be at low risk for recurrence of that malignancy. • Patients with the following cancers are eligible, even if diagnosed and treated within the past 5 years: ductal carcinoma in situ of the breast, cervical cancer in situ, and non-metastatic non-melanomatous skin cancer.
9. (9) Patients are not eligible if they have previously received endocrine therapy within 5 years prior to diagnosis of the current malignancy. This includes use for prophylactic reasons, including treatment of osteoporosis or cancer prevention with tamoxifen, raloxifene or AI. Patients may concurrently receive bisphosphonates or rank ligand inhibitors while on this study if necessary for treatment or prevention of osteopenia or osteoporosis.
10. (10) Patients on antiretroviral therapy are ineligible because of the potential for pharmacokinetic interactions or increased immunosuppression with palbociclib.
11. (11) Patients with clinically significant history of chronic liver disease, including chronic/active viral or other known hepatitis, current alcohol abuse, or cirrhosis, etc.
12. (12) Patients receiving concurrent exogenous hormone therapy (hormone replacement therapy, oral or any other hormonal contraceptives such as hormonal contraceptive coil, etc.) are not eligible but topical vaginal estrogen therapy is allowable.

Endpoints

Primary and secondary outcome measures (English text)

Primary endpoints 1

1. Invasive disease-free survival (iDFS) defined acc. to STEEP criteria

Secondary endpoints 5

1. (1) Invasive disease-free survival (iDFS) excl. second primary invasive cancers of non-breast origin as an event.
2. (2) Overall Survival (OS)
3. (3) Locoregional recurrences-free survival (LRRFS) defined as the composite of local/regional ipsilateral recurrence, contralateral invasive breast cancer or death from any cause
4. (4) Distant recurrence free survival (DRFS) is defined acc. to STEEP criteria as the composite of distant recurrence or death from any cause.
5. (5) Adverse Events

Investigational products

Investigational medicinal products (IMPs), comparators, placebo, auxiliary

Test 3

Sponsors and contacts

Sponsor organisations, regulatory contacts, third parties

ABCSG GmbH

Sponsor organisation

ABCSG GmbH

Address

Nussdorfer Platz 8, Doebling Doebling

City

Vienna

Postcode

1190

Country

Austria

Scientific contact point

Organisation

ABCSG GmbH

Contact name

Trial Office

Public contact point

Organisation

ABCSG GmbH

Contact name

Trial Office

Third parties 6

Alliance Foundation Trials LLC

Sponsor organisation

Alliance Foundation Trials LLC

Address

221 Longwood Avenue Suite 108

City

Boston

Postcode

02115-5804

Country

United States

Scientific contact point

Organisation

Alliance Foundation Trials LLC

Contact name

AFT

Public contact point

Organisation

Alliance Foundation Trials LLC

Contact name

AFT

Third parties 1

Sponsor responsibilities

Article 77 compliance

ABCSG GmbH

Contact point sponsor

ABCSG GmbH

Article 77 implementation

ABCSG GmbH

Locations

11 EU/EEA countries · 150 investigational sites

By country

Investigational sites

Country notifications

Trial-start, recruitment-start, end and early-termination notifications submitted per Member State

Oversight and notifications

Regulatory notifications under CTR Articles 38, 52, 53, 54 and 77

Serious breaches 1 · Art. 52 CTR

Results and documents

Annex IV summary of results, Annex V layperson summary, and all documents registered in CTIS for this trial

Documents 128 files

Public protocol annexes, IB summaries, regulatory submissions and post-authorisation documents registered in CTIS.

Application history

13 submissions — initial application plus substantial / non-substantial modifications