Randomized, Open Label, Phase III Trial to Evaluate the Efficacy and Safety of Palbociclib + Anti-HER2 Therapy + Endocrine Therapy vs. Anti-HER2 Therapy + Endocrine Therapy after Induction Treatment for Hormone Receptor Positive (HR+)/HER2-Positive Metastatic Breast Cancer

Overview

Sponsor-declared trial summary

Key facts

Sponsor

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

7 Nov 2024 → ongoing

Decision date (initial)

2024-11-18

Transition trial

Yes

Low-intervention

No

Rare-disease indication

No

Vulnerable population

No

Funding sources

Pfizer, INC.

External identifiers

EU CT number

2024-513540-29-00

EudraCT number

2017-000419-17

Trial design

CTIS Part I — objectives, methods, condition coding

Main objective

Scope: Safety, Efficacy

The primary objective of this study is to demonstrate that the combination of palbociclib with anti-HER2 therapy plus endocrine therapy is superior to anti-HER2-based therapy plus endocrine therapy in prolonging PFS in participants with hormone receptor-positive, HER2+ metastatic breast cancer who have not received any prior treatment beyond induction treatment in this setting.

Secondary objectives 6

1. To compare measures of tumor control (including OR, CBR, DOR) between the treatment arms
2. To compare median overall survival and overall survival probabilities at 3-years and 5-years between the treatment groups
3. To compare safety and tolerability between the treatment arms
4. To compare the incidence of CNS metastasis between the treatment arms
5. To compare patient reported time to symptom progression as assessed by the FACT-B TOI-PFB
6. To compare patient reported breast cancer specific health related quality of life (HRQOL) and general health status

Conditions and MedDRA coding

Breast Cancer

Eligibility criteria

Principal inclusion / exclusion criteria as submitted by sponsor

Inclusion criteria 23

1. Signed Preliminary Screening Informed Consent Form obtained prior to any study specific assessments and procedures
2. Age ≥18 years (or per national guidelines)
3. Participants must have histologically confirmed invasive breast cancer that is metastatic or not amenable for resection or radiation therapy with curative intent. Histological documentation of metastatic/recurrent breast cancer is not required if there is unequivocal evidence for recurrence of the breast cancer.
4. Patients must have histologically confirmed HER2+ and hormone receptor positive (ER+ and/or PR+), metastatic breast cancer. ER, PR and HER2 measurements should be performed according 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 (American Society of Clinical Oncology/College of American Pathologists) guidelines.
5. Patients must agree to provide a representative formalin-fixed paraffin-embedded (FFPE) tumor tissue block (preferred) from primary breast or metastatic site (archival) OR at least 15 freshly cut unstained slides from such a block, along with a pathology report documenting HER2 positivity and hormone receptor positivity.
6. Patients should be willing to provide a representative tumor specimen obtained from recently biopsied metastatic disease if clinically feasible. This is recommended but optional tissue.
7. Randomization Screening: Signed Main Informed Consent Form obtained prior to any study specific assessments and procedures
8. Age ≥ 18 years (or per national guidelines)
9. ECOG performance status 0-1
10. Patients must be able and willing to swallow and retain oral medication without a condition that would interfere with enteric absorption.
11. 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 the study must use adequate contraception for the duration of protocol treatment which is for 6 months after the last treatment with palbociclib if they are in Arm A and for 7 months after last treatment with trastuzumab if in either Arm A or Arm B. Adequate contraception is defined as one highly effective form (i.e. abstinence, (fe)male sterilization OR two effective forms (e.g. non-hormonal IUD and condom / occlusive cap with spermicidal foam / gel / film / cream / suppository).
12. Resolution of all acute toxic effects of prior induction anti-HER2-based chemotherapy regimen to NCI CTCAE version 4.0 Grade ≤1 (except alopecia or other toxicities not considered a safety risk for the patient at investigator's discretion) 12 weeks between last dose of chemotherapy–anti-HER2therapy and randomization are allowed. Endocrine therapy could start before study randomization.
13. Willingness and ability to comply with scheduled visits, treatment plan, laboratory tests, and other study procedures
14. Prior Treatment Specifics: Patients may or may not have received neo/adjuvant therapy, but must have a disease-free interval from completion of anti-HER2 therapy to metastatic diagnosis ≥6 months
15. Patients must have received an acceptable, standard, chemotherapy containing anti-HER2 based induction therapy for the treatment of metastatic breast cancer prior to study enrollment. For this study, chemotherapy is limited to a taxane or vinorelbine (only for trastuzumab-based regimen). Eligible patients are expected to have completed 6 cycles of chemotherapy containing anti-HER2-therapy treatment. A minimum of 4 cycles of treatment is acceptable for patients experiencing significant toxicity associated with treatment as long as they are without evidence of disease progression (i.e. CR, PR or SD). The maximum number of cycles is 8. Patients can randomize immediately following completion of their induction therapy, or for those who have already completed induction, a gap of 12 weeks between their last infusion/dose of induction therapy and the C1D1 visit is permitted. Patients are eligible provided they are without evidence of disease progression by local assessment (i.e. CR, PR or SD).
16. Patients with a history or presence of asymptomatic CNS metastases are eligible provided they meet all of the following criteria: • Disease outside the CNS is present. • No evidence of interim progression between the completion of induction therapy and the screening radiographic study • No history of intracranial hemorrhage or spinal cord hemorrhage • Not requiring anti-convulsants for symptomatic control • Minimum of 3 weeks between completion of CNS radiotherapy and Cycle 1 Day 1 and recovery from significant (Grade ≥ 3) acute toxicity with no ongoing requirement for corticosteroid
17. Baseline Body Function Specifics: Absolute neutrophil count ≥ 1,000/mm3
18. Platelets ≥ 100,000/mm3
19. Hemoglobin ≥ 10g/dL
20. Total serum bilirubin ≤ ULN; or total bilirubin ≤ 3.0 × ULN with direct bilirubin within normal range in patients with documented Gilbert’s Syndrome.
21. Aspartate aminotransferase (AST or SGOT) and alanine aminotransferase (ALT or SGPT) ≤ 3 × institutional ULN (≤5 x ULN if liver metastases are present).
22. Serum creatinine below the upper limit of normal (ULN) of the institutional normal range or creatinine clearance ≥ 60 mL/min/1.73 m2 for patients with serum creatinine levels above institutional ULN
23. Left ventricular ejection fraction (LVEF)  50% at baseline as determined by either ECHO or MUGA

Exclusion criteria 9

1. Concurrent therapy with other Investigational Products.
2. Prior therapy with any CDK 4/6 inhibitor.
3. History of allergic reactions attributed to compounds of chemical or biologic composition similar to palbociclib.
4. Patients receiving any medications or substances that are strong inhibitors or inducers of CYP3A isoenzymes within 7 days of randomization (see Section 8.6.3 for list of strong inhibitors or inducers of CYP3A isoenzymes).
5. Uncontrolled current 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.
6. 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.
7. Patients on combination antiretroviral therapy, i.e. those who are HIV-positive, are ineligible because of the potential for pharmacokinetic interactions or increased immunosuppression with palbociclib.
8. QTc interval >480 msec, Brugada syndrome or known history of QTc prolongation or Torsade de Pointes.
9. Patients with clinically significant history of liver disease, including viral or other known hepatitis, current alcohol abuse, or cirrhosis

Endpoints

Primary and secondary outcome measures (English text)

Primary endpoints 1

1. Progression-free survival (PFS) as assessed by the Investigator

Secondary endpoints 8

1. Overall Survival (OS)
2. 3-year and 5-year survival probabilities
3. Objective response (OR: CR or PR)
4. Duration of response (DOR)
5. Clinical Benefit Rate (CBR: CR or PR or SD ≥ 24 weeks)
6. Incidence of CNS metastasis
7. Safety: Type, incidence, severity (as graded by the NCI CTCAE v. 4.0), seriousness and attribution to the study medications of AEs and any laboratory abnormalities
8. Patient Reported Outcomes: Time to symptom progression (FACT-B PFB-TOI), breast cancer specific health treatment related quality of life and general health status

Investigational products

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

Test 3

Auxiliary 9

Sponsors and contacts

Sponsor organisations, regulatory contacts, third parties

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

Quality Management and Compliance

Public contact point

Organisation

Alliance Foundation Trials LLC

Contact name

Quality Management and Compliance

Locations

5 EU/EEA countries · 61 investigational sites

By country

Investigational sites

Country notifications

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

Results and documents

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

Documents 24 files

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

Application history

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