Trial Title:
Safety and Efficacy of T-DXd vs. CDK4/6i-based ET as First-line Therapy of HR-positive and HER2-low/Ultralow Advanced Breast Cancer Patients Classified as Non-luminal Subtype
NCT ID:
NCT06486883
Condition:
Advanced Breast Cancer
Advanced Breast Carcinoma
Hormone Receptor Positive Breast Carcinoma
Conditions: Official terms:
Carcinoma
Breast Neoplasms
Trastuzumab
Trastuzumab deruxtecan
Study type:
Interventional
Study phase:
Phase 2
Overall status:
Not yet recruiting
Study design:
Allocation:
Randomized
Intervention model:
Parallel Assignment
Intervention model description:
Arm A: T-DXd; Arm B CDK4/6i plus endocrine therapy (ET). The physician's choice of
CDK4/6i plus ET will be limited to one CDK4/6i plus fulvestrant or an aromatase inhibitor
(AI). The options for CDK4/6i are palbociclib, ribociclib, and abemaciclib, the options
for ET are fulvestrant, letrozole, anastrozole, and exemestane.
Primary purpose:
Treatment
Masking:
None (Open Label)
Intervention:
Intervention type:
Drug
Intervention name:
Trastuzumab deruxtecan (T-DXd, DS-8201a)
Description:
Patients will receive T-DXd 5.4 mg/kg body weight administered as an intravenous (IV)
infusion on Day 1 (D1) of each 21-day cycle. The initial dose will be administered as a
90-minute IV infusion.
Arm group label:
Arm A
Intervention type:
Drug
Intervention name:
CDK4/6i plus ET
Description:
Patients will receive physician's choice of CDK4/6 inhibitor (CDK4/6i) including
palbociclib, ribociclib, and abemaciclib; physician's choice of endocrine therapy (ET)
including fulvestrant, letrozole, anastrozole, and exemestane.
Arm group label:
Arm B
Summary:
This trial studies a type of advanced breast cancer defined as hormone receptor
HR-positive/HER2-negative and classified as non-luminal by gene expression profiling
(PAM50). Patients will be treated with trastuzumab deruxtecan (T-DXd) or with physician's
choice of CDK4/6 inhibitor (CDK4/6i) plus endocrine therapy (ET). The main purpose of the
study is to analyze the efficacy of T-DXd in patients who have HR-positive and
HER2-low/ultralow advanced breast cancer classified as non-luminal subtype.
Detailed description:
This is an international, multicenter, two-arm, randomized, phase II clinical trial for
patients with unresectable locally recurrent or metastatic HR-positive and
HER2-low/ultralow breast cancer classified as non-luminal by gene expression profiling.
Female or male patients ≥ 18 years of age with HR-positive and HER2-low/ultralow locally
recurrent inoperable or metastatic breast cancer classified as non-luminal subtype by
central PAM50 analysis will be enrolled. Patients will be randomized to T-DXd 5.4 mg/kg
body weight administered as an IV infusion on Day 1 of each 21-day cycle or physician's
choice of CDK4/6 inhibitor plus endocrine therapy. The main objective of the study is to
demonstrate that first-line T-DXd compared with CDK4/6i plus ET is superior in prolonging
the progression free survival (PFS) based on investigator assessment in patients with
HR-positive, HER2-low advanced breast cancer classified as non-luminal by central PAM50
analysis (HER2-low population) and all patients.
Criteria for eligibility:
Criteria:
Inclusion Criteria:
1. Patients must be capable to understand the purpose of the study and have signed
written informed consent form (ICF) prior to beginning specific protocol procedures.
2. Female or male patients ≥ 18 years of age at the time of signing ICF.
3. ECOG performance status of 0-1.
4. Minimum life expectancy of ≥ 12 weeks at screening.
5. Evidence of HER2-low expression (1+ by immunohistochemistry (IHC) or 2+ and negative
by an in situ hybridization [ISH] test) or HER2-ultralow (IHC 0 with faint membrane
staining and in ≤ 10% of tumor cells) breast cancer according to the most recent
American Society of Clinical Oncology (ASCO)/College of American Pathologists (CAP)
guidelines determined by a MEDSIR's designated central laboratory, using Ventana 4B5
antibody. This assessment has to be done on the most recently available (archived or
newly collected) formalin-fixed, paraffin-embedded (FFPE) tumor tissue blocks (≤ 6
weeks or FFPE of a tumor sample obtained after last prior systemic therapy) from
core or excisional biopsy from a locally recurrent (breast or locoregional lymph
nodes) or metastatic tumor lesion, excluding bone metastases.
6. Non-luminal breast cancer subtype as per central PAM50 analysis determined in the
most recently available (archived or newly collected) FFPE tumor tissue blocks (≤ 6
weeks or FFPE of a tumor sample obtained after last prior systemic therapy) from
core or excisional biopsy from a locally recurrent (breast or locoregional lymph
nodes) or metastatic tumor lesion with the exception of bone metastases.
7. Patients must have HR-positive (estrogen receptor [ER] and/or progesterone receptor
[PgR]-positive defined as ≥ 1% positive stained cells) status according to the most
recent ASCO/CAP guidelines locally determined prior to study entry.
8. Unresectable locally recurrent or metastatic breast cancer documented by
computerized tomography (CT) scan or magnetic resonance imaging (MRI) that is not
amenable to resection with curative intent.
9. Evaluable disease according to RECIST v.1.1. Patients with bone-only disease are not
allowed. Patients with bone metastases with soft tissue masses measuring > 10 mm are
eligible.
10. Patients must have endocrine resistance criteria:
• disease progression during adjuvant ET or within the first year of completing
adjuvant ET;
or endocrine sensitivity criteria:
• de novo metastatic disease or disease progression ≥ 12 months after completing
adjuvant ET with at least one of the following requirements:
- Estrogen receptor ≤ 50% positive stained cells;
- and/or high histological grade or Ki67 > 50% on primary tumor;
- and/or liver metastases;
- and/or known non-luminal subtype as per local PAM50 analysis.
11. No prior treatment with any systemic therapy for advanced disease.
12. Patients treated with a CDK4/6i in the adjuvant setting with a treatment-free
interval (TFI) ≥ 12 months following CDK4/6i treatment completion are eligible.
13. Patients have adequate bone marrow, liver, and renal function:
- Hematological (without platelet, red blood cell transfusion, and/or granulocyte
colony-stimulating factor support within 14 days before first study treatment
dose): White blood cell (WBC) count > 3.0 x 109/L, absolute neutrophil count
(ANC) ≥ 1.5 x 109/L, platelet count ≥ 100.0 x 109/L, and hemoglobin ≥ 9.0 g/dL
(≥ 5.6mmol/L).
- Hepatic: Serum albumin ≥ 2.5 g/dL; total bilirubin ≤ 1.5 times upper limit of
normal (x ULN) (≤ 3 x ULN in patients with liver metastases or know history of
Gilbert's disease); alkaline phosphatase (ALP) ≤ 2.5 x ULN (≤ 5 x ULN in
patients with liver/or bone metastases); aspartate transaminase (AST) and
alanine transaminase (ALT) ≤ 3 x ULN (≤ 5 x ULN in patients with liver
metastases).
- Renal: Creatinine clearance ≥ 30 mL/min as determined by Cockcroft Gault (using
actual body weight).
- Coagulation: International normalized ratio or prothrombin time and either
partial thromboplastin or activated partial thromboplastin time ≤ 1.5 × ULN.
14. Resolution of all acute toxic effects of prior anti-cancer therapy to Grade ≤ 1 as
determined by the US National Cancer Institute (NCI)-Common Terminology Criteria for
Adverse Events (CTCAE) version 5.0 (v.5.0) (except for alopecia or other toxicities
not considered a safety risk for the patient at investigator's discretion).
15. Women of childbearing potential who are sexually active with a non-sterilized male
partner must have a negative serum pregnancy test within 14 days before study
treatment initiation. In addition, they must agree to use one highly effective
method of birth control from the time of screening until 7 months after the last
dose of T-DXd, or within the time period specified per local prescribing guidelines
after the final dose of physician's choice of CDK4/6i plus ET. Female patients must
refrain from egg cell donation and breastfeeding during this same period.
16. Male participants who are sexually active with a female partner of childbearing
potential must be surgically sterile or using an acceptable method of contraception
from the time of screening until 4 months after the last dose of T-DXd, or within
the time period specified per local prescribing guidelines after the final dose of
physician's choice of CDK4/6i plus ET. Male participants must not donate or bank
sperm during this same period.
17. Patients must be accessible for treatment and follow-up.
Exclusion Criteria:
1. Current participation in another therapeutic clinical trial, except other
translational studies.
2. Treatment with approved or investigational cancer therapy within 3 weeks prior to
initiation of study drug.
3. Treatment with chloroquine/hydroxychloroquine within 14 days prior to initiation of
study drug.
4. Have previously been treated with T-DXd and/or fulvestrant. Note: patients who
experienced relapse after more than 1 year from completion of fulvestrant are
eligible.
Note I: previous treatment with anti-HER2 therapies in (neo-) adjuvant setting will
be allowed for participants who showed conversion from HER2-positive expression in
primary breast tumor sample to HER2-low or HER2-ultralow expression (HER2 loss) in
relapsed tumor sample.
5. Patients with advanced, symptomatic, visceral spread, that are at risk of
life-threatening complications in the short term (including patients with massive
uncontrolled effusions [pleural, pericardial, and/or peritoneal] and pulmonary
lymphangitis).
6. Impairment of gastro-intestinal (GI) function or GI disease that may significantly
alter the absorption of CDK4/6i, such as history of GI surgery which may result in
intestinal blind loops and patients with clinically significant gastroparesis, short
bowel syndrome, unresolved nausea, vomiting, active inflammatory bowel disease, or
diarrhea of CTCAE Grade > 1.
7. Known central nervous system (CNS) involvement (brain metastases and/or
leptomeningeal carcinomatosis). Subjects with clinically inactive brain metastases
may be included in the study. Subjects with treated brain metastases that are no
longer symptomatic and who require no treatment with corticosteroids or
anticonvulsants may be included in the study if they have recovered from the acute
toxic effect of radiotherapy.
8. Have a concurrent malignancy or malignancy within 5 years of study enrollment with
the exception of carcinoma in situ of the cervix and basal cell carcinoma or
squamous cell carcinoma of the skin that has been previously treated with curative
intent. For other cancers considered to have a low risk of recurrence, discussion
with the Sponsor's Medical Monitor is required.
9. Known allergy or hypersensitivity reaction to any of the investigational medicinal
products (IMPs) or their inactive ingredients.
10. Palliative radiotherapy with a limited field of radiation within 2 weeks or with
wide field of radiation or to more than 30% of the bone marrow within 4 weeks prior
to start of study treatment.
11. Major surgical procedure or significant traumatic injury within 4 weeks before the
first dose of study treatment or anticipation of need for major surgery within the
course of the study treatment.
12. Has an active cardiac disease or a history of cardiac dysfunction or conduction
abnormalities including, but not confined, to any of the following:
- Participants with a medical history of myocardial infarction within 6 months
before screening, symptomatic congestive heart failure (NYHA Class II to IV),
unstable angina pectoris, or a recent (< 6 months) cardiovascular event
including stroke. Participants with troponin levels above ULN at screening (as
defined by the manufacturer), and without any myocardial related symptoms,
should have a cardiologic consultation to rule out myocardial infarction.
- Left ventricular ejection fraction (LVEF) < 55% as determined by multigated
acquisition (MUGA) scan or echocardiogram (ECHO).
- History of arrhythmia (multifocal premature ventricular contractions, bigeminy,
trigeminy, or ventricular tachycardia), which is symptomatic or requires
treatment (NCI-CTCAE Grade 3), symptomatic or uncontrolled atrial fibrillation
despite treatment, or asymptomatic sustained ventricular tachycardia.
Participants with atrial fibrillation controlled by medication or arrhythmias
controlled by pacemakers will be permitted to enroll.
- QT interval corrected by Fridericia's formula (QTcF) prolongation to > 470 ms
(females) or > 450 ms (males) based on average of the screening triplicate
12-lead electrocardiogram (ECG).
- History of QT prolongation associated with other medications that required
discontinuation of that medication, or any current concomitant medication known
to prolong the QT interval and cause Torsades de Pointes.
- Congenital long QT syndrome, family history of long QT syndrome, or unexplained
sudden death under 40 years of age in first-degree relatives.
13. Clinically severe pulmonary compromise resulting from intercurrent pulmonary
illnesses including, but not limited to, any underlying pulmonary disorder (e.g.,
pulmonary emboli within 3 months of the study enrolment, severe asthma, severe
chronic obstructive pulmonary disease, restrictive lung disease, pleural effusion,
post COVID-19 pulmonary fibrosis, etc.), and any autoimmune, connective tissue, or
inflammatory disorders with pulmonary involvement (e.g., rheumatoid arthritis,
Sjogren's syndrome, sarcoidosis, etc.), or prior pneumonectomy (complete).
14. Has a history of non-infectious interstitial lung disease (ILD)/pneumonitis that
required steroids, has current ILD/pneumonitis, or has suspected ILD/pneumonitis
that cannot be ruled out by imaging at screening.
15. Pregnant or lactating women or patients not willing to apply highly effective
contraception as defined in the protocol.
16. Current known infection with hepatitis B virus (HBV), or hepatitis C virus (HCV).
Patients with past HBV infection or resolved HBV infection (defined as having a
negative hepatitis B surface antigen [HBsAg] test and a positive hepatitis B core
antibody [HBcAb] test, accompanied by a negative HBV DNA test), and > 6 months off
anti-viral treatment are eligible. Those participants should be closely monitored
for HBV reactivation and have access to a local hepatitis B expert during and after
the study.
17. Patients positive for HCV antibody are eligible only if polymerase chain reaction
(PCR) is negative for HCV RNA.
18. Patients with HCV co-infection or history of HCV co-infection.
19. Patients with cirrhosis or fibrosis on prior imaging or biopsy.
20. Has an active primary immunodeficiency or known human immunodeficiency virus (HIV)
infection.
21. Other active uncontrolled infection at the time of enrollment.
22. Receipt of live or attenuated vaccine within 30 days prior to the first dose of
study treatment.
23. A history of uncontrolled seizures, CNS disorders, or serious and/or unstable
pre-existing psychiatric disability judged by the investigator to be clinically
significant and adversely affecting compliance to study drugs or interfering with
subject safety.
24. Current use of food or drugs known to be potent CYP3A4 inhibitors, drugs known to be
potent CYP3A4 inducers (for examples, see the Prohibited Medications Section).
25. Known substance abuse or any other concurrent severe and/or uncontrolled medical
condition that would, in the investigator's judgment, contraindicate patient
participation.
26. Inability or unwillingness to comply with the requirements of the protocol in the
opinion of the investigator.
Gender:
All
Minimum age:
18 Years
Maximum age:
N/A
Healthy volunteers:
No
Start date:
December 2024
Completion date:
January 2028
Lead sponsor:
Agency:
MedSIR
Agency class:
Other
Source:
MedSIR
Record processing date:
ClinicalTrials.gov processed this data on November 12, 2024
Source: ClinicalTrials.gov page:
https://clinicaltrials.gov/ct2/show/NCT06486883
