Trial Title:
Trastuzumab Deruxtecan (T-DXd) With Pyrotinib in First-line HER2-positive Unresectable or Metastatic Breast Cancer Trial
NCT ID:
NCT06245824
Condition:
Breast Cancer
Conditions: Official terms:
Breast Neoplasms
Trastuzumab
Trastuzumab deruxtecan
Study type:
Interventional
Study phase:
Phase 4
Overall status:
Not yet recruiting
Study design:
Allocation:
N/A
Intervention model:
Single Group Assignment
Primary purpose:
Treatment
Masking:
None (Open Label)
Intervention:
Intervention type:
Drug
Intervention name:
Trastuzumab deruxtecan (T-DXd) with pyrotinib
Description:
T-DXd, 5.4mg/kg IV day 1 of a 21-day cycle. Pyrotinib, 400mg or 320mg, orally once a day,
daily of a 21-day cycle.
Arm group label:
All the subjects enrolled will receive the experimental intervention
Other name:
(T-DXd) with pyrotinib
Summary:
This is an exploratory, single-arm, multi-center study to assess the efficacy and safety
of T-DXd combined with pyrotinib as the first-line treatment of HER2-positive metastatic
breast cancer.
This study is planned to recruit 3 to 12 patients in safety run-in (Part A) and 39 to 42
patients in dose expansion (Part B) in several investigational sites in China. The total
number of patients enrolled in the study will be 45 to 51. Among them, 45 patients will
start at the recommended dose. Patients who fulfill all the inclusion criteria and none
of the exclusion criteria will receive T-DXd combined with pyrotinib until confirmed
progressive disease. Patients will attend a safety follow up visit 40 days after last
dose of T-DXd with pyrotinib. There are two main parts to this study; Part A, Combination
dose finding and Parts B, Dose expansion.
Tumor assessments will be performed at Screening as baseline with follow-up every 9
weeks(±7 days) from the date of first dosing date of T-DXd with pyrotinib for 54 weeks,
and then every 12 weeks (±7 days) until confirmed objective disease progression.
Primary Objective for Part A:
To define the recommended dose of pyrotinib combined with T-DXd Recommended dose
Secondary Objective for Part A:
To investigate the safety and tolerability of T-DXd + pyrotinib as first-line treatment
of HER2-positive metastatic breast cancer.
Primary Objective for Part B :
To determine the efficacy of T-DXd + pyrotinib as first-line treatment of HER2-positive
metastatic breast cancer.
Secondary Objective for Part B :
To further determine the efficacy of T-DXd + pyrotinib as first-line treatment of
HER2-positive metastatic breast cancer and To further evaluate the safety and
tolerability profile of T-DXd + pyrotinib as first-line treatment of HER2-positive
metastatic breast cancer.
Detailed description:
Combination of HER2-antibody-drug conjugate and tyrosine kinase inhibitors demonstrated
additive or synergistic anti-tumour effects in HER2-positive cell lines or metastatic
breast cancer in in vitro or in vivo studies .It is expected that the efficacy will be
further improved in early-line patients with the combination of HER2-antibody-drug
conjugate and tyrosine kinase inhibitors. Given the efficacy of T-DXd monotherapy and the
widely used of pyrotinib in second-line metastatic HER2-positive breast cancer, and no
major overlapping toxicities between T-DXd and pyrotinib, it may be a promising
combination regimen to explore in first-line HER2+ metastatic breast cancer in China.
Criteria for eligibility:
Criteria:
Inclusion Criteria:
1. Provision of informed consent prior to any study specific procedures
2. Aged at least 18 years.
3. Pathologically documented breast cancer that：
1. is advanced or metastatic;
2. is confirmed as HER2-positive Immunohistochemistry 3+（IHC3+） or in situ
hybridization+(ISH+) in the pathological examination/rechecking of primary
lesions or metastatic lesions performed by the Research site's Patholog
Laboratory;
3. hormone receptor (HR)-positive or HR-negative disease
4. No prior chemotherapy or HER2-targeted therapy for advanced or metastatic breast
cancer or only 1 previous line of endocrine therapy in the metastatic setting.
Participants who have received chemotherapy or HER2-targeted therapy in the
neo-adjuvant or adjuvant setting are eligible if > 6 months from treatment to
metastatic diagnosis
5. Asymptomatic or treated brain metastases not needing urgent neurosurgical
intervention or dehydration treatment and glucocorticoid treatment is allowed：
1. Untreated brain metastases (BM) at contrast brain screening MRI/CT
2. Previously local therapy treated stable or progressing brain metastases (BM).
6. Eastern Cooperative Oncology Group (ECOG) performance status 0-1.
7. Having at least one measurable lesion according to RECIST 1.1.
8. left ventricular ejection fraction ≥ 50% within 28 days at screening.
9. Life expectancy ≥ 12 weeks at screening.
10. Adequate organ and bone marrow function within 28 days before
randomization/enrolment as described below. Organ and bone marrow function criteria
must also be met when laboratory tests are repeated within 3 days before Cycle 1 Day
1. Note: Transfusion (red blood cell or platelet) or Granulocyte Colony-Stimulating
Factor administration is not allowed within 2 weeks prior to the day on which marrow
function is assessed:
- Absolute neutrophils count (ANC) ≥1.5x109/L (band neutrophil and segmented
neutrophil), platelets ≥100x109/L and Hb ≥90g/L [no blood transfusion or no
erythropoietin (EPO) dependence within 7 days before enrollment].
- Hepatic: total bilirubin ≤1× upper limit of normal (ULN) if no liver metastases
or <2×ULN in the presence of documented Gilbert's syndrome (unconjugated
hyperbilirubinemia) or liver metastases at baseline; Alkaline phosphatase,
alanine transaminase (ALT) and aspartate transaminase (AST) ≤1.5 ULN (or ≤5 ULN
in case of known liver involvement); Serum albumin ≥ 2.5 g/dL.
- Renal: Creatinine clearance (CCr) ≥30mL/min as determined by Cockcroft-Gault
(using actual body weight);
- International normalized ratio (INR) and prothrombin time (PT) ≤1.5 times ULN
for patients not receiving therapeutic anticoagulation
11. Has adequate treatment washout period before screen, defined as:
Major surgery ≥ 4 weeks Radiation therapy including palliative stereotactic
radiation therapy to chest≥ 4 weeks Palliative stereotactic radiation therapy to
other anatomic areas including whole brain radiation ≥ 2 weeks Hormonal therapy ≥ 3
weeks Chloroquine/Hydroxychloroquine ≥ 14 days
12. Male and female. Contraceptive use by men or women should be consistent with local
regulations regarding the methods of contraception for those participating in
clinical studies.
13. Negative pregnancy test (urine or serum) for women of childbearing potential who are
sexually active with a non-sterilised male partner.
14. Female participants must be 1 year post-menopausal, surgically sterile, or using one
highly effective form of birth control (a highly effective method of contraception
is defined as one that can achieve a failure rate of less than 1% per year when used
consistently and correctly). Women of childbearing potential who are sexually active
with a non-sterilised male partner must agree to use one highly effective method of
birth control from the time of screening and must agree to continue using such
precautions for 7 months after the last dose of study treatment (see Table 4 for
complete list of highly effective birth control methods). Female patients must
refrain from egg cell donation and breastfeeding while on study and for 7 months
after the last dose of study treatments. Non sterilised male partners of a woman of
childbearing potential must use a male condom plus spermicide (condom alone in
countries where spermicides are not approved) throughout this period. Not engaging
in heterosexual activity (sexual abstinence) for the duration of the study and drug
washout period is an acceptable practice if this is the preferred usual lifestyle of
the participant; however, periodic or occasional abstinence, the rhythm method, and
the withdrawal method are not acceptable methods of contraception.
15. Male participants who intend to be sexually active with a female partner of
childbearing potential must be surgically sterile or using an acceptable method of
contraception (see Table 4) from the time of screening throughout the total duration
of the study and the drug washout period (4 months after the last dose of study
treatment) to prevent pregnancy in a partner. Male participants must not donate or
bank sperm during this same time period. Not engaging in heterosexual activity
(sexual abstinence) for the duration of the study and drug washout period is an
acceptable practice if this is the preferred usual lifestyle of the participant;
however, periodic or occasional abstinence, the rhythm method, and the withdrawal
method are not acceptable methods of contraception.
Exclusion Criteria:
1. Ineligible for any of the agents on the study. Participants with contraindications
to pyrotinib per local prescribing information or to T-DXd per the T-DXd
Investigator's Brochure cannot be enrolled to the study.
2. Previous IP（pyrotinib or T-DXd）assignment in the present study, or prior treatment
with any other HER2 TKI agent.
3. Prior exposure to antibody drug conjugate that comprises of an exatecan derivative
that is a topoisomerase I inhibitor.
4. Any concurrent anticancer treatment. A 3-week washout period is required for female
participants using hormone replacement therapy and for participants receiving
endocrine therapy for HR positive tumours.
5. Concurrent enrolment in another clinical study, unless it is an observational
(non-interventional) clinical study or during the follow-up period of an
interventional study.
6. Refractory nausea, vomiting and diarrhea, chronic gastrointestinal disease, or
previous significant bowel resection.
7. Has substance abuse or any other medical conditions such as clinically significant
cardiac or psychological conditions, that may, in the opinion of the investigator,
interfere with the subject's participation in the clinical study or evaluation of
the clinical study results.
8. History of another primary malignancy except for malignancy treated with curative
intent with no known active disease within 5 years before the first dose of study
treatment and of low potential risk for recurrence. Exceptions include basal cell
carcinoma of the skin and squamous cell carcinoma of the skin that has undergone
potentially curative therapy, adequately resected non-melanoma skin cancer,
curatively treated in situ disease, other solid tumours curatively treated.
9. Has unresolved toxicities from previous anticancer therapy, defined as toxicities
(other than alopecia) not yet resolved to Grade ≤1 or baseline. Note: Participants
may be enrolled with chronic, stable Grade 2 toxicities (defined as no worsening to
>Grade 2 for at least 3 months prior to first exposure to study intervention and
managed with standard of care treatment) that the investigator deems related to
previous anticancer therapy, including:
- Chemotherapy-induced neuropathy
- Fatigue
- Residual toxicities from prior immuno-oncology treatment: Grade 1 or Grade 2
endocrinopathies which may include:
1. Hypothyroidism/hyperthyroidism
2. Type 1 diabetes
3. Hyperglycemia
4. Adrenal insufficiency
5. Adrenalitis
6. Skin hypopigmentation (vitiligo)
10. Has spinal cord compression or clinically active central nervous system metastases,
defined as untreated and symptomatic, or requiring therapy with corticosteroids or
anticonvulsants to control associated symptoms. Participants with clinically
inactive brain metastases may be included in the study. Participants 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. A minimum of 2 weeks must
have elapsed between the end of whole brain radiotherapy or stereotactic
radiotherapy and enrollment.
11. Has active primary immunodeficiency, known HIV infection, or active hepatitis B or C
infection, such as those with serological evidence of viral infection within 28 days
of Day 1 of Cycle 1. Participants positive for hepatitis C virus (HCV）antibody are
eligible only if polymerase chain reaction is negative for HCV RNA. Participants
should be tested for HIV prior to enrolment if required by local regulations or
Institutional Review Board/Ethics Committee. Subjects with past or resolved
hepatitis B virus (HBV) infection are eligible only if they meet all of the
following criteria:
- HBsAg(-) (for > 6 months off anti-viral treatment),
- antibody to hepatitis B core antigen (+) (IgG or total Ig), HBV DNA
undetectable,
- Absence of cirrhosis or fibrosis on prior imaging or biopsy,
- Absence of HCV co-infection or history of HCV co-infection.
- Access to a local Hepatitis B expert during and after the study.
12. Uncontrolled infection requiring IV antibiotics, antivirals, or antifungals.
13. Participants with a medical history of myocardial infarction (MI) within 6 months
before first exposure to study intervention, symptomatic congestive heart failure
(New York Heart Association Class II to IV), participants with troponin levels above
ULN at screening (as defined by the manufacturer), and without any myocardial
related symptoms, should have a cardiologic consultation before enrollment to rule
out MI.
14. History of (non-infectious) interstitial lung disease(ILD)/pneumonitis that required
steroids, has current ILD/pneumonitis, or where suspected ILD/pneumonitis cannot be
ruled out by imaging at screening.
15. Lung criteria:
1. Lung-specific intercurrent clinically significant illnesses including, but not
limited to, any underlying pulmonary disorder (eg, pulmonary emboli within 3
months of study enrolment, severe asthma, severe chronic obstructive pulmonary
disorder (COPD), restrictive lung disease, pleural effusion, post Corona Virus
Disease 2019 pulmonary fibrosis, etc,).
2. Any autoimmune, connective tissue or inflammatory disorders (eg, rheumatoid
arthritis, Sjogren's, sarcoidosis, etc.) where there is documented, or a
suspicion of pulmonary involvement at the time of screening. Full details of
the disorder should be recorded in the electronic Case Report Form (eCRF) for
participants who are included in the study.
3. Prior pneumonectomy.
16. Receipt of live, attenuated vaccine (mRNA and replication deficient adenoviral
vaccines are not considered attenuated live vaccines) within 30 days prior to the
first exposure to study intervention. Note: Participants, if enrolled, should not
receive live vaccine during the study and up to 30 days after the last dose of study
intervention.
17. Judgment by the investigator that the participant should not participate in the
study if the participant is unlikely to comply with study procedures, restrictions
and requirements.
18. Pregnant or breastfeeding female participants.
Gender:
All
Minimum age:
18 Years
Maximum age:
N/A
Healthy volunteers:
No
Locations:
Facility:
Name:
Cancer Hospital Chinese Academy of Medical Sciences
Address:
City:
Beijing
Country:
China
Start date:
January 30, 2024
Completion date:
December 1, 2026
Lead sponsor:
Agency:
Cancer Institute and Hospital, Chinese Academy of Medical Sciences
Agency class:
Other
Source:
Cancer Institute and Hospital, Chinese Academy of Medical Sciences
Record processing date:
ClinicalTrials.gov processed this data on November 12, 2024
Source: ClinicalTrials.gov page:
https://clinicaltrials.gov/ct2/show/NCT06245824
