Dual Primary objective: - To demonstrate the superiority of Dato-DXd compared to ICC by assessment of PFS in participants with inoperable or metastatic HR-positive, HER2-negative breast cancer, who have been treated with 1 or 2 lines of chemotherapy…
ID
Source
Brief title
Condition
- Breast neoplasms malignant and unspecified (incl nipple)
Synonym
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
- The target population of interest in this study is participants with
inoperable or metastatic HR-positive, HER2-negative breast cancer who have been
treated with one or two prior lines of systemic chemotherapy in the
inoperable/metastatic setting.
- To demonstrate the superiority of Dato-DXd compared to ICC by assessment of
OS in participants with inoperable or metastatic HR-positive, HER2-negative
breast cancer, who have been treated with 1 or 2 lines of chemotherapy in the
inoperable/metastatic setting.
Secondary outcome
- To demonstrate the superiority of Dato-DXd compared to ICC by assessment of
ORR in participants with inoperable or metastatic HR-positive, HER2-negative
breast cancer, who have been treated with 1 or 2 lines of chemotherapy in the
inoperable/metastatic setting, per BICR and per investigator assessment.
- To demonstrate the superiority of Dato-DXd compared to ICC by assessment of
DoR in participants with inoperable or metastatic HR-positive, HER2-negative
breast cancer who have been treated with 1 or 2 lines of chemotherapy in the
inoperable/metastatic setting.
- To demonstrate the superiority of Dato-DXd compared to ICC by assessment of
PFS in participants with inoperable or metastatic HR-positive, HER2-negative
breast cancer who have been treated with 1 or 2 lines of chemotherapy in the
inoperable/metastatic setting, per investigator assessment.
- To demonstrate the superiority of Dato-DXd compared to ICC by assessment of
DCR in participants with inoperable or metastatic HR-positive, HER2-negative
breast cancer, who have been treated with 1 or 2 lines of chemotherapy in the
inoperable/metastatic setting, per BICR and per investigator
assessment.
- To assess pain in participants treated with Dato-DXd compared to ICC.
- To assess physical functioning in participants treated with Dato-DXd compared
to ICC.
- To assess global health status/quality of life (GHS/QoL) in participants
treated with Dato-DXd compared to ICC.
- To demonstrate the superiority of Dato-DXd compared to ICC by assessment of
TFST in participants with inoperable or metastatic HR-positive, HER2-negative
breast cancer who have been treated with 1 or 2 lines of chemotherapy in the
inoperable/metastatic setting.
- To demonstrate the superiority of Dato-DXd compared to ICC by assessment of
TSST in participants with inoperable or metastatic HR-positive, HER2-negative
breast cancer who have been treated with 1 or 2 lines of chemotherapy in the
inoperable/metastatic setting.
- To demonstrate the superiority of Dato-DXd compared to ICC by assessment of
PFS2 in participants with inoperable or metastatic HR-positive, HER2-negative
breast cancer who have been treated with 1 or 2 lines of chemotherapy in the
inoperable/metastatic setting.
- To assess the PK of Dato-DXd 6mg/kg IV Q3W.
- To investigate the immunogenicity of Dato-DXd 6mg/kg IV Q3W.
- To assess the safety and tolerability profile of Dato-DXd compared to ICC.
Background summary
Breast cancer is the most common cancer in the world, with an estimated 2.2
million new cases in 2020 globally (11.7% of all new cancers). Breast cancer is
also the fifth most common cause of death from cancer, with an estimated 684000
deaths in 2020 (Sung et al 2021). In Europe, an estimated 531000 patients were
diagnosed with breast cancer in 2020, and 141000 died from the disease. Despite
advances in the diagnosis and treatment of breast cancer, around 6% of women
diagnosed with breast cancer in the US have metastatic disease at time of
diagnosis, and up to 30% of women with early-stage non-metastatic breast cancer
will develop metastatic disease (O'Shaughnessy 2005). Although treatable,
metastatic breast cancer remains virtually incurable, with a median survival of
approximately 3 years and a 5-year survival rate of approximately 25% (Cardoso
et al 2018).
Single agent chemotherapy remains the cornerstone of therapy for patients with
HR-positive, HER2 negative metastatic breast cancer who have exhausted
endocrine therapy options. However, patient prognosis is poor, and durable
antineoplastic therapy options are necessary
to improve outcomes in this patient population.
Dato-DXd is a TROP2 antibody-drug conjugate (administered via IV infusion,
Q3W). Within the Dato-DXd clinical development program, preliminary data
supporting the use of Dato-DXd in participants with HR-positive, HER2-negative
breast cancer are available from an ongoing phase 1 first-in-human study,
TROPION-PanTumor01 (NCT03401385), which is evaluating Dato-DXd in participants
with advanced non-small cell lung cancer and triple negative breast cancer,
relapsed or refractory to stand-of-care therapy. These data have demonstrated
highly encouraging efficacy across dose groups, with tumor responses observed
at doses of 4, 6, and 8 mg/kg and an acceptable and manageable toxicity profile.
Given these encouraging preliminary safety and efficacy data, the current study
is designed to provide a robust and detailed understanding of the efficacy and
safety of Dato-DXd when compared with Investigator*s choice of standard-of-care
single-agent chemotherapy (eribulin, capecitabine, vinorelbine, or gemcitabine;
henceforth referred to as ICC) in participants with inoperable or metastatic
HR-positive, HER2-negative breast cancer who have been treated with one or two
prior lines of systemic chemotherapy, for which an unmet medical need remains.
Study objective
Dual Primary objective:
- To demonstrate the superiority of Dato-DXd compared to ICC by assessment of
PFS in participants with inoperable or metastatic HR-positive, HER2-negative
breast cancer, who have been treated with 1 or 2 lines of chemotherapy in the
inoperable/metastatic setting, per BICR.
- To demonstrate the superiority of Dato-DXd compared to ICC by assessment of
OS in participants with inoperable or metastatic HR-positive, HER2-negative
breast cancer, who have been treated with 1 or 2 lines of chemotherapy in the
inoperable/metastatic setting.
Study design
This is a Phase 3, open-label, randomized study of Dato-DXd versus ICC in
participants with inoperable or metastatic HR-positive, HER2-negative breast
cancer who have been treated with one or two prior lines of systemic
chemotherapy in the inoperable or metastatic setting.
Intervention
The study intervention arms are:
- Arm 1: Dato-DXd (6 mg/kg IV on Day 1, Q3W)
- Arm 2: ICC:
* Capecitabine (1000 or 1250 mg/m2 oral BID on Days 1 to 14, Q3W); choice
between the 2 doses will be determined by standard institutional practice.
* Gemcitabine (1000 mg/m2 IV Day 1 and Day 8, Q3W)
* Eribulin mesylate (1.4 mg/m2 IV on Days 1 and 8, Q3W)
* Vinorelbine (25 mg/m2 IV on Days 1 and 8, Q3W)
Study burden and risks
Patients need to come to the hospital more often and visits are longer.
Patients will undergo the following actions during the study:
- Medical History
- Pulmonary function tests at screening and when pneumonia/ILD is suspected
- ECHO/MUGA scan (for assessment LVEF)
- Ophthalmologic assessments
- Oral Care Plan
- 12-Lead ECG
- Vital signs (blood pressure, heart rate, body temperature, respiratory rate
and oxygen saturation)
- Height and weight measurement
- ECOG performance status
- Physical examination
- Blood test
- Urinalysis
- Questionnaires
- Pregnancy test if applicable
- AE/SAE rating
- CT/MRIs of abdomen, chest and pelvis
- CT/MRI brain at screening, if there are metastases to the brain, this is
repeated several times during the treatment period
- Whole body isotopic bone scan at screening and as clinically necessary
- HRCT of the chest if pneumonia/ILD is suspected
- Administration of study drug
- Biopsy at screening, when no or insufficient tumor tissue is available
- Biopsy at progression (optional)
- Paired biopsy (optional; during screening and between C2D1 and C2D7)
The study drugs can also cause side effects. The following side effects are
related to the use of Dato-DXd:
Very common (may affect more than 1 in 10 people):
- Fatigue
- Nausea
- Alopecia (loss of hair)
- Mucosal inflammation (inflammation of whole digestive tract)
- Infusion Related Reaction including anaphylaxis
- Anemia
- Vomiting
- Decreased appetite
- Stomatitis (inflammation of lining of the mouth)
- Rash
- Diarrhea
- Dry eye
Common (may affect up to 1 in 10 people):
- Lung problems (Interstitial lung disease/pneumonitis)
- Rash maculopapular (rash made of flat discolored skin patches and small
raised bumps).
The following serious side effects have been reported with the use of Dato-DXd:
- Lung problems (ILD)
- infusion related reactions including anaphylaxis
- Eye problems (keratitis)
- Nausea and vomiting
- unexpected risks: The study medications might have other side effects that
are not known at this time
Patients receiving one of four possible chemotherapy regimens have a risk on
side effects related to these standard of care chemotherapy regimens.
Study testing risks:
- Blood draw (pain, lightheadedness, temporary discomfort, bleeding, bruising,
swelling or rarely, infection, at the site of a needle stick.
- CT/MRI: contrast dye may cause an allergic reaction and can rarely cause
kidney damage. The risk of kidney damage is higher in people who are dehydrated
or suffer from diabetes.
- MUGA: mild skin rash, the site of the injection may be uncomfortable after
the scan is completed. Allergic reactions to the radioactive tracer rarely
occur. The level of radiation released during the test is low.
- ECG: skin where the patches are placed may become slightly red or may sting
for a moment when they are removed.
- Tumor Biopsy: pain,bleeding, decrease of blood pressure, collapsed lung
(pneumothorax), infection, regional spread of cancer cells. Although very rare,
there is a risk of serious complications and death. Anaestesia is commonly used
for this type of procedure and there is a risk of complication from anaestesia.
Prinses Beatrixlaan 582
Den Haag 2595BM
NL
Prinses Beatrixlaan 582
Den Haag 2595BM
NL
Listed location countries
Age
Inclusion criteria
- Inoperable or metastatic HR-positive / HER2*negative breast cancer.
- Progressed on and not suitable for endocrine therapy per investigator
assessment, and previously treated with 1 or 2 lines of chemotherapy in the
inoperable / metastatic setting. Participant must have documented progression
on most recent line of chemotherapy. Targeted agents (such as mTOR inhibitors,
PD-1/PDL1 inhibitors), endocrine therapies, and CDK4/6 inhibitors on their own
do not contribute to the count of prior lines of chemotherapy; however,
regimens with such agents in combination with metastatic chemotherapy should be
classified as one line of chemotherapy.
- At least 1 measurable lesion not previously irradiated. Participants with
bone-only metastases are not permitted. Participants with clinically inactive
brain metastases may be included
- Adequate organ and bone marrow function; LVEF >= 50% by echocardiogram or MUGA
- All participants must have available a FFPE tumor sample
Exclusion criteria
- Uncontrolled medical conditions E.g. Cardiac Disease, leptomeningeal
carcinomatosis, systemic infections
- History of ILD, severe Pulmonary compromise
- Prior anticancer therapy with another ADC, TROP2-targeted therapy (e.g.,
Trodelvy), same ICC chemotherapy
- Concurrent anticancer treatment or hormonal therapy for non-cancer related
conditions
- Receipt of live, attenuated vaccine within 30 days before C1D1.
- Prior participation in any Enhertu (T-Dxd) study (regardless if received
T-DXd or not)
- Known hypersensitivity to Dato-DXd or any of the excipients of the product
(including, but not limited to, polysorbate 80), or any other monoclonal
antibodies
Design
Recruitment
Medical products/devices used
Followed up by the following (possibly more current) registration
No registrations found.
Other (possibly less up-to-date) registrations in this register
No registrations found.
In other registers
| Register | ID |
|---|---|
| EudraCT | EUCTR2020-005620-12-NL |
| ClinicalTrials.gov | NCT05104866 |
| CCMO | NL79019.056.21 |