This study has been transitioned to CTIS with ID 2023-507172-44-00 check the CTIS register for the current data. To demonstrate superiority of giredestrant over the control treatment in preventing breast cancer recurrence.Secondary objectives• To…
ID
Source
Brief title
Condition
- Breast neoplasms malignant and unspecified (incl nipple)
Synonym
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
Invasive disease-free survival (IDFS), defined as the time from randomization
to first occurrence of one of the following IDFS events;
ipsilateral invasive breast tumor recurrence, ipsilateral locoregional invasive
breast cancer recurrence, distant recurrence, contralateral
invasive breast cancer, and death from any cause.
Secondary outcome
1. Overall survival, defined as the time from randomization to death from any
cause
2. IDFS (per STEEP), including second primary non-breast cancer, defined in the
same way as the primary IDFS, but including second primary non-breast invasive
cancer as an event (with the exception of non-melanoma skin cancers and in situ
carcinomas of any site)
3. Disease-free survival (DFS), defined as the time from randomization to first
occurrence of an IDFS (per STEEP) event, including second primary non-breast
cancer event or contralateral or ipsilateral DCIS
4. Distant recurrence-free interval (DRFI), defined as the time from
randomization to first occurrence of a DRFI event
5. Locoregional recurrence-free interval (LRRFI), defined as the time from
randomization to first occurrence of an LRRFI event
6. Mean and mean change from baseline in physical functioning, role
functioning, and global health status/ quality of life (QoL) at relevant
timepoints as assessed through use of the European Organisation for the
Research and Treatment of Cancer Quality-of-Life Questionnaire - Core 30 (EORTC
QLQ-C30) respective scale scores
7. Incidence and severity of adverse events, with severity determined according
to NCI CTCAE 5.0
8. Change from baseline in targeted vital signs and clinical laboratory test
results
9. Plasma concentrations of giredestrant at specified timepoints
10. Change from baseline in EuroQol 5-Dimension Questionnaire, 5-level version
(EQ 5D-5L) index-based and visual analogue scale scores at relevant timepoint
Background summary
Globally, breast cancer is the most common invasive malignancy and the most
common cause of cancer-related mortality in women (Jemal et al. 2011). Breast
cancer is the second most commonly diagnosed cancer in the world and the most
commonly diagnosed cancer among women with 2.26 million new cases and
approximately 684,000 deaths in 2020 (IARC Breast Cancer 2020).
Approximately 80% of all breast cancers express the ER and the majority of
these cancers are dependent on ER for tumor growth and progression and hence
hormonal therapy is the cornerstone of treatment of ER+ breast cancer.
Giredestrant is a potent, orally bioavailable, SERD with known mode of action,
which parallels fulvestrant*s MoA. See the Giredestrant Investigator*s Brochure
for more details on MoA.
Preclinical data demonstrate superiority of giredestrant to fulvestrant at the
selected dose of 30 mg, with deeper ER pathway inhibition and higher drug
exposure. Available clinical data demonstrate promising single-agent activity
and safety at the 30 mg dose in ER+ MBC (GO39932 study). See Section 4.3.
Giredestrant also has demonstrated robust nonclinical activity in ER+ breast
cancer models of ESR1- wild type and ESR1- mutation bearing disease.
On the basis of its MoA, nonclinical and clinical activity profile,
giredestrant has the potential to be an important new drug for the treatment of
patients with ER+ breast cancer and support development of giredestrant in EBC
in addition to the ongoing development in MBC.
Detailed information on giredestrant is provided in the Giredestrant
Investigator's Brochure
Study objective
This study has been transitioned to CTIS with ID 2023-507172-44-00 check the CTIS register for the current data.
To demonstrate superiority of giredestrant over the control treatment in
preventing breast cancer recurrence.
Secondary objectives
• To evaluate the efficacy of giredestrant compared with TPC in terms of
overall survival and
other measures
• To evaluate the safety of giredestrant compared with TPC
• To characterize giredestrant PK
• To evaluate health status utility scores of participants treated with
giredestrant compared with TPC
Study design
This is a Phase III, global, randomized, open-label, multicenter, study
evaluating the efficacy and safety of adjuvant giredestrant compared with TPC
in participants with medium- and high-risk Stage I-III histologically confirmed
ER- and HER2+ EBC. Participants will be treated daily with giredestrant or TPC
for at least 5 years. During the study, participants will be regularly assessed
for efficacy, safety, and health-related quality of life. Participants who
complete the 5-year study treatment will enter long-term follow-up for at least
5 years.
An independent Data Monitoring Committee (iDMC) will monitor safety on an
ongoing basis. A Steering Committee will be formed to provide guidance on the
protocol and study design and to provide guidance on review of any relevant
study-related documents or procedures in order to be confident that the data
collected will be timely, accurate, and complete.
A study schema is provided in the protocol Section 1.2 (see Figure 1). A
schedule of activities and a sample collection schedule are provided in the
protocol Section 1.3 (see Table 1, Table 2 and Table 3.
Intervention
Eligible participants will be randomly assigned in a 1:1 ratio to one of the
following treatment arms:
• Arm A (experimental arm): giredestrant 30 mg once a day (QD)
• Arm B (control arm): TPC (dosing according to local prescribing information)
TPC is limited to either tamoxifen or one of the specified third generation
AIs : anastrozole or letrozole or exemestane.
LHRH agonists, which may include, but are not limited to, leuprolide acetate,
goserelin acetate, or triptorelin pamoate, LHRH agonist will be administered to
male participants and premenopausal/perimenopausal participants according to
local prescribing information. Pre- or perimenopausal women and men receiving
treatment with an AI or with giredestrant must receive OFS with approved LHRH
agonist therapy. Pre- or perimenopausal women and men receiving treatment with
tamoxifen may receive OFS at the discretion of the investigator.
Study burden and risks
Potential Side Effects:
• Blood clots
• Damage to the kidneys
• Damage to the liver
• Diarrhea
• Changes to female reproductive organs, including fluid-filled lump in the
ovary (ovarian cysts) and decreased uterine weight
• Nausea and vomiting
• Slow heartbeat
• Female infertility; the risk to male fertility is unknown
• Menopausal symptoms; Because giredestrant blocks the action of female sex
hormones, its effects are similar to, but potentially more severe
than, those of normal menopause such as loss of muscle and bone, hot flashes,
vaginal dryness or discharge, irritation, mood swings, and decreased interest
in sex.
• Possible harm to a developing fetus, including birth defects and miscarriage
Potential Risks:
- Drawing blood can cause pain, bruising, or infection where the needle is
inserted. Some people experience dizziness, fainting, or upset stomach when
their blood is drawn.
- Bone density scan; Although there are no known long-term harmful effects from
the radiation of a single scan, the risk of harmful effects from multiple scans
over a period of time is not known.
- Tumor assessments: (CT-scan, (PET)/CT-scan, MRI, Mammogram)
• You may have an allergic reaction to a tracer or contrast agent.
• Injected contrast agents may cause nausea, headache, hives, temporary
low blood pressure, chest pain, back pain, fever, weakness, and seizures.
There may be
pain, bruising, or infection at the injection site. You may have an
allergic reaction to the contrast agent.
• CT, PET, and MRI scanners may cause some anxiety and claustrophobia
(fear of being in small places). You may be given a mild sedative or anti
anxiety drug to
help manage your symptoms.
• Although there are no known long-term harmful effects from the radiation
of a single scan, the risk of harmful effects from multiple scans over a period
of time is
not known.
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Listed location countries
Age
Inclusion criteria
• Participants (females, regardless of menopausal status, and males) who are
age >= 18 years at the time of signing the Informed Consent Form
• Participants who have multicentric (the presence of two of more tumor foci
within different quadrants of the same breast) and/or multifocal (the presence
of two or more tumor foci within a single quadrant of the breast) breast cancer
are also eligible if all examined tumors meet pathologic criteria for estrogen
receptor (ER) positivity and HER2 negativity
• Participants who have documented ER+ tumor by immunohistochemistry, as
assessed locally on a primary disease specimen and defined as >= 1% of tumor
cells stained positive according to the ASCO/College of American Pathologists
(CAP) guidelines (Allison et al. 2020).
• Participants who have documented HER2- tumor, as assessed locally on a
primary disease specimen and defined according to ASCO/CAP guidelines (Wolff et
al. 2018)
• Participants must have undergone definitive surgery of the primary breast
tumor(s)
• Participants who received adjuvant chemotherapy must have completed adjuvant
chemotherapy prior to randomization. Participants may also have received
neoadjuvant chemotherapy. A washout period of at least 21 days is required
between last adjuvant chemotherapy dose and randomization
• Participants for whom resolution of all acute toxic effects of prior
anticancer therapy or surgical procedures to National Cancer Institute
Common Terminology Criteria for Adverse Events version 5.0 (NCI CTCAE v5.0)
Grade 1 or better
• Participants have received (neo)adjuvant chemotherapy and/or had surgery and
had no prior endocrine therapy are eligible, provided
that they are enrolled within 12 months following definitive breast cancer
surgery
•Participants who have confirmed availability of an untreated primary breast
tumor tissue specimen suitable for biomarker testing (i.e., representative
archival formalin-fixed, paraffin-embedded [FFPE] tissue block [preferred] or
15*20 slides containing unstained, freshly cut, serial sections), with
associated deidentified pathology report is required. Although 15*20 slides are
preferred, if only 10*14 slides are available, the individual may still be
eligible for the study.
• Participants who received adjuvant chemotherapy or no chemotherapy must have
the following:
o If no pathological involved nodes (pN0) primary tumor must be larger than 1
cm, and must fulfill at least one of the features as outlined in Table 5
(medium risk)
o Pathological node-positive disease (microscopic and/or macroscopic tumor
involvement >=pN1) and will be stratified in medium or high risk based on
criteria defined in Table 5.
•Participants with N1 disease are eligible if they meet additional criteria
as outlined in Table 5 (high risk)
• Any T and N2
• Any T and N3
• T4 and any N
• Participant who have Eastern Cooperative Oncology Group Performance (ECOG)
Performance Status 0, 1 or 2
• Participants who are able and willing to swallow and retain, and absorb oral
medication
• Participants who have adequate organ function
• For women of childbearing potential: participants who agree to remain
abstinent (refrain from heterosexual intercourse) or use contraception (women
assigned to tamoxifen must also agree to refrain from donating eggs) during the
treatment period and for 9 days after the final dose of giredestrant or within
the time period specified per local prescribing guidelines after the final dose
of TPC (i.e., 60 days after the final dose of tamoxifen-women must refrain from
donating eggs during this same period; 21 days after the final dose of
letrozole or anastrozole; 30 days after the final dose of exemestane).
• For men assigned: participants who agree to remain abstinent (refrain from
heterosexual intercourse) or use a condom, and agree to refrain from donating
sperm during the treatment period and for 9 days after the final dose of
giredestrant within the time period specified per local prescribing guidelines
after the final dose of TPC (i.e., 90 days after the final dose of tamoxifen;
21 days after the final dose of letrozole or anastrozole; 30 days after the
final dose of exemestane) to avoid exposing the embryo.
• For participants enrolled in the extended China enrollment phase at the
applicable sites: participants who are current residents of mainland China,
Hong Kong, or Taiwan, and of Chinese ancestry
Exclusion criteria
• Participants who are pregnant or breastfeeding, or intending to become
pregnant during the study or within 9 days after the final dose of
giredestrant, or within the time period specified per local prescribing
guidelines after the final dose of TPC
•Participants who have received treatment with investigational therapy within
28 days prior to initiation of study treatment or are currently enrolled in any
other type of medical research that is scientifically or medically compatible
with this study
• Participants receiving or planning to receive a CDK4/6i as adjuvant therapy
• Participants who have active cardiac disease or history of cardiac dysfunction
• Participants who have been diagnosed with Stage IV breast cancer
• Participants who have a history of any prior (ipsilateral and/or
contralateral) invasive breast cancer or ductal carcinoma in situ (DCIS).
Participants with a history of contralateral DCIS treated by only local
regional therapy at any time may be eligible
• Participants who have a history of any other malignancy within 3 years prior
to screening, except for appropriately treated carcinoma in situ of the cervix,
nonmelanoma skin carcinoma, or Stage I uterine cancer
•Participants who have had more than 12 weeks of any prior endocrine treatment
with selective ER modulators (e.g., tamoxifen), degraders or aromatase
inhibitor (AI). Short course of neoadjuvant or adjuvant endocrine therapy (up
to 12 weeks) is allowed
• Participants who have clinically significant liver disease consistent with
Child-Pugh Class B or C, including active hepatitis (e.g., hepatitis B virus
[HBV] or hepatitis C virus [HCV]), current alcohol abuse, cirrhosis, or
positive test for viral hepatitis
•Treatment with strong CYP3A4 inhibitors or inducers within 14 days or 5 drug
elimination half-lives (whichever is longer) prior to initiation of study
treatment
• Participants who have a known allergy or hypersensitivity to any of the study
drugs or any of their excipients
• Pre- and perimenopausal participants or male participants who have a known
hypersensitivity to luteinizing hormone-releasing hormone (LHRH) agonists
•Participants who have a documented history of hemorrhagic diathesis,
coagulopathy or thromboembolism (including deep venous thrombosis).
Note: Participants with prior superficial or vascular access-associated
thrombosis can be included. However, if they have been on anticoagulation or
intend to be for more than 3 months then inclusion into the study is not
permitted
• Participants who have had a major surgical procedure unrelated to breast
cancer within 28 days prior to randomization
• Participants who have had a serious infection requiring oral or intravenous
(IV) antibiotics within 14 days prior to screening or other
clinically significant infection (e.g., COVID-19) within 14 days prior to
screening
• Participants who have had any serious medical condition or abnormality in
clinical laboratory tests that, in the investigator's judgment, precludes an
individual's safe participation in and completion of the study
• Participants who are unable or unwilling to comply with the requirements of
the protocol in the opinion of the investigator
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 |
|---|---|
| EU-CTR | CTIS2023-507172-44-00 |
| EudraCT | EUCTR2021-000129-28-NL |
| CCMO | NL76978.068.21 |