Phase II study evaluating the addition of elacestrant, an oral selective estrogen receptor degrader (SERD), to standard-of-care olaparib in patients with hormone receptor (HR)-positive, HER2-negative locally advanced or metastatic breast cancer with gBRCA1/2 mutations – ELEMENT

Overview

Sponsor-declared trial summary

Key facts

Sponsor

GBG Forschungs GmbH

Participant type

Patients

Age range

18-64 years, 65+ years

Gender

Male and Female

Therapeutic area

Diseases [C] - Neoplasms [C04]

Trial duration

10 Dec 2024 → ongoing

Decision date (initial)

2024-03-14

Transition trial

No

Low-intervention

No

Rare-disease indication

No

Vulnerable population

Yes

External identifiers

EU CT number

2023-504925-38-00

ClinicalTrials.gov

NCT06201234

Trial design

CTIS Part I — objectives, methods, condition coding

Main objective

Scope: Therapy, Efficacy, Safety

To evaluate the impact on PFS of elacestrant with olaparib compared to olaparib alone in patients with hormone receptor (HR)-positive, HER2-negative locally advanced or metastatic breast cancer with gBRCA1/2 mutations.

Secondary objectives 9

1. To compare TTF between treatment arms (i.e., elacestrant + olaparib vs. olaparib).
2. To compare OS between treatment arms.
3. To assess and compare PRO and QoL between treatment arms.
4. To compare PFS, TTF and OS in the minimization subgroups • Pre-treatment chemotherapy in the metastatic setting yes vs. no
5. To compare PFS, TTF and OS in exploratory subgroups: • Prior fulvestrant therapy • ESR1 wild type (or not done) vs. mutant
6. To compare ORR between treatment arms.
7. To compare the CBR between treatment arms.
8. To assess and compare safety between treatment arms.
9. To assess and compare compliance between treatment arms.

Conditions and MedDRA coding

patients with hormone receptor (HR)-positive, HER2-negative locally advanced or metastatic breast cancer with gBRCA1/2 mutations

Study design 1 period

Eligibility criteria

Principal inclusion / exclusion criteria as submitted by sponsor

Inclusion criteria 11

1. Written informed consent prior to beginning specific protocol procedures, including expected cooperation of the patients for scheduled visit, the treatment and follow-up, must be obtained and documented according to the local regulatory requirements.
2. Female or male patients.
3. Age at study entry of at least 18 years.
4. Centrally confirmed locally advanced or metastatic breast cancer that is HR-positive (ER and/or PgR ≥ 10% of stained cells at IHC) and HER2-negative (IHC 0 or 1+, or 2+ and ISH negative according to ASCO/CAP guidelines).
5. Patients with deleterious or suspected deleterious gBRCA1/2 detected upon local testing.
6. Willingness and ability to provide archived formalin fixed paraffin embedded tissue (FFPE) block or a partial block from archived tumor or metastasis.
7. Indication for standard-of-care PARP inhibitor therapy and planned treatment with olaparib.
8. Eastern Cooperative Oncology Group (ECOG) performance status (PS) 0-2.
9. Resolution of all acute toxic effects of prior anti-cancer therapy including endocrine therapy or surgical procedures to NCI CTCAE version 5.0 grade ≤ 1 (except alopecia or other toxicities not considered a safety risk for the patient at investigator’s discretion).
10. Life-expectancy > 6 months.
11. For female patients: patients of childbearing potential (defined as not post-menopausal and not permanently sterile [latter defined as having undergone hysterectomy, bilateral salpingectomy, or bilateral oophorectomy]) require a negative serum or urinary pregnancy test within 72 hours before starting treatment in this study (in this case, patients need to use highly effective non-hormonal contraceptive methods as specified in the protocol). For male patients: during the intervention period and for at least 120 days after the last dose of elacestrant, patients should refrain from heterosexual intercourse or use a condom (and should also be advised of the benefit for a female partner to use a highly effective method of contraception as a condom may break or leak), and they should refrain from donating sperm.

Exclusion criteria 19

1. Known hypersensitivity reaction to one of the compounds, excipients, or substances used in this protocol.
2. Active or newly diagnosed CNS metastases, including leptomeningeal carcinomatosis, carcinomatous meningitis, or radiographic signs of CNS hemorrhage. Note: Patients with stable brain metastases are allowed. Radiotherapeutic treatment must be completed 1 week before planned day 1 of study therapy.
3. Presence of symptomatic metastatic visceral disease that are at risk of life-threatening complications in the short term, including but not confined to massive uncontrolled effusions (peritoneal, pleural, pericardial), pulmonary lymphangitis, or fulminant liver involvement.
4. Inadequate organ function prior to enrolment including: o Hemoglobin < 9 g/dL (< 5.6 mmol/L) o Absolute neutrophil count (ANC) < 1500/mm³ (< 1.5 x 10^9/L) o Platelets < 100,000/mm³ (< 100 x 10^9/L) o Alanine aminotransferase (ALT/SGPT) and/or aspartate aminotransferase (AST/SGOT) > 3 x upper normal limits (ULN). If the patient has liver metastases, ALT and AST should not be ≥ 5 x ULN. o Alkaline phosphatase (ALP) > 2.5 x ULN o Total serum bilirubin > 1.5 x ULN (exception: patients with Gilbert’s syndrome permitted up to ≤ 3 x ULN) o Serum creatinine > 1.5 x ULN or estimated creatinine clearance < 50 mL/min as calculated using the standard method for the institution.
5. Existing contraindication against the use of the elacestrant or olaparib.
6. Prior treatment with PARP inhibitors.
7. Female patients: pregnancy or lactation at the time of randomization or intention to become pregnant during the study and for a predefined period after the end of treatment (as described in protocol). Male patients: intention to get a child during the study and for a predefined period after the end of treatment (as described in protocol). According to the treatment received during the study, required contraception timelines for female and male patient after the end of therapy differ (refer to the study protocol).
8. Any of the following within 6 months prior to enrolment: myocardial infarction, severe/unstable angina, ongoing grade ≥ 2 cardiac dysrhythmias, prolonged QT corrected by Fridericia’s formula (QTcF) grade ≥ 2, uncontrolled atrial fibrillation of any grade, coronary/peripheral artery bypass graft, heart failure of New York Heart Association (NYHA) Class II or greater, or cerebrovascular accident including transient ischemic attack.
9. Uncontrolled hypertension at the time of screening (systolic BP > 140 mmHg or diastolic BP > 90 mmHg that has not been adequately treated or controlled).
10. Active and current anticoagulation for treatment purposes of thrombotic events occurring < 6 months before enrolment is not allowed (prophylactic anticoagulation, however, is acceptable). Treatment with an anticoagulant for a thrombotic event occurring > 6 months before enrolment, or for an otherwise stable and allowed medical condition (e.g., well controlled atrial fibrillation) is acceptable, provided dose and coagulation parameters (as defined by local standard of care) are stable for at least 28 days prior to the first dose of study drug.
11. Known difficulty in tolerating oral medications or conditions which would impair absorption of oral medications such as: uncontrolled nausea or vomiting (i.e., CTCAE ≥ grade 3 despite antiemetic therapy), ongoing gastrointestinal obstruction/motility disorder, malabsorption syndrome, or prior gastric bypass.
12. History of endometrial intraepithelial neoplasia in patients who have not undergone a hysterectomy.
13. Malignant disease other than breast cancer, active or being disease-free for less than 5 years (except carcinoma in situ of the cervix, DCIS, and non-melanomatous skin cancer adequately treated).
14. Uncontrolled significant active infections including HBV, HCV, and/or HIV. Patients with a positive hepatitis B surface antigen result or a positive hepatitis C antibody test result at screening or within 3 months before first dose of study treatment are excluded, except for the following:  Participants with positive anti-HBs antibody titer and confirmatory negative hepatitis B DNA polymerase chain reaction.  Participants with positive hepatitis C antibody due to prior resolved disease can be enrolled only if they have both completed curative therapy and have a hepatitis C viral load < quantifiable limit.
15. Any severe, acute, uncontrolled, or chronic medical or psychiatric condition or laboratory abnormality that may increase the risk associated with study participation or investigational or non-investigational products administration, or may interfere with the interpretation of study results, and, in the judgment of the investigator, would make the patient inappropriate for entry into this study. Moreover, patients who, by virtue of an order issued by judicial or administrative authorities, are committed to an institution or those who cannot take part in clinical trials are excluded from this study.
16. History of significant neurological or psychiatric disorders including psychotic disorders, dementia, or seizures that would prohibit the understanding and giving of informed consent.
17. Unable or unwilling to avoid medications, supplements (e.g., St. John’s wort), or foods (e.g., grapefruit, pomegranate, pomelos, star fruit, Seville oranges and their juices) that are moderate/strong inhibitors or inducers of CYP3A4 activity. Participation will be allowed if the medication, supplements, or foods are discontinued for at least 14 days prior to study entry and for the duration of the study.
18. Concurrent treatment with other experimental drugs. Participation in another clinical trial with any investigational not marketed drug within 30 days prior to study entry.
19. Receipt of live attenuated vaccination within 30 days prior to study entry. COVID-19 vaccines that do not contain live viruses are allowed (at least one week prior to study entry).

Endpoints

Primary and secondary outcome measures (English text)

Primary endpoints 1

1. PFS is defined as the time from randomization to first progression as assessed by the investigator, or death, whichever occurs first. Patients lost to follow up or progression-free at the end of the study will be censored at the date of last contact.

Secondary endpoints 7

1. TTF is defined as time from randomization to discontinuation of treatment due to disease progression, treatment toxicity, patient´s preference, or death. Patients lost to follow up or still under treatment at the end of the study will be censored at the date of last contact.
2. OS is defined as the time from randomization to death due to any reason. Patients lost to follow up or alive at the end of the study will be censored at the date of last contact.
3. Patient reported BC-specific QoL as measured by FACT–ES.
4. ORR is defined as the percentage of patients who have achieved either a confirmed complete response or partial response.
5. CBR is defined as the percentage of patients who have achieved either a confirmed complete response or partial response, or stable disease for at least 24 weeks from randomization.
6. Frequency and severity of AEs graded according to the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI-CTCAE) version 5.0.
7. Dose reductions, dose delays, treatment interruptions, and treatment discontinuation rates.

Investigational products

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

Test 2

Auxiliary 1

Sponsors and contacts

Sponsor organisations, regulatory contacts, third parties

GBG Forschungs GmbH

Sponsor organisation

GBG Forschungs GmbH

Address

Dornhofstrasse 10

City

Neu-Isenburg

Postcode

63263

Country

Germany

Scientific contact point

Organisation

GBG Forschungs GmbH

Contact name

Medicine and Research

Public contact point

Organisation

GBG Forschungs GmbH

Contact name

Medicine and Research

Third parties 4

Locations

1 EU/EEA country · 36 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 9 files

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

Application history

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