Evaluating the Addition of Elacestrant (Oral SERD) to Niraparib (PARP-inhibitor) in Patients With Advanced/Metastatic HR+/HER2- Breast Cancer

BRCA1 Mutation Clinical Trial

— ELEMENT  

Official title:

Phase II Study Evaluating the Addition of Elacestrant, an Oral Selective Estrogen Receptor Degrader (SERD), to Niraparib, a PARP-inhibitor, Compared to Niraparib Alone in Patients With Hormone Receptor (HR)-Positive, HER2-negative Locally Advanced or Metastatic Breast Cancer With g/tBRCA1/2 and/or g/tPALB2 Mutations

Clinical Trial Details — Status: Not yet recruiting

Administrative data

• NCT number: NCT06201234
• Other study ID #: ELEMENT GBG-114
• Status: Not yet recruiting
• Phase: Phase 2
• Start date: March 31, 2024
• Est. completion date: March 31, 2028

Study information

• Verified date: December 2023
• Source: German Breast Group
• Contact: Nader Hirmas, MD/PhD
• Phone: +49 61027480
• Email: element[@]gbg.de
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

Trial design:

Phase II, prospective, multi-center, randomized, open label, parallel group study in patients with HR-positive, HER2-negative locally advanced or metastatic breast cancer with g/tBRCA1/2 or g/tPALB2 mutation, with 2:1 randomization into Arm A (niraparib + elacestrant) or arm B (niraparib). Treatment in either arm will be given until disease progression, unacceptable toxicity, withdrawal of patient´s consent to study participation, or end of study.

Trial population:

Patients with HR-positive, HER2-negative locally advanced or metastatic breast cancer with g/tBRCA1/2 or g/tPALB2 mutation, having received at least one prior line of chemotherapy or endocrine-based therapy for irresectable, locally advanced, or metastatic disease (or adjuvant treatment with CDK4/6 inhibitor therapy), with ECOG performance status of 0-2 and life expectancy of > 6 months, with normal bone marrow and kidney functions and no active or newly diagnosed central nervous system (CNS) metastases or symptomatic metastatic visceral disease at risk of life-threatening complications.

Interventions:

Patients randomized to Arm A will receive 200mg niraparib daily and 400mg elacestrant daily, while patients randomized to Arm B will receive 200mg niraparib daily. Blood tests (hematology, biochemistry) will be performed at the beginning of every cycle, and imaging for tumor assessment (chest and abdominopelvic imaging) as well as QoL assessments will be performed every three months and in case of suspicion of progression/end of study.

Description:

Patients with HR-positive, HER2-negative advanced or metastatic breast cancer and g/tBRCA1/2 and/or g/tPALB2 mutations have a low progression-free survival (PFS) and represent a patient population with a high unmet need, hence further treatment options should be explored to improve patient outcomes.

Elacestrant is a novel, nonsteroidal, orally bioavailable estrogen receptor antagonist (SERD) that has shown efficacy in heavily pretreated patients with HR-positive, HER2-negative breast cancer, and in those with ESR1 mutations known to confer endocrine resistance, and has thus gained approval in 2023 by the Food and Drug Administration (FDA) and the European Medicines Agency (EMA) for postmenopausal women or adult men with ER-positive, HER2-negative, ESR1-mutated advanced or metastatic breast cancer with disease progression following at least one line of ET.

Niraparib is a poly-adenosine diphosphate ribose polymerase (PARP) inhibitor that has shown promise in patients with gBRCA mutated, HER2-negative locally advanced or metastatic breast cancer, previously treated with ≤2 prior lines of chemotherapy, as well as in patients with platinum-sensitive, recurrent ovarian cancer, regardless of the presence or absence of gBRCA1/2 mutations, with moderate bone marrow toxicity.

The purpose of the proposed study is to investigate if the addition of elacestrant to niraparib could potentially lead to an improvement in PFS compared to niraparib alone in patients with HR-positive, HER2-negative locally advanced or metastatic breast cancer with g/tBRCA1/2 and/or g/tPALB2 mutations.

ELEMENT is a phase II, prospective, multi-center, randomized, open label, parallel group study in patients with HR-positive, HER2-negative locally advanced or metastatic breast cancer with g/tBRCA1/2 or g/tPALB2 mutation, with 2:1 randomization into Arm A (niraparib + elacestrant) or arm B (niraparib). Treatment in either arm will be given until disease progression, unacceptable toxicity, withdrawal of patient´s consent to study participation, or end of study.

Recruitment information / eligibility

• Status: Not yet recruiting
• Enrollment: 176
• Est. completion date: March 31, 2028
• Est. primary completion date: March 31, 2028
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

Inclusion Criteria:

Patients will be eligible for study participation only if they comply with the following criteria:

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 g/tBRCA1/2 and/or g/tPALB2 mutations, 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. Patients who received at least one prior line of chemotherapy or endocrine-based therapy for irresectable, locally advanced, or metastatic disease, or patients with recurrent, unresectable, locally advanced, or metastatic disease after adjuvant treatment with CDK4/6 inhibitor therapy.

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 need to be either A) of non-childbearing potential (documented postmenopausal or post hysterectomy or surgical sterilization), or B) of childbearing potential with 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 study treatment, 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:

Patients will be ineligible for study participation if they fulfill any of the following criteria:

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:

• Hemoglobin < 9 g/dL (< 5.6 mmol/L)

• Absolute neutrophil count (ANC) < 1500/mm³ (< 1.5 x 109/L)

• Platelets < 100,000/mm³ (< 100 x 109/L)

• 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.

• Alkaline phosphatase (ALP) > 2.5 x ULN

• Total serum bilirubin > 1.5 x ULN (exception: patients with Gilbert's syndrome permitted up to = 3 x ULN)

• 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 niraparib.

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. Any known history of myelodysplastic syndrome (MDS) or a pretreatment cytogenetic testing result at risk for a diagnosis of MDS/acute myeloid leukemia (AML).

15. Increased bleeding risk due to concurrent conditions (e.g., major injuries or major surgery within the past 28 days before start of study treatment).

16. Received a transfusion (platelets or red blood cells) within 4 weeks before the first dose of study treatment.

17. Received radiotherapy encompassing > 20% of the bone marrow within 2 weeks, or any radiation therapy (including radiation therapy for CNS metastases) within 1 week before planned day 1 of study therapy.

18. 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.

19. Current active pneumonitis or any history of pneumonitis requiring steroids (any dose) or immunomodulatory treatment within 90 days of planned start of the study.

20. 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.

21. History of significant neurological or psychiatric disorders including psychotic disorders, dementia, or seizures that would prohibit the understanding and giving of informed consent. Also, prior history of posterior reversible encephalopathy syndrome (PRES) excludes patients from this study.

22. 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.

23. Concurrent treatment with other experimental drugs. Participation in another clinical trial with any investigational not marketed drug within 30 days prior to study entry.

24. 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).

Related Conditions & MeSH terms

• Advanced or Metastatic Breast Cancer
• BRCA1 Mutation
• BRCA2 Mutation
• Breast Neoplasms
• Hormone Receptor Positive HER-2 Negative Breast Cancer
• PALB2 Gene Mutation

Intervention

Drug:
• Niraparib + Elacestrant
Niraparib 200mg orally daily and elacestrant 400mg orally daily
• Niraparib
Niraparib 200mg orally daily

Locations

Country	Name	City	State
Germany	DIAKOVERE Henriettenstift Gynäkologie	Hannover

Sponsors (3)

Lead Sponsor	Collaborator
German Breast Group	GlaxoSmithKline, Stemline Therapeutics, Inc.

Country where clinical trial is conducted

Germany, 

References & Publications (7)

Bardia A, Kaklamani V, Wilks S, Weise A, Richards D, Harb W, Osborne C, Wesolowski R, Karuturi M, Conkling P, Bagley RG, Wang Y, Conlan MG, Kabos P. Phase I Study of Elacestrant (RAD1901), a Novel Selective Estrogen Receptor Degrader, in ER-Positive, HER2-Negative Advanced Breast Cancer. J Clin Oncol. 2021 Apr 20;39(12):1360-1370. doi: 10.1200/JCO.20.02272. Epub 2021 Jan 29. — View Citation

Bidard FC, Kaklamani VG, Neven P, Streich G, Montero AJ, Forget F, Mouret-Reynier MA, Sohn JH, Taylor D, Harnden KK, Khong H, Kocsis J, Dalenc F, Dillon PM, Babu S, Waters S, Deleu I, Garcia Saenz JA, Bria E, Cazzaniga M, Lu J, Aftimos P, Cortes J, Liu S, Tonini G, Laurent D, Habboubi N, Conlan MG, Bardia A. Elacestrant (oral selective estrogen receptor degrader) Versus Standard Endocrine Therapy for Estrogen Receptor-Positive, Human Epidermal Growth Factor Receptor 2-Negative Advanced Breast Cancer: Results From the Randomized Phase III EMERALD Trial. J Clin Oncol. 2022 Oct 1;40(28):3246-3256. doi: 10.1200/JCO.22.00338. Epub 2022 May 18. Erratum In: J Clin Oncol. 2023 Aug 10;41(23):3962. — View Citation

Gelmon KA, Fasching PA, Couch FJ, Balmana J, Delaloge S, Labidi-Galy I, Bennett J, McCutcheon S, Walker G, O'Shaughnessy J; Collaborating Investigators. Clinical effectiveness of olaparib monotherapy in germline BRCA-mutated, HER2-negative metastatic breast cancer in a real-world setting: phase IIIb LUCY interim analysis. Eur J Cancer. 2021 Jul;152:68-77. doi: 10.1016/j.ejca.2021.03.029. Epub 2021 Jun 1. — View Citation

Litton JK, Rugo HS, Ettl J, Hurvitz SA, Goncalves A, Lee KH, Fehrenbacher L, Yerushalmi R, Mina LA, Martin M, Roche H, Im YH, Quek RGW, Markova D, Tudor IC, Hannah AL, Eiermann W, Blum JL. Talazoparib in Patients with Advanced Breast Cancer and a Germline BRCA Mutation. N Engl J Med. 2018 Aug 23;379(8):753-763. doi: 10.1056/NEJMoa1802905. Epub 2018 Aug 15. — View Citation

Mirza MR, Monk BJ, Herrstedt J, Oza AM, Mahner S, Redondo A, Fabbro M, Ledermann JA, Lorusso D, Vergote I, Ben-Baruch NE, Marth C, Madry R, Christensen RD, Berek JS, Dorum A, Tinker AV, du Bois A, Gonzalez-Martin A, Follana P, Benigno B, Rosenberg P, Gilbert L, Rimel BJ, Buscema J, Balser JP, Agarwal S, Matulonis UA; ENGOT-OV16/NOVA Investigators. Niraparib Maintenance Therapy in Platinum-Sensitive, Recurrent Ovarian Cancer. N Engl J Med. 2016 Dec 1;375(22):2154-2164. doi: 10.1056/NEJMoa1611310. Epub 2016 Oct 7. — View Citation

Robson M, Im SA, Senkus E, Xu B, Domchek SM, Masuda N, Delaloge S, Li W, Tung N, Armstrong A, Wu W, Goessl C, Runswick S, Conte P. Olaparib for Metastatic Breast Cancer in Patients with a Germline BRCA Mutation. N Engl J Med. 2017 Aug 10;377(6):523-533. doi: 10.1056/NEJMoa1706450. Epub 2017 Jun 4. Erratum In: N Engl J Med. 2017 Oct 26;377(17 ):1700. — View Citation

Turner NC, Balmana J, Poncet C, Goulioti T, Tryfonidis K, Honkoop AH, Zoppoli G, Razis E, Johannsson OT, Colleoni M, Tutt AN, Audeh W, Ignatiadis M, Mailliez A, Tredan O, Musolino A, Vuylsteke P, Juan-Fita MJ, Macpherson IRJ, Kaufman B, Manso L, Goldstein LJ, Ellard SL, Lang I, Jen KY, Adam V, Litiere S, Erban J, Cameron DA; BRAVO Steering Committee and the BRAVO investigators. Niraparib for Advanced Breast Cancer with Germline BRCA1 and BRCA2 Mutations: the EORTC 1307-BCG/BIG5-13/TESARO PR-30-50-10-C BRAVO Study. Clin Cancer Res. 2021 Oct 15;27(20):5482-5491. doi: 10.1158/1078-0432.CCR-21-0310. Epub 2021 Jul 22. — View Citation

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Progression free survival (PFS)	PFS, investigator-assessed. To evaluate the impact on PFS of Elacestrant with Niraparib compared to Niraparib alone in patients with hormone receptor (HR)-positive, HER2-negative locally advanced or metastatic breast cancer with g/tBRCA1/2 and/or g/tPALB2 mutations.	PFS is defined as the time from randomization to first progression as assessed by the investigator, or death, whichever occurs first, assessed up to 48 months.
Secondary	Time-to-treatment failure (TTF)	To compare TTF between treatment arms (i.e., niraparib vs. niraparib + elacestrant).	TTF is defined as time from randomization to discontinuation of treatment due to disease progression, treatment toxicity, patient´s preference, or death, assessed up to 48 months.
Secondary	Overall survival (OS)	To compare OS between treatment arms.	OS is defined as the time from randomization to death due to any reason, assessed up to 48 months.
Secondary	Patient reported outcome (PRO) in the form of quality of life (QoL) assessment	To assess and compare patient reported breast cancer-specific QoL as measured by FACT-ES questionnaire.	At baseline, day 1 of cycle 2 (each cycle is 28 days), every 3 months starting from treatment start, and at end of treatment (an average of 12 months per patient).
Secondary	PFS in stratified and exploratory subgroups	To compare PFS in the stratified subgroups: pre-treatment chemotherapy in the metastatic setting yes vs. no.; To compare PFS in the exploratory subgroups specified in the protocol.	PFS is defined as the time from randomization to first progression as assessed by the investigator, or death, whichever occurs first, assessed up to 48 months.
Secondary	TTF in the stratified subgroups	To compare TTF in the stratified subgroups: pre-treatment chemotherapy in the metastatic setting yes vs. no.; To compare TTF in the exploratory subgroups specified in the protocol.	TTF is defined as time from randomization to discontinuation of treatment due to disease progression, treatment toxicity, patient´s preference, or death, assessed up to 48 months.
Secondary	OS in the stratified subgroups	To compare OS in the stratified subgroups: pre-treatment chemotherapy in the metastatic setting yes vs. no.; To compare OS in the exploratory subgroups specified in the protocol.	OS is defined as the time from randomization to death due to any reason, assessed up to 48 months.
Secondary	Overall response rate (ORR)	To compare ORR between treatment arms.	ORR is defined as the percentage of patients who have achieved either a confirmed complete response or partial response, assessed up to 48 months.
Secondary	Clinical benefit rate (CBR)	To compare the CBR between treatment arms.	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.
Secondary	Numbers and types of adverse events as assessed by CTCAE v5.0	To assess and compare safety between treatment arms (frequency and severity of AEs graded according to the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI-CTCAE) version 5.0).	During treatment phase, an average of 12 months per patient.
Secondary	Compliance between treatment arms as assessed by treatment delays, reductions, and interruptions	Frequencies of patients whose treatment had to be reduced, delayed, interrupted, or prematurely discontinued will be reported for both arms, together with reasons for such modifications, and comparisons between the two arms will be conducted with the ?2-test with continuity correction.	During treatment phase, an average of 12 months per patient.

External Links

•   Website of German Breast Group