Study Comparing the Efficacy and Safety of the Combination of Lasofoxifene and Abemaciclib to the Combination of Fulvestrant and Abemaciclib for the Treatment of Women and Men with Advanced Breast Cancer with an ESR1 Mutation

Overview

Sponsor-declared trial summary

Key facts

Sponsor

Sermonix Pharmaceuticals Inc.

Participant type

Patients

Age range

18-64 years, 65+ years

Gender

Male and Female

Therapeutic area

Diseases [C] - Neoplasms [C04]

Trial duration

20 Feb 2024 → ongoing

Decision date (initial)

2024-03-26

Transition trial

No

Low-intervention

No

Rare-disease indication

No

Vulnerable population

Yes

Funding sources

Sermonix Pharmaceuticals

External identifiers

EU CT number

2023-503708-10-00

WHO UTN

U1111-1290-4937

ClinicalTrials.gov

NCT05696626

Trial design

CTIS Part I — objectives, methods, condition coding

Main objective

Scope: Safety, Therapy, Efficacy

To evaluate the progression free survival (PFS) of the combination of lasofoxifene and abemaciclib compared to fulvestrant and abemaciclib for the treatment of pre- and postmenopausal women and men who have previously received ribociclib or palbociclib -based treatment and have locally advanced or metastatic estrogen receptor positive (ER+)/human epidermal growth factor 2 negative (HER2) − breast cancer with an estrogen receptor 1 (ESR1) mutation.

Secondary objectives 3

1. 1. To evaluate the antitumor response of each drug regimen as characterized by objective response rate (ORR), Overall survival (OS), Clinical benefit rate (CBR), Duration of response (DoR) in subjects with an objective response, Time to response (TTR) in subjects with an objective response
2. 2. In addition, to determine the following for the study population: Time to cytotoxic chemotherapy
3. 3. Quality of life (QoL) using Functional Assessment of Cancer Therapy Breast Cancer-Endocrine Subscale (FACT B-ES), Safety

Conditions and MedDRA coding

Locally advanced or metastatic breast cancer

Regulatory references

Plan to share IPD

No

Eligibility criteria

Principal inclusion / exclusion criteria as submitted by sponsor

Inclusion criteria 13

1. 1. Age ≥18 years of age or a country's minimal age of maturity or greater.
2. 10. Adequate organ function as shown by: a. absolute neutrophil count (ANC) ≥1,000 cells/mm3 (≥1 g/L) b. platelet count ≥100,000 cells/mm3 (≥100 g/L) c. hemoglobin ≥8.0 g/dl (80 g/L) d. ALT and AST levels ≤3 upper limit of normal (ULN) or ≤5 in the presence of liver metastasis e. total serum bilirubin ≤1.5 X ULN (≤3 X ULN for subjects known to have Gilbert Syndrome) f. alkaline phosphatase level ≤3 ULN g. creatinine clearance of 40 mL/min or greater as calculated by the Cockcroft-Gault formula or by a standard method used by the investigational site.
3. 11. Able to swallow tablets
4. 13. Able to understand and voluntarily sign a written informed consent before any screening procedures.
5. 2. Pre- or postmenopausal women or men. Postmenopausal women are defined as: a. ≥60 years of age with no vaginal bleeding over the prior year, or b. <60 years with "premature menopause" or "premature ovarian failure,” which manifests itself with secondary amenorrhea for at least 1 year and follicle stimulating hormone (FSH) and estradiol levels in the postmenopausal range according to institutional standards, or c. surgical menopause with bilateral oophorectomy.
6. 3. Every attempt should be made to obtain a biopsy of metastatic breast cancer tissue, when safe and feasible, to provide histological or cytological confirmation of ER+/HER2− disease as assessed by a local laboratory, according to American Society of Clinical Oncology/College of American Pathologists guidelines, using slides, paraffin blocks, or paraffin samples. If a biopsy is done, it may undergo genomic testing at some point to assess for ESR1 mutations and correlation with ctDNA results. If a biopsy is not possible or inappropriate from a clinical standpoint, the ER and HER2 status from the subject’s most recent biopsy must confirm that the subject is ER+ and HER2−.
7. 4. Locally advanced and/or metastatic breast cancer with radiological or clinical evidence of progression on an AI in combination with either palbociclib or ribociclib as their first hormonal treatment for locally advanced or metastatic disease. Before starting study treatment, subjects should have stopped any CDKi for at least 14 days. The subject may have received hormonal treatment in the adjuvant setting and up to 2 prior lines of endocrine therapy for metastatic disease. No prior adjuvant CDK4/6 inhibitor is allowed.
8. 5. No evidence of progression for at least 6 months on an AI/CDKi combination for advanced breast cancer.
9. 6. At least 1 or more ESR1 point mutations in the ESR1 ligand binding domain as assessed in cell-free ctDNA obtained from a blood or breast cancer tissue. Examples may include, but not be limited to, the mutations Y537S, Y537C, D538G, E380Q, S463P, V534E, P535H, L536H, L536P, L536R, L536Q, and Y537N or other ESR1 missense mutation(s) between codons 310 and 547 known to induce protein changes to the ESR1 binding domain. The ctDNA sample collection or tissue must be obtained within 90 days prior to Screening to determine eligibility and baseline
10. 7. Locally advanced or metastatic breast cancer with either measurable (according to RECIST 1.1 [Eisenhauer, et al, 2009]) or non-measurable lesions.
11. 8. Subjects may have received 1 cytotoxic chemotherapy regimen in the metastatic disease setting prior to study entry but must have recovered from chemotherapy acute toxicity excluding alopecia, and Grade 2 peripheral neuropathy. A washout period of at least 14 days is required between last chemotherapy dose and entry into the study. (Antibody drug conjugates [ADC] and poly (ADP-ribose) polymerase [PARP] inhibitors are considered systemic chemotherapy.)
12. 9. Eastern Cooperative Oncology Group (ECOG) performance score of 0 or 1
13. 12. Brain metastases are allowed only if the following 4 parameters hold: a. Asymptomatic, b. Definitively treated (e.g., radiotherapy, surgery), c. Not requiring steroids up to 4 weeks before study treatment initiation, AND d. Central nervous system disease stable for >3 months prior to registration as documented by magnetic resonance imagining (MRI).

Exclusion criteria 22

1. 1. Lymphangitic carcinomatosis involving the lung.
2. 17. Positive serum pregnancy test (only if premenopausal).
3. 6. Radiotherapy within 30 days prior to Visit 0 (Day 1) except in case of localized radiotherapy for analgesic purposes or for lytic lesions at risk of fracture, which can then be completed within 7 days prior to Visit 0 (Day 1). Subjects must have recovered from radiotherapy toxicities prior to Visit 0 (Day 1).
4. 21. Unwilling or unable to comply with the protocol
5. 22. Current participation in any clinical research trial involving an investigational drug or device within the last 30 days
6. 7. Known RB1 mutations or deletions that in the opinion of the investigator confer resistance to CDK4/6i. (Screening for RB1 mutation is not required for entry.)
7. 8. History of long QTc (Q-T interval corrected for heart rate) syndrome or a QTc of >480 msec
8. 13. Any significant co-morbidity that would impact the study or the subject’s safety, including subjects with significant malabsorption. Since the occurrence of ILD has been reported with CDKi, subjects with a history of ILD and those with severe dyspnea at rest or requiring oxygen therapy should not enter the study.
9. 14. Active systemic bacterial or fungal infection (requiring intravenous [IV] antibiotics or antifungal drugs at the time of initiating study treatment).
10. 9. History of a PE, DVT, or any known thrombophilia, unless the event occurred greater than 6 months prior to screening and the subject is treated with chronic anticoagulant therapy such as apixaban (Eliquis) or rivaroxaban (Xarelto).
11. 11. On concomitant strong CYP3A4 inhibitors such as clarithromycin, telithromycin, nefazodone, itraconazole, ketoconazole, atazanavir, darunavir, indinavir, lopinavir, nelfinavir, ritonavir, saquinavir, or tipranavir.
12. 18. Sexually active premenopausal women and men unwilling to use contraception
13. 12. On strong and moderate CYP3A4 inducers such as amprenavir, barbiturates, carbamazepine, clotrimazole, dexamethasone, efavirenz, ethosuximide, griseofulvin, modafinil, nevirapine, oxcarbazepine, phenobarbital, phenytoin, chronic prednisone treatment, primidone, rifabutin, rifampin, rifapentine, ritonavir, or topiramate.
14. 2. History of Grade 3 or Grade 4 interstitial lung disease (ILD) on previous therapy.
15. 20. History of non-compliance to medical regimens.
16. 10. Lasofoxifene is not recommended for use in subjects with conditions that place them at increased risk for VTEs (such as severe congestive heart failure [CHF] or prolonged immobilization).
17. 3. Visceral crisis in need of cytotoxic chemotherapy as assessed by the investigator.
18. 4. Prior progression of disease on abemaciclib, fulvestrant, or other selective estrogen receptor degrader (SERD) therapy.
19. 5. Subjects with a known hypersensitivity to fulvestrant or to any of the excipients.
20. 15. Known infection with HIV, Hepatitis B virus (HBV), or Hepatitis C virus (HCV). Patients with resolved HBV infection (defined as having a negative hepatitis B surface antigen [HbsAg] test and a positive hepatitis B core antibody {HbcAb] test, accompanied by a negative HBV DNA test) are eligible. Patients positive for HCV antibody are eligible only if polymerase chain reaction (PCR) is negative for HCV RNA.
21. 16. History of malignancy within the past 5 years (excluding breast cancer), except basal cell or squamous cell carcinoma of the skin curatively treated by surgery. For history of other cancers considered to have a low risk of recurrence, discussion with the Medical Monitor is required
22. 19. Women who are breast feeding

Endpoints

Primary and secondary outcome measures (English text)

Primary endpoints 1

1. Progression free survival (PFS) is defined as the time from the date of randomization [expected at Visit 0 (Day 1)] to the earliest date of first documented disease progression or death due to any cause.

Secondary endpoints 2

1. Objective response rate (ORR) is defined as the percentage of subjects with measurable disease at baseline whose best overall response post-randomization is either a confirmed CR or a confirmed PR according to RECIST 1.1.
2. Overall Survival (OS) is defined as time from the date of randomization [expected at Visit 0 (Day 1)] to death due to any cause

Investigational products

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

Test 2

Comparator 1

Sponsors and contacts

Sponsor organisations, regulatory contacts, third parties

Sermonix Pharmaceuticals Inc.

Sponsor organisation

Sermonix Pharmaceuticals Inc.

Address

250 East Broad Street Suite 250

City

Columbus

Postcode

43215-3778

Country

United States

Scientific contact point

Organisation

Sermonix Pharmaceuticals Inc.

Contact name

Simon Jenkins

Public contact point

Organisation

Sermonix Pharmaceuticals Inc.

Contact name

Simon Jenkins

Third parties 6

Locations

8 EU/EEA countries · 62 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 126 files

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

Application history

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