Clinical trial NCT05573126: Phase 1/2 Study to Evaluate Vosilasarm (EP0062) as Monotherapy and in Combination in Patients With Advanced or Metastatic AR+/HER-2-/ER+ Breast Cancer
Official title: A Modular, Open-Label, Multi-Centre Phase 1/2 Dose-Finding, Optimisation and Expansion Study to Evaluate the Safety, Tolerability, Pharmacokinetics, and Efficacy of EP0062 as Monotherapy and in Combination in Patients With Relapsed Locally Advanced or Metastatic AR+/HER-2-/ER+ Breast Cancer
Study type: INTERVENTIONAL
Overall status: RECRUITING
Phase: PHASE1
PHASE2
Conditions: Hormone Receptor-positive Breast Cancer
Hormone Receptor Positive HER-2 Negative Breast Cancer
Metastatic Breast Cancer
Lead sponsor: Ellipses Pharma
Sponsor class: INDUSTRY
First posted: 2022-10-10
Enrollment: 60
Sex: FEMALE
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NON_RANDOMIZED
Intervention model: SEQUENTIAL
Primary purpose: TREATMENT

Brief summary: The aim of this study is to identify the optimal dose for Vosilasarm (EP0062) as monotherapy and in combination with standard-of-care therapies to assess its Safety, Tolerability, Pharmacokinetics, and Efficacy in Patients with Relapsed Locally Advanced or Metastatic AR+/HER-2-/ER+ Breast Cancer

Detailed description: Vosilasarm (EP0062) is being investigated in this modular, interventional, open label, Phase 1/2 dose finding, optimisation and expansion study to determine the optimal dose of Vosilasarm given as monotherapy and for evaluation in combination with standard-of-care therapies in patients with Relapsed Locally Advanced or Metastatic AR+/HER-2-/ER+ Breast Cancer. Module A (phase 1 dose finding) has completed and an optimal dose has been selected for module B (phase 2 expansion).

Eligibility criteria: Inclusion Criteria:

1. Women 18 years or older at the time of informed consent
2. Histologically proven diagnosis of breast cancer with evidence of metastatic or locally advanced breast adenocarcinoma as defined by the American Joint Committee on Cancer/Union for International Cancer Control/Tumour Node Metastases (AJCC/UICC TNM) staging classification (8th Ed, 2017) and where no conventional therapy is available or considered appropriate by the Investigator or is declined by the patient
3. Availability of archival tumour sample (formalin-fixed, paraffin-embedded block(s) or slides from a primary tumour or biopsy of a metastatic tumour lesion or lesions); in the absence of an archival tumour sample, or if only archival bone tissue is available, a fresh biopsy will need to be collected
4. Biopsy-proven AR+ and ER+ breast cancer

   * For Module A, AR+ breast cancer is defined as ≥ 10% AR nuclei staining by central immunohistochemistry (IHC) using the Ventana assay
   * For Modules B and C, AR+ breast cancer is defined as ≥ 30% AR nuclei staining by central IHC using the Ventana assay
5. HER2-negative breast cancer, defined as negative by fluorescence in situ hybridisation (FISH) or IHC score of 0 or 1+. If IHC is equivocal at 2+, a negative FISH test (HER2/Amplification of the centromeric region of chromosome 17)CEP17 ratio of \<2.0) is required
6. Postmenopausal, as defined by at least one of the following:

   1. Age over 60 years
   2. Amenorrhea \> 12 months at the time of informed consent and an intact uterus, with follicle-stimulating hormone (FSH) and oestradiol in the postmenopausal ranges (as per local practice)
   3. FSH and oestradiol in the postmenopausal ranges (as per local practice) in women aged \<55 years who have undergone hysterectomy
   4. Prior bilateral oophorectomy
7. Module B arm 1: patients who have progressed on ≤ 2 prior lines of endocrine therapy, including a prior CDK4/6 inhibitor.
8. Module B arm 2: patients who have progressed on ≤ 2 prior lines of endocrine therapy in advanced/metastatic setting, including prior CDK4/6 inhibitor

Exclusion Criteria:

Patients with any of the following will not be included in the study:

1. Prior anti-cancer or investigational drug treatment within the following time windows:

   * Any chemotherapy within 21 days prior to the first dose of study drug
   * Any non-chemotherapy investigational anti-cancer drug \< 5 half-lives (28 days for biologics) or \< 14 days for small-molecule therapeutics or if half-life is not known
   * Tamoxifen and aromatase inhibitors within 14 days prior to the first dose of study drug
   * Fulvestrant or other investigational Selective Estrogen Receptor Degraders (SERDs) within 21 days prior to first dose of study drug
2. Currently taking testosterone, methyltestosterone, oxandrolone, oxymetholone, danazol, fluoxymesterone, testosterone-like agents (e.g., dehydroepiandrosterone, androstenedione, and other androgenic compounds, including herbals), or antiandrogens
3. Radiation therapy within 14 days prior to the first dose of study drug and scheduled to have radiation therapy during participation in this study. Short courses of palliative radiation therapy during the study might be allowed following discussion with and approval by the Medical Monitor. Palliative radiotherapy within 6 weeks prior to first dose of study drug is permitted
4. Unresolved or unstable serious toxic side effects of prior chemotherapy or radiotherapy, i.e., ≥ Grade 2 per Common Terminology Criteria for Adverse Events (CTCAE) v5.0, except fatigue, alopecia, and Grade 2 chemotherapy-induced neuropathy
5. Confirmed Corrected QT Interval by Fridericia (QTcF) \> 470 ms on screening ECG, or history of torsades de pointes (TdP), or history of congenital long QT syndrome, or immediate family history of long QT syndrome, unexplained sudden death at a young age, or sudden cardiac death
6. Any other clinically important abnormalities in rhythm, conduction, or morphology on resting ECG (e.g., complete left bundle branch block, third-degree heart block); rate-controlled atrial fibrillation is permitted
7. Concomitant medications that prolong the corrected QT interval and/or increase the risk for TdP that cannot be discontinued or substituted with another drug within 5 half-lives or 14 days before the first dose of study drug, whichever is longer
8. Congestive heart failure Grades II-IV according to the New York Heart Association at the time of screening
9. Myocardial infarction or unstable angina within the previous 6 months
10. Patients receiving medications that are known to be strong inhibitors or inducers of CYP3A4 within 5 half-lives or 14 days, whichever is longer, before the first dose of study drug
11. Prior treatment with selected combination agent

Primary outcomes:
measure: Incidence of dose-limiting toxicities (DLTs) during Cycle 1 of EP0062 treatment
timeFrame: first 28 days
measure: Maximum tolerated dose (MTD) and doses for evaluation in the expansion cohorts
timeFrame: 1 year
measure: Incidence and severity of adverse events (AEs) and serious adverse events (SAEs)
timeFrame: up to 30 days after the end of treatment
measure: Recommended clinical (dose (s) for combination therapy
timeFrame: 1 year
Secondary outcomes:
measure: Plasma pharmacokinetic (PK) parameters - Half life
timeFrame: 1, 2, 4, 8, 24 and 48 hours during cycle 1
measure: Plasma pharmacokinetic (PK) parameters - Cmax
timeFrame: 1, 2, 4, 8, 24 and 48 hours during cycle 1
measure: Plasma pharmacokinetic (PK) parameters - Area under the curve (exposure)
timeFrame: 1, 2, 4, 8, 24 and 48 hours during cycle 1
measure: Tumour response
timeFrame: screening and every 8 weeks up to 12 months
measure: Clinical Benefit Rate (CBR)
timeFrame: every 8 weeks up to 12 months
measure: Objective Response Rate (ORR)
timeFrame: every 8 weeks up to 12 months
measure: Duration of Response (DOR)
timeFrame: every 8 weeks up to 12 months
measure: Progression-free survival (PFS)
timeFrame: every 8 weeks up to 12 months
measure: Overall Survival (OS)
timeFrame: every 8 weeks up to 12 months
measure: Relationship between EP0062 efficacy parameters and the level of Androgen Receptor expression and Androgen Receptor : Oestrogen Receptor ratio
timeFrame: every 8 weeks up to 12 months
Other outcomes:
Locations:
city: New Haven
country: United States
facility: Yale School of Medicine
state: Connecticut
city: Tampa
country: United States
facility: Moffitt Cancer Center
state: Florida
city: Boston
country: United States
facility: Massachusetts General Hospital
state: Massachusetts
city: Detroit
country: United States
facility: Henry Ford Hospital
state: Michigan
city: Nashville
country: United States
facility: Sarah Cannon Research Institute
state: Tennessee
city: Dallas
country: United States
facility: Texas Oncology Baylor University Medical Center
state: Texas
city: Fairfax
country: United States
facility: Virginia Cancer Specialists
state: Virginia
city: Barcelona
country: Spain
facility: Hospital Universitari Vall d'Hebron (VHIO)
city: Madrid
country: Spain
facility: Hospital Universitario Ramón y Cajal
city: Madrid
country: Spain
facility: Hospital 12 de Octubre
city: Madrid
country: Spain
facility: NEXT Oncology Hospital Quironsalud
city: Liverpool
country: United Kingdom
facility: The Clatterbridge Cancer Centre
city: London
country: United Kingdom
facility: Sarah Cannon Research Institute UK
city: Manchester
country: United Kingdom
facility: The Christie NHS Foundation Trust
Study officials:
References: