Evexomostat Plus PI3K or AKT Inhibitor and Fulvestrant in Patients With a PI3K Alteration and HR+/Her2- Breast Cancer

NCT05455619 | Recruiting Phase 1 FDA Drug

• 1 other identifier: SDX-0103
• Study Type: interventional
• Target: 52
• Locations: 1 country
• Sites: 10

Brief Summary

This is a Phase 1b/2, open-label, parallel-arms pilot study in men and post-menopausal women with hormone receptor positive (HR+), HER2- advanced or metastatic breast cancer with an alteration in the PI3K pathway, including a mutation of the PIK3CA gene, PTEN loss, or AKT1 mutation, designed to determine the safety of evexomostat (SDX-7320) plus standard of care treatment alpelisib (BYL-719) or capivasertib and fulvestrant (each combined, the 'triplet therapy'), to measure the severity and number of hyperglycemic events, and to assess clinical, anti-tumor benefit of the triplet therapy. The purpose of this study is:

• to characterize the safety of the triplet drug combination consisting of either alpelisib or capivasertib (per the treating oncologist's choice) and fulvestrant plus evexomostat,
• to test whether evexomostat, when given in combination with either alpelisib or capivasertib and fulvestrant will reduce the number and severity of hyperglycemic events and/or reduce the number or dose of anti-diabetic medications needed to control the hyperglycemia for metabolically normal patients and those deemed at risk for capivasertib and alpelisib-induced hyperglycemia (insulin resistance, as measured by HOMA-IR, baseline elevated HbA1c or well-controlled type 2 diabetes), and
• to assess preliminary anti-tumor efficacy for each combination and changes in key biomarkers and quality of life in this patient population.

Conditions

HR+/HER2-negative Breast Cancer; Metastatic Breast Cancer

Keywords

hyperglycemia; insulin; glucose; SDX-7320; fulvestrant; apelisib; PIK3CA mutation; evexomostat; HR+ Her2- metastatic breast cancer; hyperinsulinemia; capivasertib; AKT; PTEN

Outcome Measures

Primary Outcomes (2)

• Incidence of Adverse Events

  Safety and tolerability profile will be assessed by Common Terminology Criteria for Adverse Events v5.0 and summarized by type, frequency, and severity of adverse events of evexomostat dosed in combination with alpelisib plus fulvestrant

  Up to 48 months

• Hyperglycemic Events

  Severity, number, and proportion of patients with hyperglycemic events

  Up to 42 months

Secondary Outcomes (7)

• Anti-tumor activity

  6 months

• Glucose control

  Up to 42 months

• Leptin activity

  Up to 42 months

• Adiponectin activity

  Up to 42 months

• Angiogenic activity (bFGF/FGF2)

  Up to 42 months

Study Arms (1)

Evexomostat

EXPERIMENTAL

Each subject will receive repeat doses (C1, C2…) for 28-day cycles. Participants may continue on study drug until disease progression, unacceptable toxicity, or other withdrawal criteria is met.

Drug: Evexomostat

Interventions

Evexomostat DRUG

Evexomostat (SDX-7320) is a synthetic copolymer-drug conjugate of a novel MetAP2 inhibitor.

Also known as: SDX-7320

Evexomostat

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Patient is an adult male or postmenopausal female ≥18 years old at the time of informed consent(s) and has signed informed consent(s) before any trial related activities and according to local guidelines.
• Patient with histologically and/or cytologically confirmed diagnosis of HR+, HER2- breast cancer, as determined by the local laboratory.
• Patient has identified PI3K pathway alteration, defined as a PIK3CA mutation or PTEN loss or an AKT1 mutation using a Food and Drug Administration (FDA)-approved test, as determined either during Screening or was previously determined to have the alteration as evidenced by written documentation.
• Patient has locally advanced (not amenable to curative therapy or metastatic) breast cancer meeting any of the following categories:
• Relapsed disease, not amenable to curative therapy, with documented evidence of progressive disease (PD) following receipt of both (neo) adjuvant endocrine therapy and a CDK 4/6 inhibitor therapy (either alone or in combination with endocrine therapy) in the early stage or metastatic setting.
• Newly diagnosed advanced breast cancer, with relapsed disease (i.e., documented evidence of PD) while receiving or after endocrine therapy plus a CDK 4/6 inhibitor.
• Patient has measurable disease per the Response Evaluation Criteria in Solid Tumors (RECIST) v1.1.
• For bone lesions, lytic bone lesions or mixed lytic-blastic lesions, with identifiable soft tissue components, that can be evaluated by cross-sectional imaging techniques such as computed tomography (CT) or magnetic resonance imaging (MRI) can be considered as measurable lesions if the soft tissue component meets the definition of measurability per RECIST 1.1. Blastic bone lesions are non-measurable.
• For bone metastases only (without measurable lesions), patients may be accrued to the safety Cohorts only.
• Patient has an Eastern Cooperative Oncology Group Performance Status (ECOG-PS) ≤1
• Patient has a Screening fasting plasma glucose (FPG) level ≤140 mg/dL (7.7 mmol/L) and an HbA1c ≤6.4% (47 mmol/mol) for those taking alpelisib, or an HbA1c \<8% (64 mmol/mol) for those taking capivasertib.
• Patient has a body mass index (BMI) ≥ 20 kg/m2.
• Patient is male or postmenopausal female. Postmenopausal is defined as any of the following:
• ≥45 years of age and has not had menses for \>2 years.
• Amenorrheic for \>2 years without a hysterectomy and oophorectomy and a follicle-stimulating hormone value in the postmenopausal range upon pre-study (screening) evaluation.

You may not qualify if:

• Patient has inflammatory breast cancer at screening.
• Patient has known primary brain malignancy, active brain metastasis or active central nervous system pathology or is considered by the Investigator to be neurologically unstable. Furthermore, patients must not have received corticosteroids within 4 weeks of study entry and must have unchanged brain CT or MRI findings for at least two months prior to screening.
• Patient has a known hypersensitivity to evexomostat, fulvestrant, alpelisib, or capivasertib, or to any of their excipients.
• Patient has an established diagnosis of type 1 diabetes mellitus or uncontrolled (based on fasting plasma glucose \[FPG\] \>140mg/dL or HbA1c ≥6.5% for patients assigned alpelisib) or HbA1c for patients assigned to capivasertib, type 2 diabetes or has taken insulin in the 4 weeks prior to C1D1.
• Patient has had major surgery within 30 days or minor surgery within 14 days prior to the first study drug dose, or has not recovered from major side effects from prior surgery.
• Patient has ongoing toxicities related to prior anti-cancer therapies that have not resolved to Grade 0 for bone marrow toxicities or ≤Grade 1 for other toxicities, per National Cancer Institute Common Terminology Criteria for Adverse Events, Version 5.0 (NCI CTCAE v.5.0), with the exception of alopecia.
• Patient has a Child Pugh score of B or C.
• Patient has uncontrolled human immunodeficiency virus (HIV) infection.
• Patient has received radio therapy ≤4 weeks or limited field radiation for palliation ≤2 weeks prior to enrollment, and who has not recovered to ≤Grade 1 from related side effects of such therapy (with the exception of alopecia) and/or from whom ≥25 percentage of bone marrow was irradiated.
• Patient has a concurrent malignancy other than breast cancer or had a malignancy other than breast cancer within 2 years of enrollment, with the exception of adequately treated, basal or squamous cell carcinoma, non-melanomatous skin cancer or curatively resected cervical cancer.
• Patient has impairment of gastrointestinal (GI) function or GI disease that may significantly alter the absorption of the drug alpelisib or capivasertib (e.g., ulcerative diseases, uncontrolled nausea, vomiting, diarrhea, malabsorption syndrome, gastric bypass or small bowel resection) based on Investigator discretion.
• Patient has currently documented or unresolved pneumonitis/interstitial lung disease (the chest computed tomography \[CT\] scan performed before start of study treatment for the purpose of tumor assessment should be reviewed to confirm that there are no relevant pulmonary complications present).
• Patient is currently receiving any of the following medications and cannot be discontinued at least 7 days prior to the start of the treatment:
• Strong cytochrome P450 3A4 (CYP3A4) inducers
• Inhibitors of breast cancer resistance protein (BCRP)

Sponsors & Collaborators

• SynDevRx, Inc.: lead

Study Sites (10)

Loma Linda University Cancer Center

Loma Linda, California, 92354, United States

RECRUITING

Hoag Memorial Hospital Presbyterian

Newport, California, 92663, United States

RECRUITING

SHARP Healthcare

San Diego, California, 92123, United States

RECRUITING

Miami Cancer Institute at Baptist Health

Miami, Florida, 33176, United States

RECRUITING

Hope and Healing Cancer Services

Hinsdale, Illinois, 60521, United States

RECRUITING

Trinity Health

Ypsilanti, Michigan, 48197, United States

RECRUITING

Cleveland Clinic

Cleveland, Ohio, 44195, United States

RECRUITING

Penn State Milton S Hershey Medical Center

Hershey, Pennsylvania, 17033, United States

RECRUITING

Vanderbilt University Medical Center

Nashville, Tennessee, 37232, United States

RECRUITING

Doctors Hospital of Laredo

Laredo, Texas, 78045, United States

RECRUITING

Related Publications (2)

• Rugo HS, Andre F, Yamashita T, Cerda H, Toledano I, Stemmer SM, Jurado JC, Juric D, Mayer I, Ciruelos EM, Iwata H, Conte P, Campone M, Wilke C, Mills D, Lteif A, Miller M, Gaudenzi F, Loibl S. Time course and management of key adverse events during the randomized phase III SOLAR-1 study of PI3K inhibitor alpelisib plus fulvestrant in patients with HR-positive advanced breast cancer. Ann Oncol. 2020 Aug;31(8):1001-1010. doi: 10.1016/j.annonc.2020.05.001. Epub 2020 May 13.

  PMID: 32416251 RESULT

• Rugo HS, Lacouture ME, Goncalves MD, Masharani U, Aapro MS, O'Shaughnessy JA. A multidisciplinary approach to optimizing care of patients treated with alpelisib. Breast. 2022 Feb;61:156-167. doi: 10.1016/j.breast.2021.12.016. Epub 2021 Dec 27.

  PMID: 35016012 RESULT

MeSH Terms

Conditions

Breast Neoplasms; Hyperglycemia; Insulin Resistance; Hyperinsulinism

Condition Hierarchy (Ancestors)

Neoplasms by Site; Neoplasms; Breast Diseases; Skin Diseases; Skin and Connective Tissue Diseases; Glucose Metabolism Disorders; Metabolic Diseases; Nutritional and Metabolic Diseases

Study Officials

• Medical Team

  SynDevRx, Inc.

  STUDY DIRECTOR

Central Study Contacts

David Browning

CONTACT

+1-615-975-7776; dbrowning@syndevrx.com

James M Shanahan

CONTACT

6174013110; jshanahan@syndevrx.com

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NA
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: June 22, 2022
• First Posted: July 13, 2022
• Study Start: August 26, 2022
• Primary Completion (Estimated): December 1, 2026
• Study Completion (Estimated): March 1, 2027
• Last Updated: April 22, 2026

Record last verified: 2026-04

Data Sharing

• IPD Sharing: Will not share

Locations

US (10)