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Evexomostat Plus Alpelisib and Fulvestrant in Women With the PIK3CA Mutation With HR+/Her2- Breast Cancer (Amelia-1)

Primary Purpose

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

Status

Recruiting

Phase

Phase 1

Locations

United States

Study Type

Interventional

Intervention

Evexomostat

About this trial

This is an interventional treatment trial for HR+/HER2-negative Breast Cancer focused on measuring hyperglycemia, insulin, glucose, SDX-7320, fulvestrant, apelisib, PIK3CA mutation, evexomostat, HR+ Her2- metastatic breast cancer, hyperinsulinemia

Eligibility Criteria

18 Years - undefined (Adult, Older Adult)All SexesDoes not accept healthy volunteers

Inclusion:

Patient is an adult ≥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 PIK3CA mutation status using a FDA-approved test, as determined either during Screening or was previously determined to have the mutation as evidenced by written documentation.
Patient has advanced (local regionally recurrent not amenable to curative therapy or metastatic) breast cancer meeting any of the following categories:
Relapsed disease, with documented evidence of progressive disease (PD) more than 12 months from completion of (neo)adjuvant endocrine therapy and then subsequently progressed, with documented evidence of PD while receiving or after one line of endocrine therapy plus a CDK 4/6 inhibitor for at least 12 months for their metastatic disease.
Newly diagnosed advanced breast cancer, with relapsed disease (i.e., documented evidence of PD) while receiving or after only one line of endocrine therapy plus a CDK 4/6 inhibitor for at least 12 months.
Recurrent disease or PD while receiving or after aromatase inhibitor (AI) therapy (i.e., letrozole, anastrozole, exemestane) with co-treatment with a CDK 4/6 inhibitor for at least 12 months.
Patient has either measurable disease per the Response Evaluation Criteria in Solid Tumors (RECIST) v1.1, or at least one evaluable predominantly lytic bone lesion
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 of ≥5.5 and ≤6.4% (39 and 47 mmol/mol).
Patient has a body mass index (BMI) ≥ 20 kg/m2.
Patient is postmenopausal. 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.
Post hysterectomy with oophorectomy. Documented hysterectomy or oophorectomy must be confirmed with medical records of the actual procedure or confirmed by an ultrasound. In case of oophorectomy alone, hormone level assessment (follicle-stimulating hormone, estradiol) will be done locally at Screening to confirm postmenopausal status. Patients who are on ovarian function suppression also qualify.
Patient agrees to, and is willing and able to arrive at the hospital/clinic in a fasted state (>8 hours) on designated fasting days.
Patient has adequate bone marrow and organ function as defined by the following laboratory values (as assessed by central laboratory for eligibility):

Platelet count ≥140×10^9/L

In absence of liver metastases, alanine aminotransferase (ALT) and aspartate aminotransferase (AST) <2.5 × the upper limit of normal (ULN). If the patient has liver metastases, ALT and AST <5 × ULN.

Total bilirubin ≤1.5 × ULN except for patient with Gilbert's syndrome who may only be included if the total bilirubin is ≤3.0 × ULN or direct bilirubin ≤1.5 × ULN.

Fasting serum amylase ≤2 × ULN

Hemoglobin ≥ 9 g/dl

Absolute neutrophil count [ANC]) ≥1500/mL

Creatinine clearance ≥ 60 mL/min using Cockcroft-Gault equation

Albumin > 3.5 gm/dL

Exclusion:

Patient has inflammatory breast cancer at screening
Patient has known primary brain malignancy, brain metastasis or active central nervous system pathology, any of which as determined by the Investigator
Patient has received prior PI3K/Akt/mTOR inhibitor or fulvestrant treatment
Patient has a known hypersensitivity to evexomostat, fulvestrant, or alpelisib or to any of their excipients
Patient has an established diagnosis of type 1 diabetes mellitus or uncontrolled (based on FPG >140mg/dL or HbA1c ≥6.5%) type 2 diabetes) or has taken insulin in the 4 weeks prior to C1D1

Sites / Locations

Loma Linda University Cancer CenterRecruiting
Cedars-Sinai Medical CenterRecruiting
Hoag Memorial Hospital PresbyterianRecruiting
Miami Cancer Institute at Baptist HealthRecruiting
University of Maryland BaltimoreRecruiting
Toledo Clinic Cancer CenterRecruiting
Vanderbilt University Medical CenterRecruiting

Arms of the Study

Arm 1

Arm Type

Experimental

Arm Label

Evexomostat

Arm Description

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.

Outcomes

Primary Outcome Measures

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

Hyperglycemic Events

Severity, number, and proportion of patients with hyperglycemic events

Secondary Outcome Measures

Anti-tumor activity

Number of patients without disease progression

Glucose control

Number and type of anti-diabetic agents needed for glucose control will be measured

Leptin activity

Changes from baseline in plasma levels of fasting leptin will be measured

Adiponectin activity

Changes from baseline in plasma levels of fasting adiponectin will be measured

Angiogenic activity (bFGF/FGF2)

Changes from baseline in plasma levels of angiogenic biomarkers (bFGF/FGF2, VEGFC) will be measured

Angiogenic activity (VEGFC)

Changes from baseline in plasma levels of angiogenic and tumor biomarkers will be measured

Insulin resistance

Changes from baseline in patients at risk for hyperglycemia using the homeostatic model assessment for insulin resistance (HOMA-IR) score of insulin resistance. HOMA-IR score is calculated as follows: (fasting serum insulin (μU/ml) × fasting plasma glucose (mmol per liter)/22.5).

Full Information

NCT ID

NCT05455619

First Posted

June 22, 2022

Last Updated

October 13, 2023

Sponsor

SynDevRx, Inc.

1. Study Identification

Unique Protocol Identification Number

NCT05455619

Brief Title

Evexomostat Plus Alpelisib and Fulvestrant in Women With the PIK3CA Mutation With HR+/Her2- Breast Cancer

Acronym

Amelia-1

Official Title

Phase 1b/2 Study of the Safety and Efficacy of Evexomostat Plus Alpelisib and Fulvestrant in Postmenopausal Women at Risk for Hyperglycemia With Advanced Breast Cancer and a PIK3CA Mutation Following Endocrine Therapy and a CDK4/6 Inhibitor

Study Type

Interventional

2. Study Status

Record Verification Date

October 2023

Overall Recruitment Status

Recruiting

Study Start Date

August 26, 2022 (Actual)

Primary Completion Date

March 2026 (Anticipated)

Study Completion Date

September 2026 (Anticipated)

3. Sponsor/Collaborators

Responsible Party, by Official Title

Sponsor

Name of the Sponsor

SynDevRx, Inc.

4. Oversight

Studies a U.S. FDA-regulated Drug Product

Yes

Studies a U.S. FDA-regulated Device Product

Data Monitoring Committee

5. Study Description

Brief Summary

The PIK3CA gene is frequently mutated in breast cancer, leading to disease aggressiveness and patient mortality. Alpelisib, a small molecule that inhibits the activity of the PIK3CA gene product PI3Kα, has demonstrated clinical benefit in cancer patients with this gene mutation. However, hyperglycemia, an on-target toxicity associated with alpelisib that leads to hyperinsulinemia, limits the drug's clinical efficacy and induces high grade hyperglycemia in patients with baseline metabolic dysfunction, insulin resistance and/or elevated HbA1c. Restoring insulin sensitivity and reduction in circulating concentrations of insulin have been reported to improve the activity of alpelisib. Evexomostat (SDX-7320) is a polymer-conjugate of a novel small molecule methionine aminopeptidase 2 (MetAP2) inhibitor that has demonstrated the ability to reduce alpelisib-induced hyperglycemia in multiple animal experiments and has demonstrated synergistic anti-tumor activity independent of changes in glucose or insulin. Evexomostat was well tolerated in a Phase 1 safety study in late-stage cancer patients and showed improvements in insulin resistance for patients that presented with baseline elevated insulin. Overall, the most common treatment-emergent adverse events with evexomostat (TEAEs) were fatigue (44%), decreased appetite (38%), constipation and nausea (each 28%), and diarrhea (22%). All other TEAEs occurred at an incidence <20%. The purpose of this study is to characterize the safety of the triplet drug combination (alpelisib, fulvestrant plus evexomostat), to test whether evexomostat, when given in combination with alpelisib and fulvestrant will reduce the number and severity of hyperglycemic events and/or reduce the number of anti-diabetic medications needed to control the hyperglycemia for patients deemed at risk for alpelisib-induced hyperglycemia (baseline elevated HbA1c or well-controlled type 2 diabetes), and to assess preliminary anti-tumor efficacy and changes in key biomarkers and quality of life in this patient population.

Detailed Description

This is a Phase 1b/2, open-label, single-arm pilot study in post-menopausal women with HR+, HER2- advanced or metastatic breast cancer with a mutation of the PIK3CA gene at risk for hyperglycemia designed to determine the safety of the combination of evexomostat plus standard of care treatment alpelisib (PIQRAY®/BYL-719) and fulvestrant (combined, the 'triplet therapy'), to measure the severity and number of hyperglycemic events, and to assess the anti-tumor benefit of the triplet therapy. Up to 52 patients may be enrolled, starting with dose-escalation cohort(s) of 6 patients each. Once the maximum tolerated dose (MTD) of the triplet therapy has been defined, additional patients will be enrolled until a total of up to 20 patients have completed at least two cycles of the triplet therapy at that dose. If warranted, an additional 20 patients may be enrolled to further characterize the safety profile and/or anti-tumor effect of the triplet therapy. The planned escalation scheme starts at an evexomostat dose of 36 mg/m2 (one dose below the monotherapy MTD of 49 mg/m2) in combination with alpelisib and fulvestrant given at the marketed doses. Based on aggregate safety data from the first two cycles of the first 6 patients, in the absence of ≥ 2 dose-limiting toxicities (DLTs), the Safety Review Committee (SRC), in consultation with the Sponsor and the Investigator(s), may increase the evexomostat dose for the next cohort to 49 mg/m2. In the presence of ≥2 DLTs the SRC will decrease the evexomostat dose to 27 mg/m2 and may adjust the dose of alpelisib if warranted. The dose of fulvestrant will not be adjusted. If the evexomostat dose of 49 mg/m2 is determined not to be tolerable in combination with alpelisib and fulvestrant, then current and future patients will receive evexomostat at 36 mg/m2. In the event of significantly low drug exposure of the active moiety SDX-7539 (C24 < 200 pg/mL) at evexomostat 49 mg/m2, coupled with poor biomarker response (e.g., little/no change in insulin/leptin/adiponectin from baseline) and a favorable safety profile, the SRC in consultation with the Investigator(s) and Sponsor may elect to enroll an additional cohort at 65 mg/m2, which would become the future dose in the combination if tolerated. Subsequent cumulative safety data will be reviewed on a calendar quarterly basis Patients will remain on study for up to 7 cycles on the triplet therapy to characterize the safety and tolerability of the triplet therapy as well as to capture initial efficacy data (i.e., ORR and PFS following 6 months of the triplet therapy). Patients will be allowed to remain on the triplet therapy beyond the initial 7 cycles if they are receiving clinical benefit, including stable disease, as determined by their treating oncologist. The study will consist of a 14-day pre-treatment phase of evexomostat plus fulvestrant starting on Cycle 1, Day 1 (C1D1) before adding alpelisib on C1D15.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study

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

7. Study Design

Primary Purpose

Treatment

Study Phase

Phase 1, Phase 2

Interventional Study Model

Single Group Assignment

Masking

None (Open Label)

Allocation

N/A

Enrollment

52 (Anticipated)

8. Arms, Groups, and Interventions

Arm Title

Evexomostat

Arm Type

Experimental

Arm Description

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.

Intervention Type

Drug

Intervention Name(s)

Evexomostat

Other Intervention Name(s)

SDX-7320

Intervention Description

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

Primary Outcome Measure Information:

Title

Incidence of Adverse Events

Description

Time Frame

Up to 48 months

Title

Hyperglycemic Events

Description

Severity, number, and proportion of patients with hyperglycemic events

Time Frame

Up to 42 months

Secondary Outcome Measure Information:

Title

Anti-tumor activity

Description

Number of patients without disease progression

Time Frame

6 months

Title

Glucose control

Description

Number and type of anti-diabetic agents needed for glucose control will be measured

Time Frame

Up to 42 months

Title

Leptin activity

Description

Changes from baseline in plasma levels of fasting leptin will be measured

Time Frame

Up to 42 months

Title

Adiponectin activity

Description

Changes from baseline in plasma levels of fasting adiponectin will be measured

Time Frame

Up to 42 months

Title

Angiogenic activity (bFGF/FGF2)

Description

Changes from baseline in plasma levels of angiogenic biomarkers (bFGF/FGF2, VEGFC) will be measured

Time Frame

Up to 42 months

Title

Angiogenic activity (VEGFC)

Description

Changes from baseline in plasma levels of angiogenic and tumor biomarkers will be measured

Time Frame

Up to 42 months

Title

Insulin resistance

Description

Time Frame

Up to 42 months

10. Eligibility

Sex

All

Minimum Age & Unit of Time

18 Years

Accepts Healthy Volunteers

Eligibility Criteria

Inclusion: Patient is an adult ≥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 PIK3CA mutation status using a FDA-approved test, as determined either during Screening or was previously determined to have the mutation as evidenced by written documentation. Patient has advanced (local regionally recurrent not amenable to curative therapy or metastatic) breast cancer meeting any of the following categories: Relapsed disease, not amendable to curative therapy, after completion of both (neo)adjuvant endocrine therapy and CDK 4/6 inhibitor. Newly diagnosed advanced breast cancer, with relapsed disease (i.e., documented evidence of PD) while receiving or after only one line of endocrine therapy plus a CDK 4/6 inhibitor therapy. Recurrent disease or PD while receiving or after aromatase inhibitor (AI) therapy (i.e., letrozole, anastrozole, exemestane) with co-treatment with a CDK 4/6 inhibitor. Patient has either measurable disease per the Response Evaluation Criteria in Solid Tumors (RECIST) v1.1, or at least one evaluable predominantly lytic bone lesion 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). Patient has a body mass index (BMI) ≥ 20 kg/m2. Patient is postmenopausal. 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. Post hysterectomy with oophorectomy. Documented hysterectomy or oophorectomy must be confirmed with medical records of the actual procedure or confirmed by an ultrasound. In case of oophorectomy alone, hormone level assessment (follicle-stimulating hormone, estradiol) will be done locally at Screening to confirm postmenopausal status. Patients who are on ovarian function suppression also qualify. Patient agrees to, and is willing and able to arrive at the hospital/clinic in a fasted state (>8 hours) on designated fasting days. Patient has adequate bone marrow and organ function as defined by the following laboratory values (as assessed by central laboratory for eligibility): Platelet count ≥140×10^9/L In absence of liver metastases, alanine aminotransferase (ALT) and aspartate aminotransferase (AST) <2.5 × the upper limit of normal (ULN). If the patient has liver metastases, ALT and AST <5 × ULN. Total bilirubin ≤1.5 × ULN except for patient with Gilbert's syndrome who may only be included if the total bilirubin is ≤3.0 × ULN or direct bilirubin ≤1.5 × ULN. Fasting serum amylase ≤2 × ULN Hemoglobin ≥ 9 g/dl Absolute neutrophil count [ANC]) ≥1500/mL Creatinine clearance ≥ 60 mL/min using Cockcroft-Gault equation Albumin > 3.5 gm/dL Exclusion: Patient has inflammatory breast cancer at screening Patient has known primary brain malignancy, brain metastasis or active central nervous system pathology, any of which as determined by the Investigator Patient has received prior PI3K/Akt/mTOR inhibitor or fulvestrant treatment Patient has a known hypersensitivity to evexomostat, fulvestrant, or alpelisib or to any of their excipients Patient has an established diagnosis of type 1 diabetes mellitus or uncontrolled (based on FPG >140mg/dL or HbA1c ≥6.5%) type 2 diabetes or has taken insulin in the 4 weeks prior to C1D1

Central Contact Person:

First Name & Middle Initial & Last Name or Official Title & Degree

David Browning

Phone

+1-615-975-7776

dbrowning@syndevrx.com

Overall Study Officials:

First Name & Middle Initial & Last Name & Degree

Neal Salomon, MD

Organizational Affiliation

SynDevRx, Inc.

Official's Role

Study Director

Facility Information:

Facility Name

Loma Linda University Cancer Center

City

Loma Linda

State/Province

California

ZIP/Postal Code

92354

Country

United States

Individual Site Status

Recruiting

Facility Contact:

First Name & Middle Initial & Last Name & Degree

Lorena Garcia, CRC

Phone

909-651-5612

Lcgarcia@llu.edu

First Name & Middle Initial & Last Name & Degree

Gayathri Nagaraj, MD

Facility Name

Cedars-Sinai Medical Center

City

Los Angeles

State/Province

California

ZIP/Postal Code

90048

Country

United States

Individual Site Status

Recruiting

Facility Contact:

First Name & Middle Initial & Last Name & Degree

Cristal Martinez

Phone

310-423-3277

cristal.martinez@cshs.org

First Name & Middle Initial & Last Name & Degree

Monica Mita, MD

Facility Name

Hoag Memorial Hospital Presbyterian

City

Newport

State/Province

California

ZIP/Postal Code

92663

Country

United States

Individual Site Status

Recruiting

Facility Contact:

First Name & Middle Initial & Last Name & Degree

Jericho Rabago, BSN, RN

Phone

949-764-6796

jericho.rabago@hoag.org

First Name & Middle Initial & Last Name & Degree

Chaitali Nangia, MD

Facility Name

Miami Cancer Institute at Baptist Health

City

Miami

State/Province

Florida

ZIP/Postal Code

33176

Country

United States

Individual Site Status

Recruiting

Facility Contact:

First Name & Middle Initial & Last Name & Degree

Xiaoou Pan

xiaoou.pan@baptisthealth.net

First Name & Middle Initial & Last Name & Degree

Reshma Mahtani, DO

Facility Name

University of Maryland Baltimore

City

Baltimore

State/Province

Maryland

ZIP/Postal Code

21201

Country

United States

Individual Site Status

Recruiting

Facility Contact:

First Name & Middle Initial & Last Name & Degree

Kate Tkaczuk, MD

Facility Name

Toledo Clinic Cancer Center

City

Toledo

State/Province

Ohio

ZIP/Postal Code

43623

Country

United States

Individual Site Status

Recruiting

Facility Contact:

First Name & Middle Initial & Last Name & Degree

Rex Mowat, MD

First Name & Middle Initial & Last Name & Degree

Rex Mowat, MD

Facility Name

Vanderbilt University Medical Center

City

Nashville

State/Province

Tennessee

ZIP/Postal Code

37232

Country

United States

Individual Site Status

Recruiting

Facility Contact:

First Name & Middle Initial & Last Name & Degree

The Vanderbilt-Ingram Cancer Center Patient Contact Line

Phone

800-811-8480

cip@vumc.org

First Name & Middle Initial & Last Name & Degree

Brent Rexer, MD

12. IPD Sharing Statement

Plan to Share IPD

Citations:

PubMed Identifier

32416251

Citation

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.

Results Reference

result

PubMed Identifier

35016012

Citation

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.

Results Reference

result

Learn more about this trial

Evexomostat Plus Alpelisib and Fulvestrant in Women With the PIK3CA Mutation With HR+/Her2- Breast Cancer

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