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

Study Overview
=================
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.

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

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

Intervention / Treatment
-----------------
* Drug: Evexomostat


Participation Criteria
=================
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

Ages Eligible for Study
-----------------
Minimum Age: 18 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Evexomostat<br>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<br>* Evexomostat (SDX-7320) is a synthetic copolymer-drug conjugate of a novel MetAP2 inhibitor.<br>* Other names: SDX-7320;|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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 Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Anti-tumor activity | Number of patients without disease progression | 6 months | 
| Glucose control | Number and type of anti-diabetic agents needed for glucose control will be measured | Up to 42 months | 
| Leptin activity | Changes from baseline in plasma levels of fasting leptin will be measured | Up to 42 months | 
| Adiponectin activity | Changes from baseline in plasma levels of fasting adiponectin will be measured | Up to 42 months | 
| Angiogenic activity (bFGF/FGF2) | Changes from baseline in plasma levels of angiogenic biomarkers (bFGF/FGF2, VEGFC) will be measured | Up to 42 months | 
| Angiogenic activity (VEGFC) | Changes from baseline in plasma levels of angiogenic and tumor biomarkers will be measured | Up to 42 months | 
| 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). | Up to 42 months | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
hyperglycemia, insulin, glucose, SDX-7320, fulvestrant, apelisib, PIK3CA mutation, evexomostat, HR+ Her2- metastatic breast cancer, hyperinsulinemia