Evexomostat Plus Alpelisib and Fulvestrant in Women With the PIK3CA Mutation With HR+/Her2- Breast Cancer
Evexomostat Plus Alpelisib and Fulvestrant in Women With the PIK3CA Mutation With HR+/Her2- Breast Cancer
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 PI3K, 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.
patient mortality. Alpelisib, a small molecule that inhibits the activity of the PIK3CA gene
product PI3K, 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.
Not Available
Phase I/II
Adults
Chemotherapy - cytotoxic,
Mol. targeted/Immunotherapy/Biologics
Alpelisib (PIQRAY),
Evexomostat (SDX-7320),
Fulvestrant
Rexer, Brent
International
Vanderbilt University
07-06-2023
Eligibility
18 Years
BOTH
NO
Inclusion Criteria:
Inclusion: 1. 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. 2. Patient with histologically and/or cytologically confirmed diagnosis of HR+, HER2- breast cancer, as determined by the local laboratory. 3. 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. 4. 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. 5. 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 6. Patient has an Eastern Cooperative Oncology Group Performance Status (ECOG-PS) 1. 7. Patient has a Screening fasting plasma glucose (FPG) level 140 mg/dL (7.7 mmol/L) and an HbA1c 6.4% (47 mmol/mol). 8. Patient has a body mass index (BMI) 20 kg/m2. 9. 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. 10. Patient agrees to, and is willing and able to arrive at the hospital/clinic in a fasted state (>8 hours) on designated fasting days. 11. Patient has adequate bone marrow and organ function as defined by the following laboratory values (as assessed by central laboratory for eligibility): Platelet count 14010^9/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: 1. Patient has inflammatory breast cancer at screening 2. Patient has known primary brain malignancy, brain metastasis or active central nervous system pathology, any of which as determined by the Investigator 3. Patient has received prior PI3K/Akt/mTOR inhibitor or fulvestrant treatment 4. Patient has a known hypersensitivity to evexomostat, fulvestrant, or alpelisib or to any of their excipients 5. 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
Inclusion: 1. 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. 2. Patient with histologically and/or cytologically confirmed diagnosis of HR+, HER2- breast cancer, as determined by the local laboratory. 3. 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. 4. 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. 5. 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 6. Patient has an Eastern Cooperative Oncology Group Performance Status (ECOG-PS) 1. 7. Patient has a Screening fasting plasma glucose (FPG) level 140 mg/dL (7.7 mmol/L) and an HbA1c 6.4% (47 mmol/mol). 8. Patient has a body mass index (BMI) 20 kg/m2. 9. 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. 10. Patient agrees to, and is willing and able to arrive at the hospital/clinic in a fasted state (>8 hours) on designated fasting days. 11. Patient has adequate bone marrow and organ function as defined by the following laboratory values (as assessed by central laboratory for eligibility): Platelet count 14010^9/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: 1. Patient has inflammatory breast cancer at screening 2. Patient has known primary brain malignancy, brain metastasis or active central nervous system pathology, any of which as determined by the Investigator 3. Patient has received prior PI3K/Akt/mTOR inhibitor or fulvestrant treatment 4. Patient has a known hypersensitivity to evexomostat, fulvestrant, or alpelisib or to any of their excipients 5. 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
