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The Amelia-1 study: A phase 1b/2 trial of evexomostat (SDX-7320) plus fulvestrant and alpelisib in patients with advanced breast cancer at risk for alpelisib-induced hyperglycemia.

TPS1129 Background: Alpelisib, a selective PI3K p110a inhibitor, was approved for breast cancer patients with PIK3CA mutations. An on-target toxicity of alpelisib is hyperglycemia and patients with baseline insulin resistance/elevated HbA1c are at greater risk of developing grade 3,4 hyperglycemia after receiving alpelisib. Restoring insulin sensitivity and reducing systemic insulin levels improved the efficacy of alpelisib in animal models of breast cancer. Evexomostat is a polymer-drug conjugate of a novel small molecule methionine aminopeptidase 2 (MetAP2) inhibitor. In normal mice, it reduced alpelisib-induced hyperglycemia/hyperinsulinemia and in an animal model of breast cancer synergized with alpelisib to regress tumor growth. In a Phase 1 trial, evexomostat improved insulin resistance in patients with elevated baseline insulin, reduced angiogenic factors in patients with elevated baseline levels, increased the insulin-sensitizing adipokine adiponectin and showed anti-metastatic effects in patients with advanced solid tumors. Methods: This is a phase 1b/2, open-label, single-arm pilot study (NCT05455619) in postmenopausal women with HR+, HER2- metastatic breast cancer with a PIK3CA mutation who progressed following treatment with endocrine therapy plus a CDK4/6 inhibitor and who are at risk for hyperglycemia (HbA1c between 5.5 and 6.4%inclusive). The primary goal is to determine the safety of evexomostat plus alpelisib and fulvestrant (the ‘triplet therapy’), including the severity and number of hyperglycemic events, as well as anti-tumor benefit. The starting dose of evexomostat in the triplet therapy is 36 mg/m2 (n=6; one dose below the monotherapy MTD of 49 mg/m2). Once the MTD of evexomostat in the triplet therapy has been defined, up to 20 patients will be enrolled at that dose. An additional 20 patients may be enrolled to further characterize the safety and anti-tumor effect of the triplet therapy (up to 52 patients). This trial is open to accrual at multiple sites in the USA. Safety analysis includes the type, frequency, and severity of treatment-emergent adverse events (TEAEs) per NCI CTCAE, v5, and the number and proportion of patients with grade 3 or 4 hyperglycemia during the first 2 cycles of therapy, with an estimate of the exact upper one-sided 97.5% confidence bound. Efficacy analyses include objective response rate (ORR, consisting of complete response (CR) and partial response (PR)). The number of patients without disease progression six months from the start of the triplet therapy will be assessed. The CBR of CRs, PRs plus stable disease ≥24 weeks from C1D1 will be calculated. Overall survival data will be summarized as available. QoL will be analyzed according to functional scores and recommendations in the EORTC scoring manual. ECOG performance status and change from baseline will be summarized. Clinical trial information: NCT05455619 .

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Abstract P5-05-04: Inhibition of HER2+ tumor growth with SDX-7320, a novel MetAP2 inhibitor, alone and in combination with capivasertib/AZD-5363: Reduced expression of hypoxia-inducible and innate-immune system genes

Abstract MetAP2 inhibitors have shown clinical anti-tumor activity, but CNS side effects and poor drug-like properties have generally limited their development. SDX-7320 is a polymer-drug conjugate of a novel fumagillin-derived MetAP2 inhibitor (SDX-7539) attached via a cleavable linker to a hydroxypropylmethacrylamide (HPMA) polymer backbone. This conjugation approach is intended to improve safety (i.e., limit CNS penetration) while also improving biodistribution and pharmacokinetics relative to small molecule MetAP2 inhibitors. SDX-7320 recently completed a phase I safety trial in late-stage cancer patients (NCT02743637) and was well-tolerated with no apparent CNS side effects. In prior models of breast cancer, SDX-7320 significantly inhibited the growth of syngeneic EO771 triple-negative breast cancers (TNBC) accelerated by obesity/metabolic dysfunction (i.e., “metabo-oncology”) and also synergized with the PI3Kα inhibitor alpelisib/Piqray® in ER+/Her2- MCF-7 xenografts. The objectives of these experiments were to determine the effect of SDX-7320 on the growth of Her2+ xenografts alone or in combination with the Akt/mTOR inhibitor capivasertib/AZD-5363 and to determine if SDX-7320 could attenuate hyperglycemia induced by capivasertib/AZD-5363. Female athymic, nude mice (9 weeks of age) were surgically implanted with slow-release estrogen pellets (90-day, 0.72 mg, inter-scapular) and three days later 2 x 107 BT474 cells (in Matrigel/RPMI-1640, 50/50, v/v) were injected into the fourth mammary gland. When the group mean tumor volume exceeded 100 mm3, treatment with test agents commenced. SDX-7320 (sc/q4d, 6, 12 mg/kg) exerted significant, dose-dependent inhibition of BT-474 tumor growth (TGI of 61 and 88% respectively), whereas capivasertib/AZD-5363 (po, qd, 100, 200 mg/kg) exhibited significant anti-tumor activity only at 200 mg/kg (54% TGI). The combination of SDX-7320 (12 mg/kg) plus capivasertib/AZD-5363 (200 mg/kg) produced additive effects in that a greater number of mice had tumor regression relative to mice treated with either SDX-7320 or capivasertib/AZD-5363 alone. Tumor tissue from a subset of treatment groups (Vehicle, SDX-7320-12 mg/kg, SDX-7320-12 mg/kg + AZD-5363-200 mg/kg, and AZD-5363-200 mg/kg) was snap frozen and stored at -80oC. PolyA+ RNA was isolated, cDNA libraries were constructed and RNASeq was conducted (range of 20-30 reads per million (RPM) base pairs). Analysis of RNASeq data showed that SDX-7320 alone significantly attenuated the expression of hypoxia-induced genes as well as genes related to the innate immune system. Based on these results, we conclude that SDX-7320 affected tumor growth by limiting the ability of tumors to adapt to a hypoxic microenvironment and by altering the innate tumor-immune microenvironment. In normal male, C57Bl/6 mice, capivasertib/AZD-5363 (200 mg/kg, po) elevated blood glucose after a single dose. Pretreatment with either one dose (24 hours before the Akt/mTOR inhibitor) or multiple doses (Q4D beginning 14 days prior to Akt/mTOR inhibitor) of SDX-7320 (8 mg/kg) significantly inhibited hyperglycemia induced by capivasertib/AZD-5363. In summary SDX-7320 significantly inhibited the growth of BT-474 xenografts, alone and in combination with capivasertib/AZD-5363, which was associated with suppression of hypoxia-induced genes, as well as genes of the innate immune system. In addition, SDX-7320 improved the safety profile of capivasertib/AZD-5363 by attenuating Akt/mTOR inhibitor-induced hyperglycemia, providing further support for the clinical exploration of SDX-7320 in combination with Akt/mTOR inhibitors in Her2+ breast cancer. Citation Format: Peter Cornelius, Benjamin Mayes, Pierre Dufour, Mark Kalinich, Jonathan Wang, Sara Little, Bradley Carver, James Shanahan. Inhibition of HER2+ tumor growth with SDX-7320, a novel MetAP2 inhibitor, alone and in combination with capivasertib/AZD-5363: Reduced expression of hypoxia-inducible and innate-immune system genes [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr P5-05-04.

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