# A Phase 2, Single-Arm Study of the CXCR1/2 Inhibitor SX-682 Plus Enzalutamide in Men with Abiraterone-Resistant Metastatic Castration Resistant Prostate Cancer (mCRPC)

> **NIH NIH R44** · SYNTRIX BIOSYSTEMS, INC. · 2024 · $745,050

## Abstract

Prostate cancer (PC) is the second leading cause of cancer-related death among American men, and the vast
majority of these deaths are due to metastatic, castration-resistant PC (mCRPC). Androgen suppression therapy
(AST) is used to treat PC patients, which comprise of: (1) androgen deprivation therapy (ADT) with LHRH
agonists or antagonists; (2) blocking CYP17-mediated androgen synthesis with abiraterone; and (3) androgen
receptor (AR) antagonists such as enzalutamide and others. While AR can significantly prolong overall survival
(OS) of patients with various stages of PC, acquired resistance to either is inevitable, after which limited treatment
options exist. Only about 35% of men respond to enzalutamide after developing resistance to abiraterone [1].
There is therefore a significant unmet need for new mCRPC treatments that act orthogonally and synergistically
with existing AST to increase and prolong its efficacy in mCRPC. The chemokine receptor isoforms CXCR1 and
CXCR2 (CXCR1/2) are validated as orthogonal therapeutic targets in mCRPC. Tumor-secreted CXCR1/2
ligands such as CXCL6 and CXCL8 (IL-8) mediate resistance to ASTs, exerting protumorigenic effects by binding
surface CXCR1/2 on TAMs [2], MDSCs [3-8] and AR negative (AR-) neuroendocrine (NE) cancer cells [9] in the
PC TME. MDSCs are significantly elevated in patient biopsies with CRPC vs. pre-ADT [3], as is expression of
CXCL6 [7] and CXCL8 [5, 10]. Higher patient baseline serum CXCL8 pre-ADT was prognostic for shorter OS
and time to CRPC independent of docetaxel, disease burden, and time of metastases [11]. Circulating MDSCs
positively correlated with clinical stage, and inversely with OS (median OS of 19 vs. 55 months with high vs. low
MDSCs) [12, 13]. We hypothesize that combining CXCR1/2 blockade with standard of care (enzalutamide) in
mCRPC patients progressing on first-line abiraterone will afford enhanced efficacy vs. historical standard of care
efficacy in the same population. SX-682 is a clinical-stage, small-molecule CXCR1/2 inhibitor validated in
numerous published pre-clinical cancer models including mCRPC, and which exhibits activity in patients with
melanoma, pancreatic adenocarcinoma and myelodysplastic syndromes. Through execution of the Specific
Aims, we will advance SX-682 through critical proof-of-concept (POC) efficacy testing in the first ever phase 2
one-arm, open-label trial in mCRPC of a CXCR1/2 inhibitor with enzalutamide in patients failing abiraterone.
The trial will enroll 53 evaluable patients with mCRPC diagnosis with (a) any histology, (b) measurable disease
at enrollment, and (c) currently on or previously on abiraterone with prednisone and with rising PSA (a rising
PSA requires at least 3 measurements obtained at least 1 week apart showing increase from nadir with the last
level above 2 ng/mL). The primary endpoint is clinical benefit (CB), wherein CB is a composite endpoint defined
as 1) RECIST 1.1 CR or PR, 2) confirmed PSA50 decline, or 3) prolonged...

## Key facts

- **NIH application ID:** 10884438
- **Project number:** 5R44CA278187-02
- **Recipient organization:** SYNTRIX BIOSYSTEMS, INC.
- **Principal Investigator:** Aaron D Schuler
- **Activity code:** R44 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $745,050
- **Award type:** 5
- **Project period:** 2023-07-07 → 2027-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10884438

## Citation

> US National Institutes of Health, RePORTER application 10884438, A Phase 2, Single-Arm Study of the CXCR1/2 Inhibitor SX-682 Plus Enzalutamide in Men with Abiraterone-Resistant Metastatic Castration Resistant Prostate Cancer (mCRPC) (5R44CA278187-02). Retrieved via AI Analytics 2026-06-12 from https://api.ai-analytics.org/grant/nih/10884438. Licensed CC0.

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