GlycoMimetics announced that the first patient with advanced breast cancer has been dosed in a Phase 1b clinical trial investigating the ability of its small molecule inhibitor, GMI-1359, to stop breast cancer bone metastasis.

The open-label, dose-escalation study (NCT04197999) is recruiting up to 12 patients whose breast cancer is positive for a hormone receptor (HR+) and has spread outside of the breast area (metastatic), including to the bone, but is stable or minimally progressive.

Enrollment is ongoing at this proof-of-concept trial’s sole site, Duke University Medical Center in Durham, North Carolina.

“The initiation of enrollment is an important milestone in our exploration of GMI-1359 and its potential as a novel approach to treating metastatic cancer,” Helen Thackray, MD, a senior vice president and the chief medical officer of GlycoMimetics, said in a press release. “We’re … look forward to learning more about its potential impact as clinical study advances.”

Eligible participants must be receiving an endocrine-based treatment — either an aromatase inhibitor like anastrozole, a selective estrogen receptor degrader such as fulvestrant, or a selective estrogen receptor modulator like tamoxifen — and continue with it for the entire four-month study.

Patients will receive up to three single doses of GMI-1359, administered via into-the-vein injection, and each dose will have a greater concentration of the treatment. This will help researchers determine the maximum tolerated dose in breast cancer patients. Once that is determined, patients will be given the maximum dose on three consecutive days.

The starting dose was set in a completed Phase 1 clinical trial (NCT02931214), in which researchers measured the safety and tolerability of GMI-1359 in healthy volunteers. This trial ended in late 2019.

With the first breast cancer patient dosed in the new trial, researchers will be evaluating for safety as a primary goal, how GMI-1359 moves within the body (pharmacokinetics), and particular measures of biological activity (pharmacodynamics), including changes in numbers of tumor and immune cells circulating in the blood.

This is because GMI-1359 is specifically designed to limit the ability of breast cancer to move into the bone, a common site of metastasis. GMI-1359 selectively blocks the activity of two proteins, E-selectin and CXCR4, which were both recently shown to contribute towards the movement of cancer cells and the establishment of cancer cells in bone marrow.

Both proteins are classified as adhesion molecules, so named because they are involved in the interactions between adjacent cells or a cell and its surrounding.

Preclinical research showed that E-selectin contributed to the movement of cancer cells into the bone marrow, while CXCR4 anchored breast cancer cells to protective areas in the bone marrow that allowed them to ‘hide’ from chemotherapy agents.

The findings indicate that inhibiting both proteins could remove breast cancer cells from these protective niches and block their re-entry, potentially eliminating a common site for metastases and source for relapsed disease.

A study of preclinical work that identified the role of CXCR4 and E-selectin in metastasis, “Dormant breast cancer micrometastases reside in specific bone marrow niches that regulate their transit to and from bone,” was published in Science Translational Medicine.

As a follow-up to those findings, researchers at GlycoMimetics did further work in an animal model of colon cancer. This preclinical study found that GMI-1359, in combination with an inhibitor of PD-L1, shortened the overall time to complete tumor regression. They also saw a reduction in regulatory T-cells, a type of immune system cell that suppresses immune activity, thereby creating more ideal conditions for anti-tumor activity.

Another preclinical study conducted by GlycoMimetics showed that GMI-1359 increases the ability of chemotherapy to target mobilized cancer cells in a high-risk form of mutated acute myeloid leukemia (AML).

As a proof-of-concept study, the Phase 1b trial underway aims to provide evidence of these preclinical findings in patients. Its outcomes, expected when it concludes at year’s end, will be the basis of further decisions about the development of GMI-1359.

GlycoMimetics reports that the U.S. Food and Drug Administration granted GMI-1359 orphan drug and rare pediatric disease designation for the treatment of osteosarcoma, a rare bone cancer, earlier this month.