First Patient Dosed in Phase 1/2 Trial of FLX475 in Breast, Other Advanced Cancers

First Patient Dosed in Phase 1/2 Trial of FLX475 in Breast, Other Advanced Cancers

The first patient has been dosed in a Phase 1/2 trial evaluating FLX Bio’s investigational therapy, FLX475, alone and in combination with the PD-1 inhibitor Keytruda (pembrolizumab), as a therapy for triple negative breast cancer and other advanced cancers.

The study (NCT03674567) is recruiting participants at cancer centers in the United States, Australia, and Asia, and is expected to include 375 patients.

“The dosing of our first patient with FLX475 is a significant milestone for FLX Bio as we continue to advance our novel therapeutic approach targeting the tumor microenvironment,” Brian Wong, MD, PhD, CEO of FLX Bio, said in a press release.

FLX475 is an oral, small inhibitor of the C-C chemokine receptor 4 (CCR4), a receptor protein predominantly found at the surface of regulatory T-cells, or Tregs.

Tregs are a group of cells of the immune system whose function is to keep immune responses in check and prevent other immune cells from attacking the body’s own tissues (a condition known as autoimmunity).

But Tregs can also accumulate inside and around tumors to suppress the immune system’s response. This trafficking of Tregs into the tumor mass is mediated by signaling molecules — chemokines — produced by tumor cells, such as CCL17 and CCL22.

FLX475 inhibits the binding of CCR4 to these signaling molecules, blocking the recruitment of Tregs into the tumor, unleashing the full potential of the immune system responses against the tumor cells.

Keytruda works by blocking the programmed cell death 1 (PD-1) receptor in immune cells from interacting with its ligand PD-L1 in cancer cells. This interaction works as an “off switch” in T-cells, allowing cancer cells to “hide” from the immune system.

The Phase 1/2 trial has two parts. In Part 1, patients will receive increasing doses of FLX475 to determine the best dose for further testing, either alone or in combination with Keytruda. Then in Part 2, researchers will test the therapy, alone or in combination therapy, in expanded cohorts.

The study’s main objective is to determine the safety and tolerability of FLX475 as a monotherapy or in combination with Keytruda, including its maximum tolerated dose. Another primary goal is to evaluate the treatment’s antitumor activity by measuring the proportion of patients with a reduction in tumor volume.

In preclinical studies, FLX475 inhibited the growth of the tumor and reduced its mass. When combined with other immunotherapies, including inhibitors of the PD-1 pathway, FLX475 enhanced their anti-tumor activity.

“Treg cells play fundamental roles in inhibiting the immune response to the tumor and are a major resistance mechanism to many cancer immunotherapies including PD-1 inhibitors. FLX475 represents a best-in-class approach to selectively decrease Treg numbers in the tumor, thereby unlocking the antitumor immune response,” Wong said.

Besides triple negative breast cancer tumors, which are known to have high levels of the CCR4 receptor protein, tumors including non-small cell lung cancer, head and neck cancers, and cervical cancer will be allowed into the trial.

The study will also include a group of patients carrying tumors positive for the Epstein-Barr virus (EBV), known to carry a high number of Tregs.

“[O]ur big data and proprietary informatics platform has revealed the tumor types most likely to respond to FLX475. We are excited to evaluate this new therapeutic modality in these enriched patient populations through our ongoing global Phase 1/2 clinical trial,” Wong said.

In healthy volunteers, administration of FLX475 was found to be safe and well-tolerated.

“FLX475 has demonstrated an excellent safety, pharmacokinetic and pharmacodynamic profile in a recently completed study of healthy volunteers and we believe this compound holds tremendous promise for directly addressing the suppressive effects of Treg in the tumor microenvironment,” said Bill Ho, MD, PhD, chief medical officer of FLX Bio.

“Treatment with FLX475 should allow the selective blocking of tumor-associated Treg recruitment while sparing normal tissues and beneficial cells. This may offer a safer and more efficacious treatment alternative for patients with many different types of cancer, as compared to the several existing strategies used to suppress or deplete Treg cells,” Ho added.