TTC-352 Safe for Patients Resistant to Hormone Therapy, Phase 1 Trial Finds



Phase 1 trial results

TTC-352, an investigational oral treatment for patients with metastatic ER-positive breast cancer that no longer responds to hormone therapy, was found to be safe and tolerable at high dose in a Phase 1 clinical study.

The treatment also showed a potential for effectiveness, with half of those who finished the trial achieving stable disease for several months. As such, TTC-352 may prove to be “a safe and tolerable alternative to chemotherapy” for patients no longer able to use hormone therapy, its researchers said.

Their study, “Phase 1 study of TTC-352 in patients with metastatic breast cancer progressing on endocrine and CDK4/6 inhibitor therapy,” was published in the journal Breast Cancer Research and Treatment.

Roughly 80% of breast cancers are considered ER-positive, meaning that the cancer cells express the protein estrogen receptor (ER), and respond to the presence of the hormone estrogen in promoting their growth.

Hormone therapies like tamoxifen, or fulvestrant (brand name Faslodex, by AstraZeneca), are designed to lower the production of estrogen or to block estrogen from binding to its receptors, limiting tumor growth.

Roughly half of breast cancer patients who are treated with hormone therapy, however, become resistant to this type of treatment. When this occurs, chemotherapy is often the only remaining treatment option.

Researchers at the University of Illinois Chicago (UIC) developed a potential treatment, called TTC-352, for ER-positive breast cancer patients who are resistant to hormone therapy.

“While there are many treatments for breast cancer, about half of women with ER-positive cancers become resistant to hormone therapy, leaving them with few treatments other than chemotherapy, with its well-known toxic side effects,” Debra Tonetti, PhD, a UIC professor and study author, said in a press release.

TTC-352, a small molecule, is considered an ER partial agonist, meaning that the molecule can bind to the estrogen receptor protein in the cell nucleus, preventing ER-mediated signaling and blocking the proliferation of ER-positive tumor cells.

Preclinical studies report that TTC-352 can lead to full tumor regression, and that the treatment carries a lower risk of uterine cancer than hormone therapies.

The open-label Phase 1 clinical trial (NCT03201913), a dose-establishing study, investigated the safety and early efficacy of TTC-352 given at five ascending doses (15, 30, 60, 120, 180 mg) as a treatment for breast cancer.

It enrolled 15 patients (all women, median age of 62) whose breast cancer had progressed despite at least two lines of hormone therapy, including one with a CDK4/6 inhibitor. All but one had also undergone chemotherapy.

Patients were randomly assigned to ascending dose groups to determine the maximum tolerated dose, or the highest dosage level that a person could take without severe side effects — the trial’s main goal.

TTC-352 administered as an oral capsule twice daily for 28 days (one cycle of treatment; a total of 47 cycles were given). Treatment cycles continued in this two-year study unless a patient experienced disease progression, decided to leave the study, or had significant side effects.

Researchers found that TTC-352 had no significant side effects, even at the highest dosage levels. However, there were four grade 3 toxicities, including one of asymptomatic pulmonary embolism, one of diarrhea, one of aspartate transaminase elevation (high levels of this enzyme may indicate poor liver health), and one episode of myalgia (muscle pain).

Six patients achieved stable disease, four at a 180 mg twice daily dose. Of the 12 evaluable patients, four reached stable disease at four months and two at six months. Three women left the trial before finishing treatment.

Median progression free survival time (PFS), or the length of time that the cancer does not get worse, was 58 days.

“This is very encouraging because these participants were at an advanced stage of their disease, and we saw that their cancers stopped growing for a significant amount of time,” Tonetti said.

No complete or partial responses to treatment were seen.

From these results, researchers concluded that the medication merited further clinical investigation, and determined that the 180 mg per capsule dosage level was the most appropriate for future studies.

“TTC-352 has a favorable toxicity profile and an encouraging signal of efficacy in breast cancer refractory to at least two prior hormonal therapies and CDK4/6 inhibitor,” the study concluded, recommending it move to a Phase 2 clinical trial “in patients with ER+ breast cancer who have been less heavily pretreated.”

These Phase 1 results “indicate that TTC-352 is a safe and tolerable alternative to chemotherapy — therefore, without the side effects of chemotherapy — for patients who have already been treated with hormone therapy,” Gregory Thatcher, PhD, a study co-author, added in the release.

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