‘Overwhelmingly Positive’ Data Halts Endoxifen Phase 2 Trial for Invasive Cancer



Endoxifen, Phase 2 trial

After promising results from patients enrolled to date, Atossa Therapeutics halted an Australian Phase 2 clinical trial evaluating its investigative oral therapy Endoxifen in women newly diagnosed with invasive, estrogen receptor (ER)-positive breast cancer and scheduled for surgery.

“It is a welcome event to halt an ongoing clinical trial because the results are so overwhelmingly positive,” Steven Quay, MD, PhD, Atossa’s president and CEO, said in a press release.

Interim data showed that the therapy resulted in clinically meaningful reductions in tumor activity prior to surgery in each of the first six enrolled women — meeting the trial’s main goal.

“We believe that additional enrollment will not alter these positive results so we are terminating the study early,” Quay said, noting that “this saves at least a year on the development time line allowing us to accelerate clinical development in the United States.”

“We look forward to reporting final data from all patients in the study and sharing our continued progress in the development of oral Endoxifen,” he added.

Endoxifen is the active byproduct of tamoxifen, a long-standing hormone therapy for breast cancer that works by blocking the estrogen receptor, which is present in about 80% of breast cancers; these are classified as ER-positive.

Since the growth of these tumors is driven by the hormone estrogen, blocking estrogen receptors, and thereby estrogen signaling, can be an effective treatment strategy for such tumors.

However, not all patients are able to metabolize tamoxifen into endoxifen, its active byproduct. Moreover, tamoxifen is associated with several adverse events, or side effects. Thus, Atossa is evaluating the benefits of giving endoxifen directly to patients.

The Australian Phase 2 trial was designed to evaluate the safety and effectiveness of oral Endoxifen when given within the so-called “window of opportunity” between diagnosis and surgery. Such surgery seeks to remove the tumor, or the whole breast, in women newly diagnosed with invasive, ER-positive, HER2-negative, breast cancer.

Of note, HER2 is a growth-promoting receptor protein overly produced by some breast cancers.

The trial was conducted on behalf of Atossa by Avance Clinical, a leading Australian clinical research organization.

Seven women were recruited and had been treated with Endoxifen to date. Each received oral capsules of Endoxifen (4 mg) once a day for at least 14 days up to the day of their surgery.

Before and after treatment, participants provided a tumor biopsy and a blood sample, and the surgically removed tissue also was analyzed.

The trial’s main goal was to assess whether Endoxifen resulted in clinically meaningful reductions in tumor activity prior to surgery — as assessed by measuring the levels of Ki-67, a tumor growth marker.

Secondary goals included safety and tolerability measures and an assessment of changes in the levels of estrogen and other hormone receptors.

Data from the first six patients showed that these women received Endoxifen treatment for a mean of 22 days (range, 16–40 days) and that all achieved a more than 50% drop in Ki-67 levels, with a mean reduction of 74%.

These responses were considered significant and clinically meaningful, meeting the trial’s main goal.

In addition, at the time of surgery, “all patients had Ki-67 levels lower than 25%, which is an important threshold to improve long-term survival as identified in studies by others,” Quay said.

There were no safety or tolerability issues, including common adverse events such as hot flashes and night sweats. These side effects, known as vasomotor symptoms, often are a tolerability challenge for patients receiving tamoxifen.

The company also announced a two-year update on a woman being treated with Endoxifen under an expanded access program in the U.S.

Such programs are intended to make investigational therapies available outside of a clinical trial to people whose serious or life-threatening conditions have few or no adequate treatments,  in cases in which the therapy’s benefits are thought to outweigh potential risks.

“This patient, like many breast cancer patients, was reluctant to take tamoxifen because of the well-documented side effects associated with that [therapy] and because she lacked the proper liver enzymes to properly metabolize tamoxifen,” Quay said in a separate press release.

In late 2018, the U.S. Food and Drug Administration (FDA) authorized a single-patient study under its expanded access program. That allowed this woman to receive oral Endoxifen in that window of opportunity before surgery.

Following that surgery, an additional authorization was granted by the FDA for the same patient, who has now taken Endoxifen for about 26 months (over two years) and is continuing treatment under these authorizations.

According to Sidney Goldblatt, MD, that study’s principal investigator, the woman to date “has not had a recurrence of breast cancer,” nor has she had any “treatment-related changes in periodic laboratory blood tests and general clinical examinations.”

The therapy “has been well tolerated, including an absence of typical vasomotor symptoms commonly associated with tamoxifen,” Goldblatt added.

“We are very encouraged by this patient’s experience with our Endoxifen over the past two years,” Quay said, adding that “her experience serves as a model for ongoing development efforts.”

Atossa is currently evaluating a number of Endoxifen’s potential indications in the window of opportunity setting. These include avoidance of surgery in older and frail patients, allowing breast conservation surgery, and using Endoxifen instead of other therapies usually given to shrink tumors before surgery.

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