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So far, first time’s a charm for Tonetti’s initial clinical trial

Debra Tonetti’s first clinical trial has not gone the way she anticipated. It’s gone much better.

Tonetti, PhD, a University of Illinois Cancer Center member, associate professor of pharmacology and interim head of the department of biopharmaceutical sciences, is testing a drug she helped developed with fellow UI Cancer Center member Greg Thatcher that has the potential to help women whose breast cancer has stopped responding to hormone therapy.

Patient recruitment into the Phase 1 trial of the new drug, TTC-352, has proceeded more rapidly than anticipated. The drug is a selective estrogen mimic that causes complete tumor regression, but unlike tamoxifen, it may pose a reduced risk of uterine cancer development. The trial is currently open at four sites throughout the U.S., with the University of Illinois Hospital & Health Sciences System being a fifth and final location beginning in the coming months.

About two out of three breast cancers are hormone receptor-positive, whose cells have receptors (proteins) that attach to the hormone estrogen (ER-positive cancers) and/or progesterone (PR-positive cancers). For these cancers, high estrogen levels help the cancer cells grow and spread.

Hormone therapy is considered to be highly effective at fighting estrogen receptor-positive breast cancer, but nearly 50 percent of the women who undergo this type of treatment still develop a resistance to the medication and experience a recurrence, Tonetti said. TTC-352, a selective human estrogen receptor partial agonist (ShERPA), may be as effective at treating breast cancer as other hormone therapy drugs, like tamoxifen or aromatase inhibitors, but with fewer side effects.

The Phase 1 trial will determine the maximum tolerated oral dose of TTC-352 in patients with metastatic breast cancer that has progressed despite endocrine therapy. It will also evaluate the patients’ best response to treatment; the duration of progression-free survival, as well as overall survival; the safety profile of the drug; and the drug’s pharmacokinetic profile. It will also study the association between tumor response to the drug and its expression of a specific predictive biomarker, protein kinase C alpha, or PKC alpha, Tonetti said.

“We have observed that breast cancers that develop a resistance to hormone therapy have elevated PKC alpha expression,” she said. “Our previous studies suggest that PKC alpha may predict a positive response to estrogen mimics like TTC-352.”

Phase 1 trials test for a drug’s safety, but hints of efficacy can also be observed. With initial results appearing to be promising, Tonetti said a new problem has arisen.

“The trial calls for testing five dosing levels for safety,” Tonetti said. “Now we have all these patients that are presumably going to do well and you can’t just take the drug away from them. Now we need to manufacture more of the drug.

“It may very well be that our Phase 1 trial will be finished with fewer patients and at a faster rate. This means we will be positioned well for beginning a Phase 2 trial.”

Tonetti and Thatcher, who serves as co-director of the UI Cancer Center’s Translational and Clinical Oncology Program, have also collaborated on a new orally bioavailable selective estrogen receptor downregulator (SERD) that has been licensed to G1 Therapeutics, a North Carolina-based biopharmaceutical company. The company plans to combine the SERD with G1’s cyclin dependent kinase (CDK) 4/6 inhibitor to treat estrogen receptor positive and HER2 negative breast cancer.

“Presently there is only one FDA-approved SERD on the market,” Tonetti said. “When it comes to endocrine therapy there are few options. We believe this new drug is promising as well.”

Tonetti, who co-founded the biopharmaceutical company TTC Oncology LLC with Thatcher in 2016 to produce the drug TTC-352, became interested in studying cancer while serving a postdoctoral fellowship at Argonne National Laboratory, working with the PKC signaling pathway conducting research on differentiation mechanisms in promyelocytic leukemia. She then trained under V. Craig Jordan, known as the “Father of Tamoxifen”, at Northwestern University before coming to UIC in 2001. Her research has been funded by the National Institutes of Health, the Chicago Biomedical Consortium, the Avon Foundation, and the Susan G. Komen Breast Cancer Foundation, among other organizations.

Although the Phase 1 trial on TTC-352 is not yet complete, Tonetti is optimistic that the drug will one day be a viable option to treat patients with breast cancer.

 “We’re encouraged by the initial findings, and we’re optimistic about the successful treatment of patients in the future,” she said.