A phase 2 clinical trial is underway at Georgetown Lombardi Comprehensive Cancer Center to investigate a new combination therapy for the treatment of advanced, recurrent thymic carcinoma (cancer of the thymus).

The study, which will include 26 patients, is designed to increase the significant benefit as well as contain the side effects seen with the use of pembrolizumab (MK-375) in a previous Georgetown Lombardi clinical trial. Results of that study were published Feb. 25, 2018, in Lancet Oncology.

Pembrolizumab is an approved immunotherapy that can be used in many solid tumors. It is a so-called “immune checkpoint inhibitor” (the checkpoint molecule is called PD-1), which takes the cancer-induced brakes off the immune system, allowing the body to work naturally against tumors. Epacadostat (INCB024360), the second drug to be used in this study, is a different kind of immune system modulator.

“This clinical trial builds upon the very promising response we saw in the single use of pembrolizumab in our previous study of 40 patients with thymic carcinoma. In that phase 2 clinical trial, this checkpoint inhibitor produced a longer and deeper response than we have seen with other therapies for this rare cancer,” says the trial’s lead investigator, Giuseppe Giaccone, MD, PhD, associate director for clinical research at Georgetown Lombardi.

But while response was high—1 (3%) patient achieved a complete response, 8 (20%) achieved partial responses, and 21 (53%) achieved stable disease—6 patients (15%) developed severe autoimmune toxicity.

“Because severe autoimmune disorders are more frequent in thymic carcinoma than in other tumor types, careful monitoring is essential,” says Giaccone. He adds that while thymic carcinoma, in general, is not associated with autoimmune disorders, pembrolizumab, by blocking PD-1, turns the immune response on very effectively—to the extent that the immune system starts responding also to normal cells, he explains.

Use of epacadostat in combination with pembrolizumab has been tested in several clinical trials of other tumor types, and in particular in patients with melanoma and lung cancer. In these tumor types, the combination of the two immunotherapies doubled the response rates without an increase in side effects, Giaccone says.

Giaccone and his team at Georgetown Lombardi are one of the few groups that conduct both basic and clinical research on thymic carcinoma, which is not only rare but also aggressive.

He says that thymic tumors represent an interesting tumor model because they contain different cancer types with very different prognoses. The least aggressive forms of these tumors likely originate through an initial genetic mutation of a single gene that promotes cancer development, and is associated with less risk. In more aggressive thymic tumors (known as thymic carcinoma), this initial mutation is mainly lost and other mutations are gained that are more commonly seen in other tumor types.

“This is an important process of transformation and progression in a cancer that has a simple genome,” Giaccone says. “Studying this progression might give us a general perspective as to how cancer develops from normal tissue.”