Constellation’s Epigenetic Inhibitors Show Early Signs of Activity in Advanced Lymphoma Patients

Constellation’s Epigenetic Inhibitors Show Early Signs of Activity in Advanced Lymphoma Patients

Two investigative compounds targeting epigenetic DNA modification have shown encouraging preliminary activity in B-cell lymphoma patients, according to results from two Phase 1 trials. The inhibitors, called CPI-1205 and CPI-0610, were found to be safe and well tolerated, with no treatment-related serious adverse effects.

The findings were recently presented at the TAT International Congress 2018 in Paris. The posters were titled, “A phase 1 study of CPI-1205, a small molecule inhibitor of EZH2, preliminary safety in patients with B-cell lymphomas” and “A phase I study of CPI-0610, a bromodomain and extra terminal protein (BET) inhibitor in patients with relapsed or refractory lymphoma.”

Under development by Constellation Pharmaceuticals, CPI-1205 and CPI-0610 belong to a class of compounds called epigenetic inhibitors, which affect gene expression. While CPI-1205 blocks the activity of the EZH2 enzyme, CPI-0610 inhibits BET proteins.

EZH2 is known to prevent the production of proteins that act as breaks for cancer progression, whereas BET proteins promote cancer growth by enabling the production of pro-cancer signaling molecules. Both EZH2 and BET are often mutated in cancer and linked to poor prognosis.

Previous studies testing similar epigenetic inhibitors have demonstrated that they target rare and aggressive leukemia, lymphoma, and solid cancer cells, providing proof-of-concept for this approach. However, these compounds have been linked to unwanted adverse events, which may limit their administration. In addition, their real clinical impact has not yet been fully revealed.

“Compounds approved for lymphoma in the last five years had single-agent Phase-1 response rates above 30%, but activity with BET inhibitors is less than 30%,” Anastasios Stathis, head of new drugs development at the Oncology Institute of Southern Switzerland, said in a press release. “The hope is to identify the patients that would benefit most and test BET inhibitors in combination with other compounds. In addition, there are new classes of BET inhibitors in preclinical studies and we need to wait to see if they have better activity.”

In an ongoing Phase 1 trial (NCT02395601), researchers evaluated the safety and tolerability of CPI-1205. The study included 32 adult patients, of whom 17 had diffuse large B-cell lymphoma, four had follicular lymphoma, two had marginal zone lymphoma, and nine had other lymphoma subtypes. All had failed to respond to prior therapy.

Participants randomly received one of four CPI-1205 oral doses — 200, 400, 800, or 1,600 mg — twice daily.

In general, the investigational therapy was well-tolerated and safe. The most common treatment-related adverse events included nausea, decreased lymphocyte count, anemia, fatigue, and hypertension, which were all considered manageable.

Early analysis revealed that one patient experienced tumor clearance (a complete response) after six treatment cycles, and five patients showed no signs of cancer progression. These findings supported the study’s extension to include a group receiving 800 mg twice daily, followed by dosing three times a day.

“If approved by health authorities, EZH2 inhibition may become a new treatment paradigm in relapse or refractory EZH2 mutant follicular lymphoma patients,” said Adrian Senderowicz, senior vice president and chief medical officer at Constellation Pharmaceuticals, and co-author of the study.

A second Phase 1 trial (NCT01949883) evaluated Constellation’s BET small molecule inhibitor CPI-0610 in 64 patients with relapsed or refractory lymphomas. Participants were randomly included in one of 11 dosing groups ranging from 6 mg to 225 mg, either in capsule or tablet form.

The most frequent treatment-related adverse events were platelet deficiency, fatigue, nausea, decreased appetite, and anemia. The impact on platelet levels was a serious limiting factor previously linked to BET inhibitors.

CPI-0610 showed promising anti-cancer activity in these patients. Two patients experienced complete response, three patients had tumor reduction, and five patients had stable disease for more than six months.

“CPI-0610 is a well-tolerated, oral BET inhibitor that has demonstrated anti-tumor activity in advanced lymphoma patients,” the researchers stated.

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