On June 4, 2021 Constellation Pharmaceuticals, Inc. (Nasdaq: CNST), a clinical-stage biopharmaceutical company using its expertise in epigenetics to discover and develop novel therapeutics, reported in a poster presentation preliminary data from the ongoing Phase 1/2 trial of CPI-0209, a novel, second-generation, small molecule inhibitor of Enhancer of Zeste Homolog 2 (EZH2) (Press release, Constellation Pharmaceuticals, JUN 4, 2021, View Source [SID1234583530]). These data were published online in conjunction with the American Society of Clinical Oncology (ASCO) (Free ASCO Whitepaper) Annual Meeting, and show comprehensive target engagement and durable exposure of CPI-0209. Anti-tumor activity of CPI-0209 in pre-clinical models was demonstrated across several advanced hematologic and solid tumor types.

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"We designed CPI-0209 to improve on first-generation EZH2 inhibitors in a number of ways, including increased potency, long residence time on target, and a lack of auto-induction of metabolism. These enhancements translate in the clinic, which we believe will be key to unlocking the full therapeutic potential of EZH2 inhibition," said Jigar Raythatha, president and chief executive officer of Constellation Pharmaceuticals. "I am also pleased that dosing is under way in our Phase 2 expansion cohorts at the selected dose."

Preliminary Data Highlights

A total of 40 patients were treated across 14 tumor types.
A 350mg oral, once-daily dose of CPI-0209 has been selected for evaluation in Phase 2.
As of the data cut of March 9, 2021, of the 4 BAP1 loss mesothelioma patients, 1 patient had a durable partial response (PR) after four cycles of treatment and 2 had stable disease (SD). Subsequently, to the data cut, the fourth patient also had SD.
High levels of target engagement observed preclinically are now corroborated clinically.
Safety

A total of 40 patients were evaluated for safety. CPI-0209 was generally well tolerated, with a manageable adverse event profile. Across all dose cohorts, 43% of patients had at least one Grade 3 or greater treatment emergent adverse event (TEAE), 28% of patients had at least one serious adverse event (SAE). The most common TEAEs (≥ 15%) included thrombocytopenia (reversible and dose dependent), diarrhea, asthenic conditions, nausea, anemia, dysgeusia, abdominal pain and alopecia. 23% of patients reported a TEAE that led to dose reduction or interruption. Four patients discontinued treatment because of TEAEs. One patient in the highest dose cohort (375mg) experienced Grade 4 thrombocytopenia, and one patient experienced a Grade 5 adverse event due to progressive disease.

For further details, please view the ASCO (Free ASCO Whitepaper) poster.

ASCO Poster Presentation

TITLE: Phase 1/2 First-in-Human Study of CPI-0209, a Novel Small Molecule Inhibitor of Enhancer of Zeste Homolog 2 (EZH2) in Patients with Advanced Tumors (Abstract Code 3104)

About CPI-0209

CPI-0209 is a second-generation EZH2 inhibitor designed to achieve comprehensive target coverage through extended on-target residence time and enhanced potency compared with first-generation EZH2 inhibitors. These features lead to faster onset and a more comprehensive on-target action than first-generation EZH2 inhibitors, as well as robust anti-tumor activity in models of multiple hematologic and solid cancer types.

About CPI-0209 clinical trial

The Phase 1 portion of the CPI-0209 Phase1/2 clinical trial is an open label, dose escalation study in patients with advanced tumors. A total of 41 patients were enrolled, of which 40 patients received CPI-0209. The primary objective of the Phase 1 portion is to evaluate safety and determine the recommended Phase 2 dose of CPI-0209.

The Phase 2 portion is an open label, single arm study, currently enrolling 20 to 29 patients per cohort in the following tumor types: relapsed urothelial carcinoma, relapsed ovarian clear cell carcinoma, and relapsed endometrial carcinoma all with known ARID1A mutation; relapsed or refractory lymphomas; malignant pleural or peritoneal mesothelioma with known BAP1 loss; as well as metastatic castration-resistant prostate cancer. The goal of these cohorts is to establish the safety and the antitumor activity of CPI-0209 as a monotherapy for patients with these tumor types.