Study of PC-002 (Sepantronium Bromide), a First-in-Class Inhibitor of Deubiquitinases (DUBs) Targeting Myc Degradation in Relapsed/Refractory c-Myc Rearranged High-Grade B Cell Lymphoma (HGBCL): Updated Phase 2 Results
Authors: Yoon Sung-Soo , Li Zhiming , Kim Seokjin , Eom Ki-Seong , Zhou Keshu , Lim Sung-Nam , Zhou Xiaoxi , Guo Ye , Oh Sung Yong , Zhang Huilai , Youssoufian Hagop , Jiang Vernon , Huang Zanchun , Kilfoil Georgina , Wang Xin , Cao Zhixiang , LI Xiang , Lin Yihai , Wu Alexander , Chen Yiyou , Song Yuqin 
Published: December 2024

Background:
C-Myc rearrangement is a hallmark of high-grade B-cell lymphoma (HGBCL) and Burkitt lymphoma (BL) [1], effective treatment for relapsed/refractory disease represents an unmet need. Previous studies have demonstrated that c-Myc-driven lymphomas can be suppressed via c-Myc inhibition [2]. PC-002 (also known as Sepantronium Bromide, SepB) is a small molecule survivin suppressant with antitumor activity against a variety of tumor types. Recently, we discovered that PC-002 possesses another novel mechanism by targeting Myc-driven cancers [3]. PC-002 inhibits the deubiquitinase activity of ubiquitin-specific proteases (USPs), which leads to Myc protein degradation. This discovery prompted us to initiate this Phase 2 proof-of-concept clinical trial in patients with relapsed/refractory c-Myc rearranged HGBCL, including Burkitt lymphoma (https://clinicaltrials.gov/ct2/show/NCT05263583). Here, we present updated results of safety and efficacy of PC-002 monotherapy for c-Myc rearranged HGBCL, including BL.
Methods:
Patients (Pts) are treated with escalating doses (starting at 3.6 mg/m2/day) of single-agent PC-002 administered by continuous intravenous infusion for 168 hours in 21-day cycles. Cohorts of 3 pts are enrolled at each dose level (DL) for PC-002 with expansion to six pts, if necessary, to assess toxicity. Following the completion of 2 cycles of treatment for each cohort, a Safety Review Committee reviewed the available safety data and made a decision on whether to escalate to the next DL or change the plan. An additional 6 pts will be enrolled at the recommended Phase 2 dose (RP2D). The primary objective was to determine the safety and tolerability and RP2D, with secondary objectives including objective response rate (ORR), duration of response (DoR), clinical benefit rate, overall survival and progression-free survival.
Results:
As of 30 June 2024, 3 pts were enrolled in Cohort 1 at a DL of 3.6 mg/m2/day, 5 pts were enrolled in Cohort 2 at a DL of 4.8 mg/m2/day, and 6 pts were enrolled in the RP2D Cohort and received PC-002 at a DL of 4.8 mg/m2/day. BL pts had received a median of 4 regimens previously. As of the data cut-off date, two pts remain on study and 1 additional patient is to be enrolled to complete the RP2D Cohort. No dose-limiting toxicities (DLT) were observed during the safety run-in period.
Of the 13 pts enrolled as of the data cut-off, 7 (53.8%) were HGBCL and 6 (46.2%) were BL. Eleven of these pts were considered evaluable for efficacy. Responses were observed across HGBCL and BL, with 40.0% ORR in HGBCL, 80.0% in BL, and a disease control rate (DCR) 60.0% in HGBCL, 100.0% in BL. The mean DoR was 27 days in HGBCL, and 94.5 days in BL. The maximum DoR was 138 days in BL with 1 pt who achieved CR maintaining the response at the time of data cut-off.
Conversely, one patient developed progressive disease (PD) at the time of the Cycle 2 response assessment. The patient was then enrolled into an optional salvage rescue phase and received PC-002 in combination with Rituximab (Rit). The patient exhibited stable disease (SD) at Cycle 4 and partial response (PR) at cycle 6 and cycle 8.
Conclusions:
PC-002 monotherapy demonstrated high clinical activity in heavily pretreated BL patients with a good safety profile. Initial successful salvage attempt with the addition of Rit suggests that a SepB-Rit combination will lead to greater clinical benefit, and warrants further clinical investigation of the combination of PC002 with rituximab in patients with relapsed/refractory c-Myc driven Burkitt lymphoma or diffuse large B-cell lymphoma.
References: Alsharif, R. and K. Dunleavy, Burkitt Lymphoma and Other High-Grade B-Cell Lymphomas with or without MYC, BCL2, and/or BCL6 Rearrangements. Hematol Oncol Clin North Am, 2019. 33(4): p. 587-596. Choi, P.S., et al., Lymphomas that recur after MYC suppression continue to exhibit oncogene addiction. Proc Natl Acad Sci U S A, 2011. 108(42): p. 17432-7. Li, X., et al., YM155 inhibits neuroblastoma growth through degradation of MYCN: A new role as a USP7 inhibitor. European Journal of Pharmaceutical Sciences, 2023. 181.