Treatment of Relapsed/Refractory Hgbcl and Bukitt's Lymphoma with c-Myc Rearrangement: A Multi-Center, Open-Label, Phase 2 Study of PC-002 (SepB), a First-in-Class Deubiquitinase Inhibitor Inducing Myc Degradation
Authors: Yoon Sung-Soo , Li Zhiming , Zhou Keshu , Zhou Xiaoxi , Guo Ye , Zhang Huilai , Eom Ki-Seong , Kim Seok Jin , Oh Sung Yong , Lim Sung-Nam , Youssoufian Hagop , Jiang Vernon , Huang Zhanchun , Kilfoil Georgina , Wang Xin , Cao Zhixiang , LI Xiang , Lin Yihai , Wu Alexander , Chen Yiyou , Song Yuqin 
Published: December 2023

Background:
Burkitt lymphoma (BL) is one of the most aggressive B cell malignancies that is a high unmet need and characterized classically by c-Myc rearrangement. However, c-Myc is considered “undruggable” due to its structure and a lack of kinase activity. Degradation of c-Myc is mediated through the ubiquitin-proteasome system. Therefore, modulation of deubiquitination catalysis process may reduce the stability of c-Myc. PC-002 (also known as Sepantronium Bromide, or SepB) is a small molecule previously identified as a survivin suppressant with antitumor activity against a range of tumor types. More recently, we discovered that PC-002 has another novel mechanism of targeting cancers with Myc gene amplification by inhibiting the deubiquitinase activity of ubiquitin-specific proteases (USPs), which leads to Myc protein degradation. Preclinically, PC-002 shortens the half-life of c-Myc protein, induces rapid apoptosis of cells with c-Myc rearrangement, and demonstrates rapid tumor regression in c-Myc-rearranged BL and high grade B cell lymphoma (HGBCL) murine xenograft models. This discovery prompted us to initiate a 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).
Aims:
The aim of this trial ( https://clinicaltrials.gov/ct2/show/NCT05263583) is to study safety and efficacy of PC-002 as monotherapy for c-Myc rearranged HGBCL, including Burkitt Lymphoma.
Methods:
NCT05263583 is a multicenter, open-label, Phase 2 dose-finding study of PC- 002 (Sepantronium Bromide, or SepB) in patients with relapsed/refractory HGBCL and Burkitt's lymphoma with c-Myc rearrangement. Patients will be treated with escalating doses (3.6 and 4.8 mg/m 2/day) of single-agent PC-002 administered by continuous intravenous infusion for 168 hours in 21-day cycles at two dose levels. The primary objective is to determine the safety, tolerability and recommended Phase 2 dose of PC-002. Cohorts of three patients will be enrolled at each dose level for PC-002 with expansion to six patients, if necessary, to assess toxicity. An additional 6 patients will be enrolled at the RP2D. Secondary objectives are Objective Response Rate (ORR), Duration of Response (DoR), Clinical Benefit Rate (CBR), Overall Survival (OS) and Progression-Free Survival (PFS). Exploratory objectives are aimed to measure PC-002 exposure and its relationship to clinical outcome and to assess the relationship between biomarkers and PC-002 efficacy.
Results:
As of 28 July 28, 2023, 3 patients of cohort 1 (3.6 mg/m 2/day) with a median age of 33 years (range 19-67 years) had received ≥ 2 cycles of dosing (A cycle is defined as 7 days of treatment plus 14 days of rest). Two of the patients (2 males) have Burkitt Lymphoma and one (female) has HGBCL (DLBCL-TH). Adverse events deemed related to PC-002 included anemia and neutropenia. No dose-limiting toxicities have been reported. Preliminary assessment by image analysis and Lugano criteria showed partial response (PR) in 2 heavily pre-treated patients with relapsed/refractory BL after receiving 2 cycles of treatment. The duration of response in these two patients was 3 months and patients received at least 4 cycles of treatment. ORR of the 3 patients in Cohort 1 is 66.7% at 3.6 mg/m 2/day dose. To date, 3 patients with a median age of 58 years (range 25-60 years) had been enrolled of cohort 2 (4.8 mg/m 2/day) and completed at least one cycle of treatment.
Summary/Conclusion:
At the time of abstract submission, the 1 st cohort (3.6 mg/m 2/day) of 3 patients have completed at least four cycles of treatment. PC-002 is generally well-tolerated at 3.6 mg/m 2/day and progression to Cohort 2 at a dose of 4.8 mg/m 2/ day was approved by the Safety Review Committee. Two patients with relapsed/refractory Burkitt Lymphoma at the starting dose of 3.6 mg/m 2/day achieved a confirmed PR. ORR of the 3 patients in Cohort 1 is 66.7% after 2 cycles of 3.6 mg/m 2/day (2 PRs). Three patients have been enrolled in Cohort 2 (4.8 mg/m 2/day) and completed at least one cycle of treatment to date.