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1754 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

Program: Oral and Poster Abstracts
Session: 627. Aggressive Lymphomas: Clinical and Epidemiological: Poster I
Hematology Disease Topics & Pathways:
clinical trials, Research, Clinical Research
Saturday, December 9, 2023, 5:30 PM-7:30 PM

Sung-Soo Yoon, MD, PhD1, Zhiming Li2*, Keshu Zhou, MD3*, Xiaoxi Zhou, MD4*, Ye Guo, MD5*, Huilai Zhang, MD6*, Ki-Seong Eom7*, Seok Jin Kim, MD, PhD8, Sung Yong Oh, MD9*, Sung-Nam Lim, MD10*, Hagop Youssoufian, MD11*, Vernon Jiang, PhD12*, Zhanchun Huang11*, Georgina Kilfoil11*, Xin Wang11*, Zhixiang Cao11*, Xiang LI13*, Yihai Lin11*, Alexander Wu, Ph.D.11*, Yiyou Chen, Ph.D.11* and Yuqin Song, MD14

1Seoul National University Hospital, Seoul, South Korea
2Department of Medical Oncology, Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangzhou, China
3Department of Hematology, Affiliated Cancer Hospital of Zhengzhou University, Zhengzhou, China
4Department of Hematology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
5State Key Laboratory of Experimental Hematology, National Clinical Research Center for Blood Diseases, Haihe Laboratory of Cell Ecosystem, Institute of Hematology & Blood Diseases Hospital, Chinese Academy of Medical Sciences&Peking Union Medical College, Tianjin, China
6Tianjin Medical Univ. Cancer Institute & Hospital, CHN, Tianjin, CHN
7Department of Hematology, Catholic Hematology Hospital, Seoul St. Mary's Hospital, College of Medicine, The Catholic University of Korea, Seoul, Korea, Republic of (South)
8Samsung Med. Ctr., Seoul, Korea, Republic of (South)
9Dong-A University Hospital, Busan, Korea, Republic of (South)
10Department of Hematology-Oncology, Inje University Haeundae Paik Hospital, Busan, Korea, Republic of (South)
11Cothera Bioscience, San Mateo,, CA
12Cothera Bioscience, San Mateo, CA
13Cothera Bioscience, BEIJING, China
14Department of Lymphoma, Key laboratory of Carcinogenesis and Translational Research (Ministry of Education), Peking University Cancer Hospital & Institute, BEIJING, China


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).


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.


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/m2/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.


As of 28 July 28, 2023, 3 patients of cohort 1 (3.6 mg/m2/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/m2/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/m2/day) and completed at least one cycle of treatment.


At the time of abstract submission, the 1st cohort (3.6 mg/m2/day) of 3 patients have completed at least four cycles of treatment. PC-002 is generally well-tolerated at 3.6 mg/m2/day and progression to Cohort 2 at a dose of 4.8 mg/m2/ day was approved by the Safety Review Committee. Two patients with relapsed/refractory Burkitt Lymphoma at the starting dose of 3.6 mg/m2/day achieved a confirmed PR. ORR of the 3 patients in Cohort 1 is 66.7% after 2 cycles of 3.6 mg/m2/day (2 PRs). Three patients have been enrolled in Cohort 2 (4.8 mg/m2/day) and completed at least one cycle of treatment to date.

Disclosures: No relevant conflicts of interest to declare.

*signifies non-member of ASH