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2967 A Phase I/II Study (JACKPOT8) of DZD4205, a Selective JAK1 Inhibitor, in Refractory or Relapsed Peripheral T- Cell Lymphoma

Program: Oral and Poster Abstracts
Session: 624. Hodgkin Lymphoma and T/NK Cell Lymphoma—Clinical Studies: Poster III
Hematology Disease Topics & Pathways:
Biological, Diseases, Non-Biological, Therapies, Non-Hodgkin Lymphoma, T-Cell Lymphoma, Lymphoid Malignancies, Clinically relevant, pharmacology, TKI
Monday, December 7, 2020, 7:00 AM-3:30 PM

Won-Seog Kim1*, Dok-Hyun Yoon, MD, PhD2*, Hyeon-Seok Eom3*, Youngil Koh, MD, PhD4, Jae-Yong Kwak5, Won-Sik Lee6, Jong-Seok Lee7*, Ho-Jin Shin8*, Yuqin Song, MD, PhD9*, Haiyan Yang, MD, PhD10*, Mei Wang11*, Jingrun Li, MD, PhD11*, Xubin Huang11*, Xueyuan Deng11*, Kan Chen11*, Zhenfan Yang11* and Jun Zhu12

1Department of Hematology and Oncology, Samsung Medical Center, Seoul, Korea, Republic of (South)
2Department of Oncology, Hematologic Cancer & BMT center, Asan Medical Center, Seoul, Korea, Republic of (South)
3Center for Hematologic Malignancy, National Cancer Center, Goyang, Korea, Republic of (South)
4Department of Internal Medicine, Seoul National University Hospital, Seoul, South Korea
5Department of Hematology and Oncology, Chonbuk National University Hospital, Jeonju, Korea, Republic of (South)
6Department of Hematology and Oncology, Inje University Busan Paik Hospital, Busan, Korea, Republic of (South)
7Division of Hematology & Medical Oncology, Seoul National University Bundang Hospital, Seoul, Korea, Republic of (South)
8Department of Internal Medicine, Pusan National University Hospital, Busan, Korea, Republic of (South)
9Department of Lymphoma, Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Peking University Cancer Hospital & Institute, Beijing, China
10Department of Lymphoma, Zhejiang Cancer Hospital, Hangzhou, China
11Dizal Pharmaceuticals, Shanghai, China
12Department of Lymphoma, Beijing Cancer Hospital, Beijing, China

Background: Peripheral T-Cell Lymphoma (PTCL) is an aggressive malignancy which lacks effective treatment. Emerging data suggests that the JAK-STAT pathway may play an important role in mediating pathogenesis of PTCL. DZD4205 (AZD4205) is an orally available, potent and highly selective JAK1 inhibitor. In T-cell lymphoma cell lines, DZD4205 modulates pSTAT3 pathway and suppresses cell proliferation, and in tumor xenograft models, DZD4205 exhibits dose-dependent anti-tumor activities, with good correlation with drug exposure and modulations of pSTAT3 in tumor tissues. A phase I/II study (JACKPOT8) was initiated to assess the safety, tolerability, pharmacokinetics and anti-tumor efficacy of DZD4205 in patients with refractory/relapsed (r/r) PTCL.

Methods: The JACKPOT8 study (ClinicalTrials.gov Identifier: NCT04105010) included two parts: Part A, dose escalation and Part B, dose expansion. In Part A, patients with r/r PTCL who have progressed on or were refractory to systemic therapy will be enrolled and treated with DZD4205 at two different dose levels, 150 mg or 250 mg once daily. In Part B, patients will receive DZD4205 treatment at a defined dose. The primary objective is to assess the safety and tolerability of DZD4205, and the secondary objectives include anti-tumor efficacy and pharmacokinetics. Evaluation of safety/tolerability and tumor response will be based on the CTCAE version 5.0 and 2014 Lugano classification, respectively. Patients will be treated until disease progression, intolerance to adverse events, or withdrawal of consent.

Results: As of June 30, 2020, a total of 23 patients with r/r PTCL were enrolled and received DZD4205 at 150 mg (n = 19) or 250 mg (n = 4) once daily. Patient characteristics: median age (range): 65.0 years (34-79); median prior systemic therapies (range): 2 lines (1-8). Four patients had undergone prior hematopoietic stem cell transplantation (HSCT). Six patients had bone marrow involvement at the study entry. Histological subtypes included peripheral T-cell lymphoma not otherwise specified (PTCL-NOS) (n = 10, 43.5%), angioimmunoblastic T-cell lymphoma (AITL) (n = 10, 43.5%), ALK-negative anaplastic large cell lymphoma (ALCL ALK-) (n = 2, 8.7%) and extra-nodal nasal NK/T-cell lymphoma (NKTCL) (n = 1, 4.3%) .

Preliminary data showed that 20 patients experienced treatment emergent adverse events (TEAEs), among whom 13 (56.5%) had ≥ grade 3 TEAEs. Based on local investigators’ assessment, eight patients (34.8%) had ≥ grade 3 TEAEs which were considered to be related to DZD4205. The most common (> 5% incidence) DZD4205-related TEAEs (any grade) included thrombocytopenia (n = 6, 26.1%), neutropenia (n = 4, 17.3%), decreased appetite (n = 3, 13.0%), nausea (n = 2, 8.7%), interstitial lung disease (n = 2, 8.7%) and pneumonia (n = 2, 8.7%). Most TEAEs were manageable with dose interruption and reduction.

Preliminary PK data is available in 20 patients (n = 19 at 150 mg, n = 1 at 250 mg). Exposure at 250 mg is higher than 150 mg following a single and multiple dose. As expected from long t1/2 of DZD4205, accumulation of about 3 folds in AUC was observed. DZD4205 had flat PK profile with small difference between Css,max and Css,min after 22 days of once daily dosing, which is an optimal PK profile to maintain DZD4205 concentrations above effective levels throughout the dosing interval.

As of June 30, 2020, 22 patients (n = 19 at 150 mg, n = 3 at 250 mg) had at least one post-treatment Lugano assessment. In 150 mg cohort, 8 out of 19 patients showed tumor response, with objective response rate (ORR) of 42%, among whom 4 (21%) had complete response (CR) and another 4 (21%) partial response (PR). In 250 mg cohort, 1 out of 3 patients showed tumor response, with ORR of 33%. Tumor response was observed in subtypes including AITL, PTCL-NOS, ALCL (ALK-) and NKTCL. At the data cut-off date, the longest duration on treatment was > 8 months. Patient enrolment is ongoing. Updated clinical data will be shared at the meeting.

Conclusion: DZD4205 shows good tolerability, pharmacokinetic profiles and promising anti-tumor efficacy in patients with r/r PTCL, indicating its potential as a therapeutic option for this unmet medical need.

Disclosures: Kim: Donga: Research Funding; Kyowa-Kirin: Research Funding; Roche: Research Funding; Johnson&Johnson: Research Funding; Celltrion: Research Funding; Mundipharma: Research Funding. Yoon: Celltrion: Honoraria; Samyang: Research Funding; Amgen, Chongkundang, Celgene, Astrazeneca: Consultancy. Wang: Dizal Pharmaceuticals: Current Employment. Li: Dizal Pharmaceuticals: Current Employment. Huang: Dizal Pharmaceuticals: Current Employment. Deng: Dizal Pharmaceuticals: Current Employment. Chen: Dizal Pharmaceuticals: Current Employment. Yang: Dizal Pharmaceuticals: Current Employment.

*signifies non-member of ASH