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PDF file - 83K, JAK1 and JAK3 mutation status in NKTCL cases

PDF file - 110K, Non-synonymous somatic mutations identified in the Discovery set of four NKTCL cases

PDF file - 75K, Sequence analysis summary of tumor and blood samples from four NKTCL cases

PDF file - 74K, Primer sets used for Sanger sequencing and HRM analysis

PDF file - 185K, Representative HRM curves of a NKTCL case confirmed as heterozygous JAK3A573V mutation

Supplementary Figure from Co-Targeting of MDM2 and CDK4/6 with Siremadlin and Ribociclib for the Treatment of Patients with Well-Differentiated or Dedifferentiated Liposarcoma: Results from a Proof-of-Concept, Phase Ib Study

Purpose:Well-differentiated (WDLPS) and dedifferentiated (DDLPS) liposarcoma are characterized by co-amplification of the murine double minute-2 (MDM2) and cyclin-dependent kinase-4 (CDK4) oncogenes. Siremadlin, a p53–MDM2 inhibitor, was combined with ribociclib, a CDK4/6 inhibitor, in patients with locally advanced/metastatic WDLPS or DDLPS who had radiologically progressed on, or despite, prior systemic therapy.Patients and Methods:In this proof-of-concept, phase Ib, dose-escalation study, patients received siremadlin and ribociclib across different regimens until unacceptable toxicity, disease progression, and/or treatment discontinuation: Regimen A [4-week cycle: siremadlin once daily (QD) and ribociclib QD (2 weeks on, 2 weeks off)], Regimen B [3-week cycle: siremadlin once every 3 weeks; ribociclib QD (2 weeks on, 1 week off)], and Regimen C [4-week cycle: siremadlin once every 4 weeks; ribociclib QD (2 weeks on, 2 weeks off)]. The primary objective was to determine the maximum tolerated dose (MTD) and/or recommended dose for expansion (RDE) of siremadlin plus ribociclib in one or more regimens.Results:As of October 16, 2019 (last patient last visit), 74 patients had enrolled. Median duration of exposure was 13 (range, 1–174) weeks. Dose-limiting toxicities occurred in 10 patients, most of which were Grade 3/4 hematologic events. The RDE was siremadlin 120 mg every 3 weeks plus ribociclib 200 mg QD (Regimen B). Three patients achieved a partial response, and 38 achieved stable disease. One patient (Regimen C) died as a result of treatment-related hematotoxicity.Conclusions:Siremadlin plus ribociclib demonstrated manageable toxicity and early signs of antitumor activity in patients with advanced WDLPS or DDLPS.

Supplementary Data from Co-Targeting of MDM2 and CDK4/6 with Siremadlin and Ribociclib for the Treatment of Patients with Well-Differentiated or Dedifferentiated Liposarcoma: Results from a Proof-of-Concept, Phase Ib Study

The molecular pathogenesis of natural killer/T-cell lymphoma (NKTCL) is not well understood. We conducted whole-exome sequencing and identified Janus kinase 3 (JAK3) somatic–activating mutations (A572V and A573V) in 2 of 4 patients with NKTCLs. Further validation of the prevalence of JAK3 mutations was determined by Sanger sequencing and high-resolution melt (HRM) analysis in an additional 61 cases. In total, 23 of 65 (35.4%) cases harbored JAK3 mutations. Functional characterization of the JAK3 mutations support its involvement in cytokine-independent JAK/STAT constitutive activation leading to increased cell growth. Moreover, treatment of both JAK3-mutant and wild-type NKTCL cell lines with a novel pan-JAK inhibitor, CP-690550, resulted in dose-dependent reduction of phosphorylated STAT5, reduced cell viability, and increased apoptosis. Hence, targeting the deregulated JAK/STAT pathway could be a promising therapy for patients with NKTCLs. Significance: Gene mutations causing NKTCL have not been fully identified. Through exome sequencing, we identified activating mutations of JAK3 that may play a significant role in the pathogenesis of NKTCLs. Our findings have important implications for the management of patients with NKTCLs. Cancer Discov; 2(7); 591–7. ©2012 AACR. This article is highlighted in the In This Issue feature, p. 569.

Background: Well-differentiated/dedifferentiated liposarcoma (WDLPS/DDLPS) is characterized by a consistent coamplification of human double minute 2 homolog (HDM2) and cyclin-dependent kinase 4 (CDK4) which inactivates the tumor suppressor pathways p53 and Rb, respectively. HDM201 is a selective inhibitor of the p53-HDM2 interaction and ribociclib is a CDK4/6 inhibitor. Preclinical studies suggested a synergy in in vitro and in vivo models of WDLPS/DDLPS and both agents have demonstrated single-agent clinical activity in solid tumors. We aim to determine the optimal dose and regimen of HDM201 + ribociclib and to assess the preliminary antitumor activity of this combination in patients (pts) with liposarcoma. Methods: In this multicenter, open-label, Phase Ib ongoing study, pts with locally advanced or metastatic liposarcoma that had unequivocally progressed on, or despite prior systemic therapy were treated orally with HDM201 + ribociclib. Three treatment regimens were explored: Regimen (Reg) 1 (HDM201 + ribociclib daily for the first 2 wks [QD 1st 2 wks] in a 4-wk cycle), Reg 4 (HDM201 every 3 wks + ribociclib QD 1st 2 wks in a 3-wk cycle), and Reg 5 (HDM201 every 4 wks + ribociclib QD 1st 2 wks in a 4-wk cycle). Results: As of Nov 21, 2017, 74 pts received HDM201 + ribociclib (Reg 1 n=26; Reg 4 n=29; Reg 5 n=19); 12 pts (6 each in Reg 4 and 5) were still receiving treatment. Ten pts (Reg 1 n=3; Reg 4 n=6; Reg 5 n=1) discontinued treatment due to adverse events (AEs) and 2 pts (1 each in Reg 4 and 5) died. The most common AE of any grade, regardless of cause, reported across regimens (Reg 1; Reg 4; Reg 5) was nausea (81%; 76%; 63%) which was mainly Grade 1/2 and not dose limiting. Common Grade 3/4 AEs regardless of cause included neutropenia (39%; 52%; 42%), thrombocytopenia (35%; 45%; 42%), anemia (27%; 17%; 21%), leukopenia (27%; 28%; 37%), and lymphopenia (15%; 14%; 21%). Dose-limiting toxicities were reported in 16 pts (2; 9; 5) and all except 1 (prolonged QT) were hematologic (including neutropenia [n=5], thrombocytopenia [n=4], febrile neutropenia, and anemia [n=2 each]). Partial responses were observed in 3 (4%) pts (2 in Reg 4; 1 in Reg 5). Stable disease was achieved by 36 (49%) pts (11 in Reg 1; 16 in Reg 4; 9 in Reg 5). The median progression-free survival (PFS) was 2.7 mo (95% confidence interval [CI]: 1.9-8.2 mo) in Reg 1, 4.8 mo (95% CI: 3.9 mo-not reached) in Reg 4, and 2.1 mo (95% CI: 1.4 mo-not reached) in Reg 5. Conclusions: HDM201 + ribociclib demonstrated a manageable safety profile and preliminary efficacy in pts with locally advanced or metastatic WDLPS/DDLPS, with hematologic toxicities being dose limiting. The median PFS in Reg 4 compares favorably with single-agent CDK4 inhibitors and, alongside a tolerable safety profile, suggests further exploration of this regimen may be warranted in Phase II studies of HDM201 + ribociclib in this patient population. Citation Format: Albiruni Abdul Razak, Sebastian Bauer, Jean-Yves Blay, Richard Quek, Cristina Suárez, Chia-Chi Lin, Marie L. Hütter-Krönke, Ricardo Cubedo, Stephane Ferretti, Christophe Meille, Ensar Halilovic, Giorgia Clementi, Maria Santos-Rosa, Nelson Guerreiro, Astrid Jullion, Claire Fabre, Antoine Italiano. Results of a dose- and regimen-finding Phase Ib study of HDM201 in combination with ribociclib in patients with locally advanced or metastatic liposarcoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr CT009.