Arindam Dhar

Abstract CT014: GSK525762, a selective bromodomain (BRD) and extra terminal protein (BET) inhibitor: results from part 1 of a phase I/II open-label single-agent study in patients with NUT midline carcinoma (NMC) and other cancers

Background: GSK525762 is a potent, selective pan-BET inhibitor that abrogates binding of BET family proteins (BRD2, BRD3, BRD4 and BRD-T) to acetylated histones. In pre-clinical models this results in suppression of BET target genes that drive oncogenic pathways, resulting in growth inhibition of cancer cell lines (median IC50 of 50-1698 nM for solid tumors and 50 nM for NMC). GSK525762 is being evaluated clinically for treatment of pts with hematologic malignancies and solid tumors including NMC, a rare, aggressive cancer with few treatment options. NMC is characterized by BRD3-/BRD4-NUT fusion oncoproteins that represents a rational therapeutic target for BET inhibitors. Methods: Primary objectives of Part 1 were to determine safety, tolerability, and maximum tolerated dose (MTD) for GSK525762 in solid tumors, using a combined N-CRM and 3+3 dose escalation. Secondary objectives include PK and PD analysis and preliminary evaluation of activity. Oral once daily (qd) and twice daily (bid) schedules have been evaluated. PD activity was assessed with [18F]-deoxy-glucose-PET scans and changes in cytokine release from LPS-stimulated PBMC of treated pts. The dose-limiting toxicity (DLT) observation period was 28 days. Response evaluation was by RECIST 1.1 and pts were followed to disease progression, discontinuation due to adverse events, withdrawal of consent or death. Results: As of 28-Jan 2016, a total of 70 (including 17 NMC) pts have been treated at doses of 2-100 mg qd and 20 and 30 mg bid. The most common adverse events (all grades, ?20%) observed were thrombocytopenia (44%), nausea (40%), vomiting (29%), anemia (26%), fatigue (26%), decreased appetite (24%), diarrhoea (23%) and dysgeusia (20%). DLTs occurred in 5 pts at doses of 60 mg (n = 1, 11%), 80 mg (n = 3, 14%) and 100 mg (n = 1, 11%). The most common AEs leading to dose interruption were thrombocytopenia and hyperbilirubinemia (each n = 7, 10%). Limited data shows similar tolerability at bid doses. PK was dose-proportional after single and repeat dosing with large between patient variability. Dose dependent inhibition of LPS stimulated BRD regulated cytokine (IL-6, TNF-α, MCP-1, IL-8) release suggests target engagement. Of 11 NMC pts treated at 60-100 mg qd, evaluation is awaited on 1 pt. Of 10 pts evaluated, 2 (20%; 95% CI (2.5%, 56%)) had confirmed PR (15 and 23 weeks) and 4 (40%; 95% CI (12%, 74%)) had SD. An 80mg once-daily dose will be evaluated in NMC and other solid tumor expansion cohorts. Conclusion: GSK525762 is an active, orally bio-available BET inhibitor showing dose-proportional PK and good tolerability up to 80 mg qd dosing. Preliminary evidence of clinical activity observed in pts with NMC provides a rational targeted therapy for this aggressive tumor and proof of concept for BET inhibitors in the clinic. Study funded by GSK (NCT01587703). Citation Format: Peter J. O’Dwyer, Sarina A. Piha-Paul, Christopher French, Sara Harward, Gerladine Ferron-Brady, Yuehui Wu, Olena Barbash, Anastasia Wyce, Meg Annan, Thierry Horner, Nigel J. Parr, Rab K. Prinjha, Christopher Carpenter, Geoffrey Shapiro, Arindam Dhar, Christine Hann. GSK525762, a selective bromodomain (BRD) and extra terminal protein (BET) inhibitor: results from part 1 of a phase I/II open-label single-agent study in patients with NUT midline carcinoma (NMC) and other cancers. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr CT014.

Abstract CT104: A first-in-human phase I dose escalation study of BET inhibitor GSK2820151 in patients with advanced or recurrent solid tumors cancers

Background The Bromodomain (BRD) Extra Terminal (BET) family of proteins (BRD2, 3, 4 and T) contain bromodomains that recognize and bind acetylated histone tails. Binding affects chromatin structure facilitating recruitment of transcriptional complexes to specific genes regulating gene expression and mRNA elongation in a context and signal dependent fashion. BET proteins are involved in regulating transcription, cell growth and survival. Inhibiting BET protein binding to chromatin decreases expression of growth promoting genes and blocks both expression and transcriptional functions of MYC resulting in significant antitumor effects. GSK2820151 is a potent and selective small molecule BET inhibitor. In preclinical studies, GSK2820151 potently inhibited proliferation of several solid tumor cell types in culture and demonstrated efficacy in xenograft models. These data plus understanding derived from the clinical progression of the BET inhibitor GSK525762 in solid (NCT01587703) and hematological (NCT01943851) tumors form the rationale for investigating the therapeutic potential of this structurally differentiated molecule GSK2820151 in a broad array of solid tumor types in this study. Methods 201893 is a first-time in human phase I open-label, dose escalation study to investigate the maximum tolerated dose (MTD) and a recommended phase 2 dose (RP2D) based on the safety, pharmacokinetics (PK), pharmacodynamics, and clinical activity of orally administered GSK2820151 in patients with solid tumors. This study will utilize an accelerated dose titration followed by a conventional 3+3 dose escalation phase to achieve MTD. The dose will be escalated based on PK data, the safety profile of prior cohorts, as well as the predicted dose-limiting toxicity (DLT) rates on all potential doses from the Neuenschwander Continual Reassessment Method (N-CRM) analysis. This is a single-arm study in which all subjects will receive GSK2820151 and will continue treatment until disease progression, unacceptable toxicity, or withdrawal of consent. A subject will be considered to have completed the study 2 years after the last treatment or if the subject dies or is still in follow-up at the time the study is closed or terminated, whichever is sooner. Approximately 30-50 patients will be enrolled. The study population will be adults, with advanced or recurrent, histologically or cytologically confirmed, solid malignancy that is either metastatic or unresectable, who either: o refuse or are not candidates for standard curative or palliative therapy, o have a disease for which no non-investigational therapy exists, OR o have progressed on prior therapy Trial is opened to recruitment and as of January 12, 2017 one patient has been enrolled in the study. The trial is continuing as planned, results will be presented at a later date. ClinicalTrials.gov identifier: NCT02630251 Study is funded by GlaxoSmithKline Citation Format: Shirish Gadgeel, Vicki Keedy, Simon Taylor, Khalid Amin, Thierry Horner, Yuehui Wu, Rab Prinjha, Arindam Dhar, Brandon Kremer. A first-in-human phase I dose escalation study of BET inhibitor GSK2820151 in patients with advanced or recurrent solid tumors cancers [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr CT104. doi:10.1158/1538-7445.AM2017-CT104

Abstract CT038: A phase I, open-label, dose-escalation study to investigate the safety, pharmacokinetics, pharmacodynamics, and clinical activity of GSK3326595 in subjects with solid tumors and non-Hodgkin's lymphoma

Background Protein arginine methyltransferase 5 (PRMT5) is the primary enzyme responsible for symmetric arginine dimethylation of multiple proteins that impact cell proliferation. Its substrates include histones and proteins involved in signal transduction, gene transcription, DNA repair, and mRNA splicing. PRMT5 overexpression occurs in a number of different cancers, and higher expression is correlated with poor prognosis. Additional published data implicates PRMT5 in tumorigenesis, and as such it represents a novel target for therapeutic intervention in oncology. GSK3326595 is a potent, specific, and reversible inhibitor of PRMT5 that inhibits proliferation and induces cell death in a broad range of solid and hematologic tumor cell lines. It also exhibits potent antitumor activity in vivo in animal models. Methods Study 204653 is a Phase I, two-part, open-label, dose escalation/expansion study assessing the safety and tolerability of GSK3326595 in adult subjects with relapsed/refractory solid tumors and non-Hodgkin’s lymphoma. Dose escalation is being performed in subjects with solid tumors of any histology. An accelerated dose titration is employed with one subject per dose level until the occurrence of a ≥ Grade 2 non-disease related toxicity. Thereafter, subjects are enrolled in cohorts of approximately 3, and a modified toxicity probability interval (mTPI) method is used to guide dose escalation decisions. Dose escalation continues until the maximum tolerated dose (MTD) is identified. All data, including safety, tolerability, pharmacokinetics (PK), pharmacodynamics (PD), and clinical activity, will be used to identify a recommended Phase 2 dose (RP2D). In Part 1, approximately 42 subjects are to be enrolled (30 subjects in dose escalation and an additional 12 subjects at or about the MTD to collect additional data, including PD and metabolites); no hypothesis will be tested, and all analysis will be descriptive and exploratory. In Part 2, the clinical activity of GSK3326595 will be evaluated in expansion cohorts of subjects with select tumor types. Based on preclinical data, enrollment is initially limited to subjects with triple-negative breast cancer (TNBC), metastatic bladder cancer (mBC), glioblastoma multiforme (GBM), and non-Hodgkin’s lymphoma (NHL); additional cohorts may be added based on emerging preclinical and clinical data. Two cohorts of NHL are scheduled, allocated by TP53 wild type versus mutant status. Up to 138 subjects may be enrolled in Part 2, and cohorts may be closed early for futility. As of 17 January 2017, recruitment is ongoing across four centers (USA, Canada, Netherlands, and France), and four subjects have been enrolled into the dose-escalation cohorts. ClinicalTrials.gov identifier: NCT02783300 Study is funded by GlaxoSmithKline Citation Format: Drew Rasco, Anthony Tolcher, Lillian L. Siu, Kimberley Heinhuis, Sophie Postel-Vinay, Olena Barbash, Jacqueline L. Egger, Shelby Gorman, Thierry Horner, Arindam Dhar, Brandon E. Kremer. A phase I, open-label, dose-escalation study to investigate the safety, pharmacokinetics, pharmacodynamics, and clinical activity of GSK3326595 in subjects with solid tumors and non-Hodgkin9s lymphoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr CT038. doi:10.1158/1538-7445.AM2017-CT038