Background: Insights into molecular biology and signaling pathways have led to the development of innovative therapeutic strategies to treat B-cell malignacies. In R/R CLL, targeted agents including Bruton tyrosine kinase inhibitors (BTKi) and B-cell lymphoma 2 inhibitors (Bcl-2i) have emerged as new standard of care (Ghia, 2019; Seymour, 2018). More recently, the combination of these two agents has shown impressive and synergistic clinical results with significantly higher complete response (CR) rates reported compared with either agent alone (Jain, 2019). This combination leverages the ability of BTKi to mobilize and egress malignant B-cells from the protective tumor microenvironment and to disrupt cell adhesion-mediated resistance; thereby increasing B-cell sensitivity to novel pro-apoptotic mechanisms (e.g. Bcl-2i).
KRT-232 is a potent and highly selective second-generation inhibitor of MDM2 which rapidly activates p53 to induce apoptosis in malignant hematopoetic stem cells and progenitor cells. Studies in CLL and DLBCL cell lines showed MDM2i overcame Bcl-2 overexpression leading to induction of apoptosis through the upregulation of p21, BAX, and PUMA and downregulation of Bcl-xL (Drakos, 2011; Ciardullo, 2019). As such, targeting the p53-driven apoptotic pathway may be a novel mechanism, independent of Bcl-2 inhibition, to treat B-cell malignacies. KRT-232-driven apoptosis requires tumor cells to express the wild-type encoding p53 gene (TP53WT) found in ~60% and ~80% of pts with R/R CLL and R/R DLBCL, respectively (Miao, 2019; Lazarian, 2017).
Acalabrutinib is a potent and highly selective second-generation inhibitor of BTK with established efficacy in R/R CLL and an improved safety profile (Ghia, 2020). In pts with R/R DLBCL, acalabrutinib monotherapy was well tolerated and demonstrated promising clinical activity (24% overall response rate [ORR], 19% CR; Dyer 2018). Aberrant signaling through BTK drives malignant B-cell proliferation, trafficking and sequestering into protective niches causing lymphadenopathy. BTK signaling plays a critical role in CXCR4-CXCL12 driven chemotaxis and integrin-mediated adhesion. Stromal interactions within the protective microevironment have been associated with aberrant B-cell proliferation, treatment resistance and protection against apoptosis (Montresor, 2018).
The combinination of KRT-232, a novel cell-death pathway agent, with acalabrutinib, a selective and potent cell trafficking modulator, has the potential to demonstrate synergistic clinical activity across a broad range of B-cell malignancies with a differentiated safety profile compared with similar targeted combinations. To this effect, nonclinical synergy has been demonstrated with combinations of MDM2i and BTKi in CLL (Voltan, 2016) and DLBCL (Gu, 2019).
Study Design and Methods:
KRT-232 + acalabrutinib is being evaluated in a Phase 1b-2 open-label, global, multicenter study in pts with R/R TP53WT DLBCL (Cohort 1) or R/R TP53WT CLL (Cohort 2; Figure). Pts aged ≥18 years with histologically confirmed disease and ECOG PS of 0-2 will be enrolled. Pts with known CNS involvement, prior exposure to MDM2i or BTKi and recent prior therapy (anticancer treatment <28 days [d], allogenic stem cell transplantation [SCT] <6 mo, autologous SCT <3 mo) are excluded.
Phase 1b will determine the maximum tolerated dose and recommended phase 2 dose (RP2D) for KRT-232 in combination with standard dose of acalabrutinib (100 mg BID) using a 3+3 dose escalation design (Figure). KRT-232 will be administered d1-7 of 28-d cycles with 3-6 pts per dose level. Phase 2 will include expansion arms (Cohort 1: N≈40; Cohort 2: N=19) where pts will be treated with the RP2D of KRT-232 + acalabrutinib. For phase 2, the primary end points are CR (Cohort 1) and CR/CR with incomplete hematologic recovery (Cohort 2). Secondary end points include ORR, duration of response, MRD (Cohort 2 only), PFS, OS, safety/tolerability, and pharmacokinetics. [NCT04502394].
Hillmen:F. Hoffmann-La Roche: Honoraria, Research Funding; Astra Zeneca: Honoraria; Gilead: Research Funding; AbbVie: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company), Research Funding, Speakers Bureau; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company), Research Funding, Speakers Bureau; Pharmacyclics: Research Funding. Qamoos:Kartos Therapeutics: Current Employment, Current equity holder in private company. Uyei:Kartos Therapeutics: Current Employment. Rothbaum:Quogue Capital: Current Employment; Iovance Biotherapeutics: Current equity holder in publicly-traded company, Membership on an entity's Board of Directors or advisory committees; Acerta Pharma: Current equity holder in private company; Kartos Therapeutics: Current equity holder in private company, Membership on an entity's Board of Directors or advisory committees, Patents & Royalties; Telios Pharma: Current equity holder in private company, Membership on an entity's Board of Directors or advisory committees, Patents & Royalties; Quogue IP Holdings: Patents & Royalties. Jurczak:Roche: Research Funding; Takeda: Research Funding; Pharmacyclics: Research Funding; MeiPharma: Research Funding; Janssen: Research Funding; Bayer: Research Funding; Acerta: Research Funding; Jagiellonian University, Krakow, Poland: Ended employment in the past 24 months; Maria Sklodowska-Curie National Research Institute of Oncology, Krakow, Poland: Current Employment; TG Therapeutics: Research Funding. Thieblemont:Kite, a Gilead Company: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company); Roche: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company), Research Funding; Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: travel support; Bristol-Myers Squibb: Consultancy, Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company); Amgen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company); Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company); AbbVie: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company); Cellectis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company), Speakers Bureau; Incyte: Honoraria; Bayer: Honoraria; Hospira: Research Funding. Byrd:Vincera: Research Funding; Novartis: Research Funding; Trillium: Research Funding; Leukemia and Lymphoma Society: Other; Janssen: Consultancy; Pharmacyclics LLC, an AbbVie Company, Gilead, TG Therapeutics, BeiGene: Research Funding; Pharmacyclics LLC, an AbbVie Company, Gilead, TG Therapeutics, Novartis, Janssen: Speakers Bureau; Pharmacyclics LLC, an AbbVie Company, Janssen, Novartis, Gilead, TG Therapeutics: Other; Acerta Pharma: Research Funding; Syndax: Research Funding; Kartos Therapeutics: Research Funding.
KRT-232 is an investigational small molecule MDM2 inhibitor. This trial-in-progress abstract describes a clinical trial that will evaluate the safety and efficacy of KRT-232 + acalabrutinib for patients with R/R DLBCL or R/R CLL.
