istisociclib (KB-0742)

P1/2, N=280, Recruiting, Kronos Bio | N=170 --> 280

Compound 28 exhibits in vivo antitumor activity in mouse xenograft models and a projected human PK profile anticipated to enable efficacious oral dosing. Notably, 28 is currently being investigated in a phase 1/2 dose escalation and expansion clinical trial in patients with relapsed or refractory solid tumors.

NVP-2, MC180295, fadraciclib, KB-0742, LZT-106, and 21e have been developed mainly for treating solid tumors, and most of them work only on certain genotypes of solid tumors. Only VIP152 has been proven to benefit the patients with advanced high-grade lymphoma (HGL) and solid tumors in clinical trials. Continued efforts to explore the molecular mechanisms underlying the inhibitory effects, and to identify suitable tumor genotypes and combination treatment strategies, are crucial to demonstrate the efficacy of selective CDK9 inhibitors and degraders in tumor therapy.

P1/2, N=170, Recruiting, Kronos Bio | Phase classification: P1 --> P1/2 | N=120 --> 170 | Trial completion date: Mar 2024 --> Dec 2025 | Trial primary completion date: Nov 2023 --> Dec 2025

To demonstrate the utility of a selective CDK9 inhibitor for treatment of hematologic patients with an unmet medical need such as high-grade B cell lymphoma (HGBL) and chronic lymphocytic leukemia who relapse or are refractory to ibrutinib and venetoclax (R/R CLL)...Differential expression (DE) analysis from VIP152, atuveciclib and KB-0742 treatment of 2 lymphoma cell lines by RNA seq is compared to DE of samples from 7 VIP152 treated HGBL patients...With high ATP, VIP152, AZD4573 and alvocidib maintain potency in low nM range, while fadraciclib and KB-0742 have 760 nM-1.7 µM IC50s...Selective transcriptional downregulation is observed with 30mg IV weekly. Samples from patients with DLBCL or CLL are sensitive to VIP152 and updated PK, PD and ctDNA dynamics from the ongoing phase 1 trials (NCT02635672, NCT04978779) will be presented.

The tumor growth inhibition (TGI) rate ranged from 54% to 92%, with tumor regressions observed in 2 of the 4 models, and 1 model showed greater TGI with KB-0742 than the SOC.These data support the development of KB-0742 as a potential treatment for SCLC. Patients with relapsed or refractory solid tumors or non-Hodgkin lymphoma are currently being enrolled in a phase 1/2 clinical trial of KB-0742 (NCT04718675) with an expansion arm for SCLC being planned after the recommended phase 2 dose is identified.

The dose-escalation phase is opened to relapsed or refractory solid tumors or non-Hodgkin lymphoma. Once a recommend phase 2 dose is determined, we plan to open dedicated expansion arms enrolling patients with MYC over-expression/amplification within the tumor types supported by these studies.

"Tempus...today announced six abstracts accepted for poster sessions at the 2021 San Antonio Breast Cancer Symposium (SABCS) taking place December 7 - 10. The presented findings highlight the unique insights that Tempus’ data and smart diagnostics generate to advance breast cancer research."

Broad inhibition of cyclin dependent kinases (CDK) and associated alternative target enzymes with agents such as flavopiridol or dinaciclib have demonstrated significant clinical activity in CLL but are hindered by a relatively narrow therapeutic window...Kinase profiling revealed the IC 50 of VIP152 was lowest for CDK9/Cyclin T1 and CDK9/Cyclin T2 with close similarity to dinaciclib and greater than 1 log superiority over KB-0742... Our data demonstrate VIP152 to be a highly selective and potent CDK9 inhibitor that disrupts the CDK9 nuclear complex and mediates significant preclinical activity against CLL cell lines and primary CLL cells. VIP152 also demonstrates predictable and new pharmacodynamic markers to assess target engagement. Collectively, these data support the recently initiated CLL clinical trial (NCT04978779).

KB-0742 demonstrated cytostatic and cytotoxic effects on cell growth and superior inhibitory effects on cell growth in the TNBC organoid cultures as compared with paclitaxel and gemcitabine. These data demonstrate the efficacy of KB-0742 in preclinical models of breast cancer and supports clinical testing in TNBC patients. KB-0742 is currently being evaluated in a phase I dose-escalation trial in patients with relapsed or refractory solid tumors or non-Hodgkin lymphoma (NCT04718675).

In 22Rv1 cells, KB-0742 rapidly downregulates nascent transcription, preferentially depleting short half-life transcripts and AR-driven oncogenic programs. In vivo, oral administration of KB-0742 significantly reduced tumor growth in CRPC, supporting CDK9 inhibition as a promising therapeutic strategy to target AR dependence in CRPC.