Abstract B159: A first-in-human study of CDK9 inhibitor KB-0742 demonstrates evidence of tolerability and clinical activity
Authors: Villalona-Calero Miguel , Mita Monica , Mita Alain , Federman Noah , Rasco Drew , Spigel David , Luo Jia , Hanna Glenn J , Cote Gregory M , Cutler Richard E , Kumar Pavan , MacKenzie Crystal , Lin Charles , DiMartino Jorge F , Olek Elizabeth A , Van Tine Brian 
Published: December 2023

Background: Cyclin-dependent kinase 9 (CDK9) is a transcriptional regulator that mediates expression and downstream activity of oncogenic transcription factors (TFs) including MYC and chimeric TFs. Inhibiting CDK9 presents a promising approach to treat transcriptionally addicted cancers. KB-0742 is a potent, selective, orally bioavailable inhibitor of CDK9 that is currently being studied in a phase 1/2 dose escalation in solid tumors and NHL and cohort expansion for patients with transcription-dependent tumors (NCT04718675).

Methods: KB-0742 is administered orally once daily for 3 consecutive days with 4 days off, weekly, in 28-day cycles until toxicity or disease progression. Eligibility criteria include age &gt; 18 years, relapsed or refractory solid tumors or NHL, acceptable organ function and ECOG PS &lt; 2. Study objectives include evaluation of safety, tolerability, PK, PD, and identification of KB-0742 MTD and RP2D using a modified Continuous Reassessment Method (mCRM).  PK was measured from patient plasma and PD was assessed in peripheral blood mononuclear cells (PBMCs). PD measurements included analysis of phosphorylation of the CDK9 substrate serine 2 of the RNA Polymerase II C-terminal domain (pSER2), and changes in gene expression of prospectively defined CDK9 responsive genes.

Results: As of 1 June 2023, 28 patients enrolled in dose escalation up to 60 mg. Patients had received a median of 4 (2-11) prior lines of therapy and remained on KB-0742 for a median of 86 days (10-311+). Twelve of 28 patients received at least 4 cycles of KB-0742. The most common tumor types enrolled were colorectal (5), chordoma (4), sarcoma (4), and breast (3). Treatment-emergent adverse events (TEAEs) occurring in &gt;20% of patients included nausea, vomiting, anemia, fatigue, nervous system disorders, and peripheral edema. The most common reasons for treatment discontinuation were progressive disease, TEAEs, and withdrawal of consent. Across 4 dose levels, AUC and Cmax of KB-0742 increased linearly with a terminal half-life of 24 hours. At 60 mg, evidence of target engagement was observed by pSER2 reduction and proportional changes to CDK9 responsive genes. In the escalation phase 60 mg cohort, three patients, (2 colorectal and 1 PTCL) had MYC over-expressing tumors and achieved SD. Of the two patients with myxoid liposarcoma, both exhibited radiographic regression of their target lesions. One patient achieved 26% reduction in the sum of partial diameters lasting &gt; 5 mos. The second patient achieved a RECIST 1.1 partial response and remains on treatment at &gt; 12 mos. Consistent with the therapeutic hypothesis, both patients had TF fusions.

Conclusions: KB-0742 treatment was well tolerated with manageable toxicity and no evidence of neutropenia. CDK9 inhibition was observed at the 60 mg dose level, and expansion cohorts in tumor types with a high prevalence of MYC amplification or overexpression and other transcriptionally addicted tumors are accruing. The MTD has not been reached and further dose escalation is continuing.

Citation Format: Miguel Villalona-Calero, Monica Mita, Alain Mita, Noah Federman, Drew Rasco, David Spigel, Jia Luo, Glenn J Hanna, Gregory M Cote, Richard E Cutler, Pavan Kumar, Crystal MacKenzie, Charles Lin, Jorge F DiMartino, Elizabeth A Olek, Brian Van Tine. A first-in-human study of CDK9 inhibitor KB-0742 demonstrates evidence of tolerability and clinical activity [abstract]. In: Proceedings of the AACR-NCI-EORTC Virtual International Conference on Molecular Targets and Cancer Therapeutics; 2023 Oct 11-15; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2023;22(12 Suppl):Abstract nr B159.