Full Press Release Details
Identification of Original Research: Original Research
Identification of Clinical Trials: Clinical Trial, ClinicalTrials.gov Identifier: NCT04718675
Funding Source: Kronos
Bio; Biotechnology Company.
AACR/NCI/EORTC submission details: Submitted on behalf of authors by Crystal Kraft, MJH Life Sciences, ckraft@mjhlifesciences.com
AACR/NCI/EORTC Member Sponsor:
Corresponding author:
Abstract character count: 3099/3100 with spaces
Topic Category: Therapeutic agents: small molecule kinase inhibitors
Shortened title (for internal AACR tracking):
Presentation preference: Oral
Abstract keywords (up to 3):
Disclosures: required
for all authors (may list up to 20, full name, academic degree(s), institution, address, email address, and disclosure of information for each author)
Title: A First-In-Human Study of CDK9 Inhibitor KB-0742 Demonstrates Evidence of Tolerability and Clinical Activity.
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 J. MacKenzie, Charles Lin, Jorge F. DiMartino, Elizabeth A. Olek, Brian Van Tine
| Name | Degree | Affiliation | |
| Miguel Villalona-Calero | MD | City of Hope National Medical Center, California, USA | mvillalona@coh.org |
| Monica Mita | MD MDSc | Cedars-Sinai Cancer Institute, California, USA | monica.mita@cshs.org |
| Alain Mita | MD | Cedars-Sinai Cancer Institute, California, USA | alain.mita@cshs.org |
| Noah Federman | MD | UCLA Jonsson Comprehensive Cancer Center, California, USA | nfederman@mednet.ucla.edu |
| Drew Rasco | MD, FASCO | START - San Antonio, Texas, USA | drasco@startsa.com |
| David Spigel | MD | Sarah Cannon Research Institute at Tennessee Oncology PLLC, Tennessee, USA | david.spigel@sarahcannon.com |
| Jia Luo | MD | Dana-Farber Cancer Institute, Massachusetts USA | jia_luo@dfci.harvard.edu |
| Gregory M. Cote | MD PhD | Massachusetts General Hospital, Massachusetts USA | gcote@partners.org |
| Glenn J Hanna | MD | Dana-Farber Cancer Institute, Massachusetts USA | gjhanna@partners.org |
| Richard E. Cutler | PhD | Kronos Bio, California, USA | rcutler@kronosbio.com |
| Pavan Kumar | PhD | Kronos Bio, Massachusetts, USA | pavan.kumar@kronosbio.com |
| Crystal MacKenzie | BS | Kronos Bio, California USA | crystal.mackenzie@kronosbio.com |
| Charles Lin | PhD | Kronos Bio, California USA | charles.lin@kronosbio.com |
| Jorge F. DiMartino | MD PhD | Kronos Bio, California USA | jorge.dimartino@kronosbio.com |
| Elizabeth A Olek | DO, MPH | Kronos Bio, California USA | eolek@kronosbio.com |
| Brian Van Tine | MD PhD | Washington University in St. Louis, Missouri, USA | bvantine@wustl.edu |
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, and 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).
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 included age > 18 years, relapsed or refractory solid tumors or NHL, acceptable organ function and ECOG PS < 2.
Study objectives include evaluation of safety, tolerability, PK, PD, and identification of KB-0742 MTD and RP2D using a modified Continuous Reassessment
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 of changes in gene expression of prospectively defined CDK9 responsive genes.
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 >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 60mg, evidence of target engagement was
observed by pSER2 reduction and proportional changes to CKD9 responsive genes.
In the escalation phase 60 mg cohort, 3 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 > 5 mos. The second patient achieved a RECIST 1.1 partial response and remains on
treatment at > 12 mos. Consistent with the therapeutic hypothesis, both patients had TF fusions.
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.