Phase I/II trial of RVU120 (SEL120), a CDK8/CDK19 inhibitor in patients with relapsed/refractory metastatic or advanced solid tumors.

Abstract

e15091 Background: CDK 8 /CDK19 are kinases involved in transcriptional control of embryonic development and cellular homeostasis via the mediator complex. They are also described to maintain tumor dedifferentiation and stem cell properties. A variety of cancer cells hijack the mediator complex and targeting cancer-specific gene transcription via CDK8/19 inhibition has potential for treatment of solid tumors. RVU120 (SEL120) is a selective CDK8/19 inhibitor with preclinical efficacy in hematologic malignancies and a variety of solid tumor types (Rzymski et al. 2017). RVU120 showed strong anticancer activity in preclinical triple-negative breast cancer (TNBC) models, especially in the mesenchymal stem-like (MSL) molecular subtype (Rzymski et al SABCS 2021). Methods: A Phase I/II clinical trial of RVU120 in solid tumors is currently ongoing (NCT05052255). Patients with metastatic or advanced solid tumors without available treatments receive increasing doses of RVU120 as a single oral dose every other day (QOD) for a total of 7 doses on Days 1, 3, 5, 7, 9, 11 and 13, in a 3-week treatment cycle. Primary objectives of the study are safety / tolerability of RVU120 as single agent and determination of the recommended Phase II dose (RP2D) via a 3+3 dose escalation design. Secondary objectives include objective response rate (ORR) (RECIST criteria v1.1) and PK of RVU120. Results: As of 11FEB 2022, 5 pts have been enrolled into the trial: 3 into cohort 1, 75 mg dose, 2 into cohort 2, 100 mg. None of the pts experienced a DLT, SAEs or > Grade 3 AE. Treatment-related AEs were all G1 except for G2 diarrhea and weakness. Cohort 1 patients had at least 1 post-baseline tumor assessment. A 62 YO patient, stage IV esophago-gastric junction carcinoma, metastases to the liver, retroperitoneum, adrenal gland and portocaval lymph nodes, progressing after 4 lines of previous therapy, achieved a SD with a +4% change of target lesion size and progressed in cycle 6. A 65 YO patient, stage IV adenoid cystic carcinoma of the trachea, metastases to the lung and refractory to antiandrogens and radiotherapy, achieved a SD with -4% change of target lesion size after 3 cycles and is currently ongoing in cycle 5. A 43 YO pt stage IV thymic carcinoma, metastases to the lung, mediastinum, pleura and lymph nodes, progressing under cisplatin/etoposide, stopped study drug at the end of cycle 3 for PD in non-target lesions, target lesions increased by 11%. Cohort 2 patients, a 65 YO pt with pancreatic cancer stage IV, metastases to liver and lung, and a 55 YO pt with TNBC stage IV, metastases to the lung, will be evaluated end of cycle 3. Conclusions: In the first dose escalation level with single agent RVU120, no DLTs or ≥G3 AEs were observed in patients with previously progressive solid tumors. Initial assessments in 3 pts demonstrated stable disease in 2 patients. Collection of further data at higher doses is ongoing with 2 patients enrolled at 100 mg. Clinical trial information: NCT05052255.

Discovery of a Novel and Potent Cyclin-Dependent Kinase 8/19 (CDK8/19) Inhibitor for the Treatment of Cancer

“…We leveraged our extensive drug design experience − to identify a novel, potent CDK8/CDK19 inhibitor by structure-based optimization of RVU120. ,, It is noted that CDK8 and CDK19 showed over 80% sequence percent identity and that RVU120 inhibited kinase activities of both CDK8/CycC and CDK19/CycC complexes with comparable IC 50 values (4.4 nM for CDK8 vs 10.4 nM for CDK19). ,, With the lack of available crystal structure of CDK19 in protein data bank (PDB), we built the binding mode of RVU120 with CDK8 ( Figure A) based on the crystal structure of CDK8 (PDB ID: 5XS2) and the description of the RVU120/CDK8 complex (its PDB ID was previously not disclosed), assuming that structure modification of RVU120 based on CDK8 leads to the change of inhibition potency toward CDK8/CDK19 in a similar way. As previously described, the Br atoms of RVU120 form halogen bonds with the carbonyl group of D98 and the backbone NH of A100, respectively, and one Br atom also interacts with the π-system of Y99.…”

“…We leveraged our extensive drug design experience 28−31 to identify a novel, potent CDK8/CDK19 inhibitor by structure-based optimization of RVU120. 18,32,33 It is noted that CDK8 and CDK19 showed over 80% sequence percent identity and that RVU120 inhibited kinase activities of both CDK8/CycC and CDK19/CycC complexes with comparable IC 50 values (4.4 nM for CDK8 vs 10.4 nM for CDK19). 18,32,33 With the lack of available crystal structure of CDK19 in protein data bank (PDB), we built the binding mode of RVU120 with CDK8 (Figure 1A) based on the crystal structure of CDK8 (PDB ID: 5XS2) and the description of the RVU120/CDK8 complex (its PDB ID was previously not disclosed), 18 assuming that structure modification of RVU120 based on CDK8 leads to the change of inhibition potency toward CDK8/CDK19 in a similar way.…”

Hypoxia-inducible factor in cancer: from pathway regulation to therapeutic opportunity

“…202 Notably, one CDK8 inhibitor, RVU120 (SEL120), is currently under investigation in a phase I/II clinical trial involving patients with relapsed metastatic solid tumours. 203 Methylation and acetylation modifications on histone residues are detected by specific chromatin reader proteins, that couple alterations in histones to transcriptional regulation. One such chromatin reader is Zinc Finger MYND-type containing 8 (ZMYND8), which recognises methylation and acetylation of histone 3 and 4.…”