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Phase 1b study of RGX-202-01, a first-in-class oral inhibitor of the SLC6A8/CKB pathway, in combination with FOLFIRI and bevacizumab (BEV) in second-line advanced colorectal cancer (CRC)
Background
A proprietary in vivo target discovery screen identified creatine kinase-B (CKB) as a cancer driver in KRAS mutant (KRAS-mut) CRC. CKB promotes tumor growth and survival under hypoxia. CKB generates the energetic metabolite phospho-creatine (PCr), which is imported into cells through the creatine transporter, SLC6A8. PCr generates intracellular ATP that enables tumoral survival. RGX-202-01 is a small molecule inhibitor of SLC6A8 that depletes intracellular PCr and ATP, resulting in apoptosis. In a completed phase 1a study, RGX-202-01 monotherapy demonstrated objective anti-tumor activity in the relapsed/refractory KRAS-mut CRC setting without dose-limiting toxicity. The objectives of this ongoing phase 1b study are to evaluate safety, PK/PD, and efficacy of RGX-202-01 in combination with standard-of-care (SOC) FOLFIRI + BEV in second-line CRC, a setting where SOC therapy results in an ORR and mPFS of approximately 15% and 6 months, respectively.
Methods
Subjects with advanced CRC who had disease progression after receiving a first-line oxaliplatin-containing regimen were eligible. As of 02-24-2022, 17 patients (pts) have been enrolled. 8 pts were enrolled in 2 dose escalation cohorts of RGX-202-01: 2400mg BID (4 pts) and 3000mg BID (4 pts) combined with FOLFIRI and BEV. 9 pts were enrolled in the dose expansion phase of the study and received RGX-202-01 3000mg BID combined with FOLFIRI and BEV.
Results
No DLTs were observed and the MTD was not reached in the dose escalation phase. Most common G2 TRAEs were nausea and diarrhea (50%) and most common G3 TRAEs were fatigue (12%) and hypertension (12%) There were no Grade 4-5 TRAEs. At the RP2D of 3000 mg BID, PK analysis showed sustained RGX-202-01 drug exposures above target levels (IC50). In addition, Serum and urine creatine measurements indicated robust SLC6A8 target inhibition (in both escalation cohort). 9 pts had KRAS-mut CRC, and all were evaluable for RECIST 1.1 response. 5 of these pts had PR (confirmed) and 4 pts have SD as best response (ORR 56%, DCR 100%). 5 of these pts remain on study for a duration ranging from 15-58 weeks. One patient with a PR at 16 weeks had surgery with curative intent and was observed off therapy with no evidence of disease until week 44 when a CT identified a recurrence. 8 pts had KRAS WT CRC. Of the 5 KRAS WT pts evaluable for response, 1 has a PR on first scan and is ongoing and 4 pts have SD as best response. (ORR 20%, DCR 100%)3 patients remain on study at 8, 20 and 24 weeks respectively.
Conclusions
RGX-202-01 combined with FOLFIRI and BEV was well tolerated with no DLTs at the dose levels evaluated which induced potent inhibition of SLC6A8. Encouraging efficacy was observed in patients with RAS mutate mCRC, with 56% response rate exceeding that expected with SOC. Preferential activity in patients with RAS mutated tumors is consistent with pre-clinical studies. Enrollment in the expansion phase continues and a phase 2/3 trial in 2L CRC with RAS mut is planned.
Clinical trial identification
NCT03597581.
Legal entity responsible for the study
The author.
Funding
Inspirna Inc.
Disclosures
A. Hendifar: Advisory / Consultancy: Novartis, Ipsen, Perthera, Celgene, Abbvie, ; Research grant / Funding (institution): Inspirna. A. Cercek: Advisory / Consultancy: Bayer, Merck, Seagen; Research grant / Funding (institution): Seagen, GSK, Rgenix. D. Spigel: Research grant / Funding (institution): • Aeglea Biotherapeutics • Agios • Apollomics • Arcus • Arrys Therapeutics • Astellas • AstraZeneca • Bayer • BeiGene • BIND Therapeutics • BioNTech RNA Pharmaceuticals • Blueprint Medicine • Boehringer-Ingelheim • Bristol-Myers Squibb • Calither. S. Tavazoie: Advisory / Consultancy: Inspirna; Shareholder / Stockholder / Stock options: Inspirna; Licensing / Royalties: Inspirna . E. Rowinsky: Full / Part-time employment: Inspirna; Officer / Board of Directors: Inspirna. M. Szarek: Full / Part-time employment: Inspirna. F. Gonsalves: Shareholder / Stockholder / Stock options: Inspirna Inc.; Full / Part-time employment: Inspirna Inc. I. Kurth: Advisory / Consultancy: Inspirna, Inc.; Shareholder / Stockholder / Stock options: Inspirna, Inc. R. Busby: Advisory / Consultancy: Inspirna, Inc.; Shareholder / Stockholder / Stock options: Inspirna, Inc. S. Spector: Advisory / Consultancy: Inspirna. D. Darst: Leadership role: Inspirna, Inc.; Shareholder / Stockholder / Stock options: Inspirna, Inc.; Full / Part-time employment: Inspirna, Inc.; Officer / Board of Directors: Inspirna, Inc.; Spouse / Financial dependant: Inspirna, Inc. N. Lebaka: Shareholder / Stockholder / Stock options: Inspirna; Full / Part-time employment: Inspirna. n. Bechar: Shareholder / Stockholder / Stock options: Inspirna Inc. M. Tavazoie: Shareholder / Stockholder / Stock options: Inspirna; Full / Part-time employment: Inspirna; Officer / Board of Directors: Inspirna. R. Wasserman: Leadership role: Inspirna Inc; Travel / Accommodation / Expenses: Inspirna Inc; Shareholder / Stockholder / Stock options: Inspirna Inc.,; Licensing / Royalties: Inspirna Inc.,; Full / Part-time employment: Inspirna Inc.,; Officer / Board of Directors: Inspirna Inc.,. M. Fakih: Honoraria (self): Guardant Health, Incyte; Advisory / Consultancy: Incyte, Seattle Genetic, GSK; Research grant / Funding (institution): Verastem, Amgen, BMS. All other authors have declared no conflicts of interest.
