CVM-1118: A potent oral anti-vasculogenic mimicry (VM) agent in patients with advanced neuroendocrine tumors (NETs)—A phase IIa study.

person Wu-Chou Su Department of Oncology, National Cheng Kung University, Tainan, Taiwan info_outline Wu-Chou Su, Ming Huang Chen, Li-Yuan Bai, Jen-Shi Chen, Yen-Yang Chen, Yu-Hsuan Shih, I-Chen Wu, John Gutheil, Teresa J. Melink, Yi-Wen Chu, Yen-Ling Chen, Chun-Man Chen, Du-Shieng Chien

Authors person Wu-Chou Su Department of Oncology, National Cheng Kung University, Tainan, Taiwan info_outline Wu-Chou Su, Ming Huang Chen, Li-Yuan Bai, Jen-Shi Chen, Yen-Yang Chen, Yu-Hsuan Shih, I-Chen Wu, John Gutheil, Teresa J. Melink, Yi-Wen Chu, Yen-Ling Chen, Chun-Man Chen, Du-Shieng Chien Organizations Department of Oncology, National Cheng Kung University, Tainan, Taiwan, Department of Oncology, Taipei Veterans General Hospital, Taipei, Taiwan, Division of Hematology and Oncology, China Medical University Hospital, and China Medical University, Taichung, Taiwan, Department of Hematology-Oncology, Linkou Chang Gung Memorial Hospital, Taoyuan, Taiwan, Division of Pulmonary and Critical Care Medicine, Kaohsiung Chang Gung Memorial Hospital, Kaohsiung, Taiwan, Taichung Veterans General Hospital, Taichung City, Taiwan, Kaohsiung Medical University Hospital, Kaohsiung, Taiwan, SciQuus Oncology, Inc, La Jolla, CA, TaiRx, Inc., Taipei, Taiwan Abstract Disclosures Research Funding Pharmaceutical/Biotech Company TaiRx, Inc. Background: CVM-1118 is a potent anti-tumor new chemical entity with multiple mechanisms of action including induction of apoptosis, cell cycle arrest, and inhibition of VM network formation. The Phase I trial in Asia determined an MTD of 600 mg daily (300 mg BID) with a favorable safety profile. The best response was stable disease with measurable tumor reduction in one patient with NET. We present preliminary results for this ongoing Phase IIa study. Methods: Eligible patients had advanced NETs (low/intermediate grade lung or WHO grade 1 or 2 gastrointestinal or pancreatic origin) which were refractory to standard of care therapy and progressed within 6 months prior to screening. Patients received oral CVM-1118 at 200 to 300 mg BID (400 to 600 mg daily) in 28-day cycles. Pharmacokinetics (PK) was assessed. The primary endpoint was progression-free survival (PFS) and secondary endpoints were objective response rate (ORR), disease control rate (DCR), duration of overall response (DoR), time-to-progression (TTP), and overall survival (OS). Planned enrollment is 33 evaluable patients. Results: As of February 10, 2023, 30 patients were enrolled, of which 21 evaluable patients (12 M/9 F; median age 61 y, range 37–82 y) were predominately grade 2 pNET (12/21, 57%) or GI NET (8/21, 38%). The majority (14/21, 67%) had disease progression after prior treatment with chemotherapy or small molecule inhibitor (median of 1 prior therapy). The duration of CVM-1118 treatment ranged from 1.4–34.6 mos (median 3.8 mos) with 4/21 (19%) patients remaining on treatment for more than 20 mos (range 22–34 mos). The median PFS was 6.9 mos (95% CI 3.3–10.3 mos), which exceeded the historical estimate for PFS of 4–6 mos (Raymond et al., 2011; Yao et al., 2016). The 8-mo and 12-mo PFS rates were 42% (95% CI 25–64%) and 29% (95% CI 14–50%), respectively. The DCR was 66.7% (95% CI 45–83%) with an ORR of 4.8% (1 PR with ongoing tumor reduction of 46% in pNET group). The most common treatment-related AEs ≥ grade 3 included ALT/AST increased (3.3%), diarrhea (3.3%), anemia (3.3%), neutrophil count decreased (3.3%), and tumor lysis syndrome (3.3%). No CVM-1118-related SAEs were reported. PK results showed CVM-1118 was rapidly metabolized to the active metabolite CVM-1125 in all patients following oral dosing. On Day 1, the mean drug exposure of CVM-1125 was C max 418 ng/mL and AUC 0-24 2170 ng·hr/mL. Intersubject variability of drug exposure appeared to be high; the T 1/2 of CVM-1125 was ~2.2 hr. No clear correlation between drug exposure and adverse effects or tumor reduction was observed. Conclusions: CVM-1118 has demonstrated a durable DCR with acceptable safety and tolerability. PK results showed good drug exposure with T 1/2 of CVM-1125 ~2.2 hr. These data support future studies in patients with advanced NETs. Raymond E et al ., 2011. N Eng J Med 364(6): 501-513. Yao JC et al ., 2016. Lancet 387(10022): 968-977. Clinical trial information: NCT03600233.

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