CVM-1118: A potent oral anti-vasculogenic mimicry (VM) agent in patients with advanced neuroendocrine tumors (NETs)—A phase IIa study.
Authors: Su Wu-Chou , Chen Ming Huang , Bai Li-Yuan , Chen Jen-Shi , Chen Yen-Yang , Shih Yu-Hsuan , Wu I-Chen , Gutheil John , Melink Teresa J. , Chu Yi-Wen , Chen Yen-Ling , Chen Chun-Man , Chien Du-Shieng 
Published: June 2023

e16235

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 Cmax 418 ng/mL and AUC0-24 2170 ng·hr/mL. Intersubject variability of drug exposure appeared to be high; the T1/2 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 T1/2 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 .