A phase 1, multi-center, open-label, dose-escalation, and dose-expansion study of CBP-1018, a bi-ligand-drug conjugate in patients with heavily treated advanced solid tumors.
Authors: Li Kaiwen , Wu Junyan , Ye Suiwen , Liu Yanqiong , Huang Hao , Fan Fan , Lai Yiming , Zhuang Suili , Zhou Liyan , Huang Robert , Xu Mo , Pan Bin , Zhang Jian , Shi Yehui , Huang Hai 
Published: June 2024

5047 Background: CBP-1018 is a first-in-class bi-ligand-drug conjugate targeting both PSMA and FRα with monomethyl auristatin E (MMAE) as payload. It delivers the conjugated payload into target cells highly efficiently and specifically which had been proven by preclinical studies. CBP-1018 shows good antitumor activity in various Patient-Derived Tumor Xenograft/Cell Derived Xenograft (PDX/CDX) models of lung cancer, ovarian cancer, prostate cancer, breast cancer and pancreatic cancer, up to 96% Tumor growth inhibition (TGI). Methods: This phase 1 study includes both dose-escalation and expansion stage. In the dose-escalation stage, an accelerated titration was conducted in single patient at 0.03mg/kg followed by an i3+3 design for dose levels (DLs) ≥ 0.06 mg/kg, Q2W. In dose-expansion stage, 0.12 mg/kg and 0.14 mg/kg were selected for dose expansion. The primary objectives are to evaluate the safety and tolerability, determine dose limiting toxicity (DLT) and maximum tolerated dose (MTD). Additionally, pharmacokinetics (PK) and preliminary efficacy will also be evaluated. Results: As of 31 Dec 2023, 59 pts (57 mCRPC, 1 bladder cancer and 1 ureteral carcinoma) were enrolled at 7 DLs (1 pt at 0.03 mg/kg, 3 pts each at 0.06, 0.08, 0.10 mg/kg, 17 pts each at 0.12 mg/kg and 29 pts at 0.14 mg/kg, and 3 pts at 0.16 mg/kg). No DLTs, no drug-related deaths were observed. Enrolled mCRPC pts received a median 9 prior systematic antitumor drugs (median 2 prior chemotherapy, 72.9% pts had received chemotherapy, and median 4 new hormonal agents). Median age was 67.5 (range 57, 78). Median PSA was 82.2 ng/ml (range 0.006, 2995ng/ml) at baseline. 89.8% pts have an ECOG score of 1 or 2. Most treatment-related adverse events (TRAEs) were grade 1 or 2, ≥ grade 3 TRAEs mainly includes neutrophil decrease (29.5%), WBC decrease (19.7%), lymphocyte decrease (11.5%). Among 7 efficacy evaluable pts with mCRPC per RECIST v1.1 at 0.14 mg/kg or higher dose levels, best overall response (BOR) of 3 PR and 4 SD were observed, with ORR 42.9%, DCR 100%. Overall median radiographic progression-free survival (rPFS) was 9.2 months (95%CI, 5.0-NA) in 28 evaluable (who have at least one tumor assessment after study treatment) mCRPC pts per RECIST1.1 and PCWG3. Cmax and AUC0-t of CBP-1018 and free MMAE increased with dose, and the t1/2 of CBP-1018 was ranged from 0.54 to 1.15 h in different dose cohorts, respectively. Accumulation, Cmax and AUC0-t of CBP-1018 were not observed. Conclusions: CBP-1018 was well-tolerated at DLs of 0.03-0.16 mg/kg Q2W with no DLTs. MTD was not reached. Promising preliminary efficacy ORR and rPFS were observed, supporting a further investigation in large scale clinical trial for mCRPC patients. Yehui Shi and Hai Huang is the corresponding author. Kaiwen Li and Junyan Wu contributed equally to this work. Clinical trial information: NCT04928612 .