Phase I and Pharmacokinetic Study of Pegylated Liposomal CKD-602 in Patients with Advanced Malignancies

Abstract

Purpose: S-CKD602 is a pegylated liposomal formulation of CKD602, a semisynthetic camptothecin analogue. Pegylated (STEALTH) liposomes can achieve extended drug exposure in plasma and tumor. Based on promising preclinical data, the first phase I study of S-CKD602 was done in patients with refractory solid tumors. Experimental Design: S-CKD602 was administered i.v. every 3 weeks. Modified Fibonacci escalation was used (three to six patients/cohort), and dose levels ranged from 0.1to 2.5 mg/m 2 . Serial plasma samples were obtained over 2 weeks and total (lactone + hydroxyl acid) concentrations of encapsulated, released, and sum total (encapsulated + released) CKD602 measured by liquid chromatography-tandem mass spectrometry. Results: Forty-five patients (21males) were treated. Median age, 62 years (range, 33-79 years) and Eastern Cooperative Oncology Group status, 0 to 1 (43 patients) and 2 (2 patients). Dose-limiting toxicities of grade 3 mucositis occurred in one of six patients at 0.3 mg/m 2 , grade 3 and 4 bone marrow suppression in two of three patients at 2.5 mg/m 2 , and grade 3 febrile neutropenia and anemia in one of six patients at 2.1 mg/m 2 . The maximum tolerated dose was 2.1 mg/m 2 . Partial responses occurredin two patients with refractory ovarian cancer (1.7 and 2.1mg/m 2 ). Highinterpatient variability occurred in the pharmacokinetic disposition of encapsulated and released CKD602. Conclusions: S-CKD602 represents a promising new liposomal camptothecin analogue with manageable toxicity and promising antitumor activity. Phase II studies of S-CKD602 at 2.1mg/m 2 i.v. once every 3 weeks are planned. Prolonged plasma exposure over 1to 2 weeks is consistent with STEALTH liposomes and provides extended exposure compared with single doses of nonliposomal camptothecins.

Mechanism-based model characterizing bidirectional interaction between PEGylated liposomal CKD-602 (S-CKD602) and monocytes in cancer patients

“…30,31 The study design and clinical results have been reported elsewhere. 30,31 Forty-five patients (21 males) received S-CKD602 at 0.1 to 2.5 mg/m 2 IV × 1 over approximately 1 hour, every 3 weeks. No premedications were administered prior to S-CKD602.…”

“…Pertinent eligibility criteria included adequate bone marrow, as well as hepatic and renal function evidenced by the following laboratory parameters: (i) absolute neutrophil count $ 1,500/µL, (ii) platelet count $ 100,000/µL, (iii) total bilirubin # 1.5 × upper limit of the institutional normal range, (iv) aspartate aminotransferase # 1.5 × upper limit of the institutional normal range if liver metastases were not present and #4 × ULN if liver metastases were present, and (v) the absence of microscopic hematuria published. 30,31 The mean age of the patients was 60.6 (range 33-79) years. In this study, serial plasma samples were obtained prior to drug administration; at the end of the infusion (at around 1 hour); and at 3, 5, 7, 24, 48, 72, 96, 168 (day 8), and 336 hours (day 15) after the start of the infusion.…”

“…21,[25][26][27][28][29] The clinical results of the phase I and PK study of S-CKD602 have been previously published. 30 The PK study of S-CKD602 using the conventional compartment model has also been published, and the dose-dependent clearance of S-CKD602 was modeled using Michaelis-Menten kinetics. 31 This is the first study to evaluate the bidirectional interaction between a nanoparticle agent and the monocytes of the MPS in patients using PK-PD modeling.…”

A Review of Study Designs and Outcomes of Phase I Clinical Studies of Nanoparticle Agents Compared with Small-Molecule Anticancer Agents

“…The ratio of MTD to starting dose of nanoparticles was approximately 7-fold higher than small molecule (P ¼ 0.005). For the nanoparticles, including NKTR-102 (PEGylated irinotecan), liposomal vincristine (Marqibo), liposomal vinorelbine, NK-105 (PEGylated paclitaxel), S-CKD602 (liposomal CKD-602), and IHL-305 (PEGylated liposomal irinotecan), it was confirmed that the starting doses in clinical phase I studies were based on toxicology studies in dog (18)(19)(20)(22)(23)(24).…”

“…Data was collected for 9 nanoparticles and matching small-molecule anticancer agents. [16][17][18][19][20][21][22][23][24]. The small molecules were paclitaxel, irinotecan, lurtotecan, vinorelbine, CKD-602, and oxaliplatin (25)(26)(27)(28).…”