Immune checkpoint inhibitors have revolutionized the treatment of advanced melanoma. The representative drugs include monoclonal antibodies against programmed cell death receptor-1 (PD-1) [1, 2], cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) , and lymphocyte-activation gene 3 (LAG3) , which inhibit T cell activity and contribute to immune evasion from the tumor. Nivolumab and pembrolizumab are recommended for the treatment of metastatic cutaneous melanoma in the National Comprehensive Cancer Network (NCCN) guideline, monotherapy or combined with ipilimumab .
Camrelizumab is a humanized IgG4-kappa anti-PD-1 monoclonal antibody. It was first approved in China for Hodgkin’s lymphoma, and later extended to advanced hepatocellular carcinoma, non-small cell lung cancer, esophageal squamous cell carcinoma, and nasopharyngeal carcinoma successively [6,7,8,9,10]. However, there are currently no efficacy and safety data reported in melanoma about camrelizumab.
In April 2016, a phase I clinical trial on the safety and tolerability of camrelizumab in patients with advanced melanoma (NCT02738489) was initiated at Peking University Cancer Hospital. In the first in human study conducted in Australia in 2015, camrelizumab was administrated in patients with solid tumors at 1 mg/kg, 3 mg/kg, 6 mg/kg, and 10 mg/kg every 2 weeks, and showed acceptable safety profile and potential antitumor activity . Considering the safety data reported and convenience of drug administration, a fix dose of 60 mg, 200 mg and 400 mg Q2W were selected for this trial. This study aimed to summarize the safety and activity data of camrelizumab in the treatment of advanced melanoma to provide a basis for clinical application and subsequent trial design.
Patients and methods
This study is an open-label, single-arm, and single-center trial approved by the Ethics Committee of Peking University Cancer Hospital. Patients with unresectable or metastatic melanoma (included acral, mucosal, uveal, cutaneous or other melanoma) who had progressed after standard treatment (cytotoxic drugs and/or anti-angiogenic agent at the time of study), or without effective treatment were allowed to participate. Other enrollment criteria included an Eastern Cooperative Oncology Group Performance Score (ECOG PS) of 0-1, without prior anti-PD1 agents or other immune checkpoint inhibitors, adequate hematologic, hepatic, and renal function, and measurable lesions defined by Response Evaluation Criteria In Solid Tumors (RECIST), version 1.1. Detailed inclusion and exclusion criteria were presented in the Additional file 1. All patients have signed informed consent forms. The study was conducted in accordance with the Declaration of Helsinki.
This trial was registered prospectively at ClinicalTrials.gov (ID, NCT02738489) on 14/04/2016. The study is divided into two phases, dose-escalation and subsequent dose-expansion phase. In the first stage, the traditional “3 + 3” mode was adopted, and three fixed doses of camrelizumab were given, including 60 mg, 200 mg, and 400 mg every 2 weeks, respectively. If one dose-limited toxicity (DLT) occurs in the first cycle of three subjects, then three more subjects will be added. If DLT is not observed in the last three subjects, we moved to the next dose group. If one or more DLT occurs again in the last three subjects, the dose escalation is terminated, and the previous dose is defined as the maximum tolerated dose (MTD). No escalation was conducted beyond 400 mg even if MTD was not reached.
The primary endpoint of the study was the safety and tolerability of camrelizumab in patients with advanced melanoma. The secondary endpoints included pharmacokinetics (PK) and pharmacodynamics (PD) parameters of camrelizumab, anti-drug antibody (ADA) produced by patients, and anti-tumor activity of camrelizumab for advanced melanoma, including objective response rate (ORR), disease control rate (DCR), progression-free survival (PFS), and overall survival (OS). PFS was defined as the time from camrelizumab initiation to disease progression determined by RECIST 1.1 or death, whichever came first. OS was defined as the time from camrelizumab initiation to death due to any cause.
DLT was defined in this study as follows: ≥ grade 3 hematologic toxicities, ≥ grade 4 non-hematologic toxicities, grade 3 non-hematologic toxicities which demanded medical intervention, hospitalization, or lasted more than 3 days with best supportive care, and grade 3 laboratory abnormities with clinical significance. DLT was observed after the first administration in 4 weeks. The administration of camrelizumab was repeated every 2 weeks afterward, and the whole DLT observation period was 56 days. After the observation period of a dose group without DLT, the second phase of expansion at this dose can be carried out simultaneously with the subsequent dose escalation. Treatment continued until intolerable toxicity, progressive disease, or withdrawal of consent.
The severity of adverse reactions was graded according to the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE), version 4.03. Delayed DLT (occurring after the DLT observation period) would not influence the dose escalation, but the ethics committee will be notified for further consideration. Delayed DLT in this study mainly referred to autoimmune reactions, including immune-related pneumonia, uveitis, colitis, aseptic meningitis, pancreatitis, hepatitis, nephritis, hyperthyroidism, hypothyroidism, hypophysitis, and hyperglycemia.
Imaging evaluation was performed every two cycles, with every two administrations as one cycle. Objective response rate was assessed based on the RECIST 1.1 criteria by investigator. For clinically stable patients who have progressed in the initial radiological evaluation, treatment beyond disease progression was allowed according to the investigator’s choice.
Pharmacokinetics and pharmacodynamics
Blood samples were collected after the first administration at pre-dose (in 0.5 h), 5 min (±5 min), 2 h (±10 min), 6 h (±10 min), 24 h (±30 min), 48 h (±30 min), day 8 (±60 min), day 15 (±60 min), day 22 (±60 min), and pre-dose (in 0.5 h), 5 min (±5 min) on day 1 and day 15 after multiple administrations for analyses of PK and receptor occupancy (RO) rate. PK parameters included half-life time(t1/2), time to maximum concentration (Tmax), maximum concentration (Cmax), area under the concentration-time curve, and the accumulation ratio Rac calculated by Cmax. RO rate was defined as the ratio of PD-1 receptor occupied by camrelizumab on peripheral CD3 + T lymphocytes by flow cytometry.
SAS software version 9.4 was used for statistical analysis. Counting data is represented by the number of cases or percentages, and measurement data is described as mean ± standard deviation (SD) or median (range). The PK and PD parameters were tabulated and analyzed descriptively, and presented using median and coefficient of variation (CV). The PK parameters were calculated using non-compartmental approaches by WinNonlin 7.0 software. The PD parameters were calculated using SAS software. The Clopper-Pearson method was used to estimate the two-sided 95% confidence interval (CI) for ORR and DCR. The survival curve was generated and analyzed by the Kaplan-Meier method.