This open-label, phase 1 trial in patients with ABC was conducted in China (ClinicalTrials.gov identifier: NCT02684266). The study consisted of dose-escalation and dose-expansion phases. In the dose-escalation phase, the primary objective was to establish the maximum tolerated dose (MTD) for oral SHR6390. In the dose-expansion phase, three selected dose cohorts were expanded to further characterize the safety profile, tolerability, PK parameters and preliminary anti-tumor activity of SHR6390.
Eligible patients were aged 18-65 years, with histologically confirmed ABC who failed standard therapy. Other inclusion criteria included Eastern Cooperative Oncology Group performance status 0-1, life expectancy ≥ 3 months, adequate bone marrow function (hemoglobin > 110 g/L, neutrophils > 2.0×109 per L and platelets > 100×109 per L), adequate liver or renal function (total bilirubin < 1.5 times the upper limit of normal [ULN], alanine transaminase [ALT] and aspartate aminotransferase [AST] ≤ 1.5 times ULN [≤ 5 times ULN in the presence of liver metastases] and creatinine ≤ 1 ULN), and adequate cardiac function (left ventricular ejection fraction ≥ 50% and Fridericia corrected-QT interval < 450 ms in males or < 470 ms in females). The key exclusion criteria were prior or current treatment with CDK4/6 targeted therapy, cytotoxic chemotherapy within three weeks (six weeks for mitomycin C or nitrosamine) or any other anti-tumor therapy within three weeks (except for endocrine therapy, which had to be discontinued before the time of informed consent), untreated or uncontrolled/unstable brain metastases (as judged by the investigator) or requirement of long-term use of steroids.
For dose escalation, a traditional 3 + 3 design was used with three to six patients enrolled per dose level and the escalation continued until two or more patients had dose-limiting toxicities (DLTs) in one dose cohort during the DLT assessment period (from the administration of the first study dose to the end of the first cycle). The starting dose of SHR6390 was 25 mg and was escalated by 25 mg increments up to 175 mg (25 mg, 50 mg, 75 mg, 100mg, 125 mg, 150 mg and 175 mg) in a modified Fibonacci schema. At 25 mg dose level, one patient was enrolled as a sentinel; if no grade ≥ 2 toxicity was observed during the sentinel patient’s DLT assessment period, escalation could proceed to 50 mg dose level immediately. DLT was defined as an adverse event (AE) that met any of the following criteria: grade 4 hematologic toxicity, grade 3 neutropenia with infection or fever ≥ 38.5℃, grade 3 thrombocytopenia with apparent clinical bleeding tendency, grade ≥ 3 non-hematologic toxicity (excluding untreated nausea, vomiting, and diarrhea or AEs considered tolerable by the patients, such as alopecia) or grade ≥ 2 cardiac or renal toxicity. Based on the tolerability, PK, and anti-tumor activity revealed from dose-escalation phase, three dose cohorts were selected to expand to 8‒10 patients.
All patients were first given a single dose of oral SHR6390. After a ≥ 7-day washout period, the patient was then administered once-daily continuous doses of SHR6390 for three weeks in 28-day cycles. Dose interruption or reduction was permitted after the initiation of the second cycle of treatment. Patients who achieved complete response [CR], partial response [PR] or stable disease [SD]) at first efficacy assessment after receiving two cycles of SHR6390 could continue treatment until disease progression, intolerable toxicity, withdrawal of patient consent or investigator decision.
The primary endpoint was MTD of oral SHR6390 and pharmacokinetic parameters in patients with ABC. MTD was the highest dose level at which <33% of the patients reported a DLT within the first cycle of multiple dosing. The secondary endpoints included safety and the investigator-assessed objective response rate (ORR, defined as the proportion of patients with CR and PR as the best overall response) and disease control rate (DCR, defined as the proportion of patients with CR, PR or SD ≥ 6 weeks) per RECIST v1.1.
Safety was regularly monitored from the time of informed consent until 30 days after the last dose of study drug. AEs were graded according to Common Terminology Criteria for Adverse Events v4.0. Tumor response was assessed using computerized tomography or magnetic resonance imaging at baseline and every two cycles after the start of multiple once-daily dosing. The response was classified as CR, PR, SD or progressive disease (PD) according to RECIST v1.1 by the investigators 18. A CR or PR was required to be confirmed with a subsequent scan four weeks after the initial assessment.
For PK analysis, blood samples were collected in all enrolled patients from predose and at intervals up to 24 h (0.5 h, 1 h, 2 h, 3 h, 4 h, 6 h, 8 h, 10 h and 24 h) on day 1 and every 24 h thereafter through day 6 at a single dose stage; and on day 1 (predose), day 8 (predose), day 15 (predose), day 21 (predose and 0.5 h, 1 h, 2 h, 3 h, 4 h, 6 h, 8 h and 10 h postdose) and day 22 through day 26 (every 24 h) of cycle 1 at the multiple-dose stage. The plasma concentrations of SHR6390 were measured by liquid chromatography with tandem mass spectrometry.
The DLT analysis set included all patients who received at least one dose of the study drug and completed the first cycle of treatment or discontinued study drug due to AE during the first cycle of treatment. PK was analyzed in patients who received at least one dose of the study drug and had evaluable post-treatment PK data. Safety and efficacy were analyzed in all patients who received at least one dose of the study drug. Descriptive statistics were reported for the safety and efficacy outcomes and PK parameters. The ORR and DCR were calculated, with the corresponding 95% Clopper-Pearson confidence intervals (CIs) provided. The Kaplan-Meier method was used to analyze PFS, and the median PFS (month) was estimated. The two-sided 95% CI of the median PFS was calculated by the Brookmeyer Crowley method. PK parameters were analyzed using the non-compartmental model with WinNonlin 7.0 (Pharsight, Mountain View, CA). Statistical analyses were conducted with SAS 9.4 (SAS Institute Inc., Cary, NC).