This Phase I, open-label, dose-escalation study of single-agent ribociclib was undertaken in patients with Rb+ advanced solid tumors or lymphomas to determine the maximum tolerated dose (MTD)/recommended dose for expansion (RDE) of ribociclib, and to characterize the dose-limiting toxicities (DLTs) associated with ribociclib. The study also aimed to assess the safety, pharmacokinetics (PK), pharmacodynamics (PD), and preliminary activity of ribociclib in patients with solid tumors, including tumors that harbored aberrations in the cyclin D–CDK4/6–INK4–Rb pathway and other cancer-related genes.
Patients received escalating doses of oral ribociclib either on a 3-weeks-on/1-week-off schedule, or a continuous 28-day schedule until disease progression, unacceptable toxicity, death, or consent withdrawal. Ribociclib dose escalation (starting dose: 50 mg/day 3-weeks-on/1-week-off; selected based on 4-week preclinical studies) was guided by the adaptive Bayesian Logistic Regression Model (BLRM) including Escalation With Overdose Control (EWOC) principle (11 (link)). DLTs were evaluated during the first treatment cycle (28 days) and were defined according to Common Terminology Criteria for Adverse Events (CTCAE) version 4.0. as adverse events (AEs) or clinically significant abnormal laboratory values suspected to be related to ribociclib treatment, which prevented the start of a new cycle of treatment within 7 days of the scheduled new cycle start date. In order to be eligible for a second or later cycle of treatment, patients were required to have had an absolute neutrophil count ≥1.0 × 109/L, platelet count ≥75.0 × 109/L, and no current non-hematologic toxicities ≥ CTCAE grade 2. Patients falling outside these criteria were deemed to have a DLT. DLTs also comprised: grade 4 neutropenia lasting ≥7 consecutive days; grade 4 thrombocytopenia; grade 3/4 neutropenia with fever (temperature ≥38.5°C); serum creatinine >2 ×upper limit of normal; grade ≥3 total bilirubin, or grade 2 total bilirubin with grade 2 increase in alanine transaminase (ALT), or aspartate aminotransferase; grade ≥3 ALT increase; QT corrected (QTc) interval ≥501 ms on ≥2 separate electrocardiograms; grade ≥3 nausea or vomiting despite optimal anti-emetic therapy; grade ≥3 diarrhea despite optimal antidiarrhea treatment; any grade 3/4 non-hematologic AE (including biochemical findings) except for brief (<72 hours) grade 3 fatigue; grade 3 alopecia, or grade 3 electrolyte disturbance (supplementation allowed) resolving to grade ≤1 within 7 days of drug interruption.
In order to declare a dose as the MTD, at least six evaluable patients must have been treated at that dose level. The starting dose for the continuous schedule was to be at least one dose level below the MTD established with the 3-weeks-on/1-week-off schedule, and was also determined by available safety and PK data. Upon determination of the MTD/RDE, an expansion phase sought to further evaluate the safety and tolerability, preliminary clinical activity, PK, and PD of ribociclib at the RDE.
Patients received escalating doses of oral ribociclib either on a 3-weeks-on/1-week-off schedule, or a continuous 28-day schedule until disease progression, unacceptable toxicity, death, or consent withdrawal. Ribociclib dose escalation (starting dose: 50 mg/day 3-weeks-on/1-week-off; selected based on 4-week preclinical studies) was guided by the adaptive Bayesian Logistic Regression Model (BLRM) including Escalation With Overdose Control (EWOC) principle (11 (link)). DLTs were evaluated during the first treatment cycle (28 days) and were defined according to Common Terminology Criteria for Adverse Events (CTCAE) version 4.0. as adverse events (AEs) or clinically significant abnormal laboratory values suspected to be related to ribociclib treatment, which prevented the start of a new cycle of treatment within 7 days of the scheduled new cycle start date. In order to be eligible for a second or later cycle of treatment, patients were required to have had an absolute neutrophil count ≥1.0 × 109/L, platelet count ≥75.0 × 109/L, and no current non-hematologic toxicities ≥ CTCAE grade 2. Patients falling outside these criteria were deemed to have a DLT. DLTs also comprised: grade 4 neutropenia lasting ≥7 consecutive days; grade 4 thrombocytopenia; grade 3/4 neutropenia with fever (temperature ≥38.5°C); serum creatinine >2 ×upper limit of normal; grade ≥3 total bilirubin, or grade 2 total bilirubin with grade 2 increase in alanine transaminase (ALT), or aspartate aminotransferase; grade ≥3 ALT increase; QT corrected (QTc) interval ≥501 ms on ≥2 separate electrocardiograms; grade ≥3 nausea or vomiting despite optimal anti-emetic therapy; grade ≥3 diarrhea despite optimal antidiarrhea treatment; any grade 3/4 non-hematologic AE (including biochemical findings) except for brief (<72 hours) grade 3 fatigue; grade 3 alopecia, or grade 3 electrolyte disturbance (supplementation allowed) resolving to grade ≤1 within 7 days of drug interruption.
In order to declare a dose as the MTD, at least six evaluable patients must have been treated at that dose level. The starting dose for the continuous schedule was to be at least one dose level below the MTD established with the 3-weeks-on/1-week-off schedule, and was also determined by available safety and PK data. Upon determination of the MTD/RDE, an expansion phase sought to further evaluate the safety and tolerability, preliminary clinical activity, PK, and PD of ribociclib at the RDE.
