CDK4/6 and Cyclin D1 are significantly expressed in approximately 80% of esophageal and gastroesophageal junction tumors suggesting that CDK4/6 inhibition may be a successful strategy in these chemotherapy and immunotherapy resistant diseases.
This is a multicenter, open label, phase I/II safety study that will enroll 30 subjects with metastatic esophageal and gastroesophageal junction adenocarcinomas post first line systemic chemotherapy. Subjects will be treated with oral Abemaciclib 150 mg PO daily bid given with ramucirumab 8mg/kg every 2 weeks iv until evidence of disease progression or unacceptable toxicities. A total of 30 subjects will be enrolled. The primary goal is to describe the safety profile of Abemaciclib in combination with Ramucirumab among all enrolled subjects. If grade 3 or higher treatment-related adverse events occur in 20 subjects, the upper bound of 95% Wilson confidence interval for the adverse event rate would be below 81% (16.7% - 47.9%). The safety analysis will be performed in all treated subjects. Adverse event data will be listed individually and graded according to the National Cancer Institute Common Terminology Criteria, version 4.03. Summary statistics will include counts and proportions as well as rates with 95% confidence intervals. Toxicities will be reported as a tabulated table by type and grade. Objective response rate is defined as the percentage of subjects who achieve an objective response by RECIST1.1 criteria (i.e. Complete response or Partial Response) to Abemaciclib in combination with Ramucirumab. We will estimate the objective response rate, along with the Wilson 95% confidence interval, for the population of subjects. Overall survival will be defined as the time from study enrollment to death. This will be summarized using a Kaplan-Meier curve. The proportion of subjects with grade 4 or higher treatment-related adverse events will be monitored continuously throughout the trial using a Bayesian stopping guideline. A Beta (1, 19) prior, representing a toxicity rate of 5%, slightly lower than the expected rate of 6%, was used in the development of our guidelines. The therapy will be re-evaluated if the posterior probability that the toxicity rate exceeds 10% is greater than 75%. Table 3 summarizes the stopping boundaries starting with the initial cohort of 3 subjects through the maximum sample size of 30 subjects. The probability of triggering the stopping guidelines was assessed for a range of possible toxicity rates using simulations with 5000 replicates. The probability of stopping to re-evaluate was 1% if the true proportion with an unacceptable toxicity was 5%. In comparison, the probability of stopping early was 99.6% if the true proportion with an unacceptable toxicity was 40%
Study Type
INTERVENTIONAL
Allocation
NA
Purpose
TREATMENT
Masking
NONE
Enrollment
26
150mg dose administered orally twice daily every day
8mg/kg iv every 2 weeks until evidence of disease
Baylor University Medical Center, Charles A Sammons Cancer Center
Dallas, Texas, United States
Safety of Abemaciclib + Ramucirumab
The safety profile was assessed by counting the number of patients who experienced adverse events (AEs) and serious adverse events (SAEs) of Grade 3 or higher while on study using CTCAE v4.0 criteria.
Time frame: From date of study enrollment, through treatment, and during follow-up until 100-days after the last dose of study medication or death, from any cause, whichever occurred first, assessed up to 24 months
Objective Response Rate
Objective response rate is defined as the number of subjects who achieve an objective response by RECIST1.1 criteria (i.e., Complete Response or Partial Response) to Abemaciclib in combination with Ramucirumab.
Time frame: From date of study enrollment until the date of death, from any cause, assessed up to 24 months
Progression Free Survival
The duration of progression-free survival is measured from the time of randomization to radiographic tumor progression or death.
Time frame: From date of study enrollment until the date of first radiographic tumor progression or death from any cause, whichever came first, assessed up to 24 months.
Overall Survival
Overall survival will be defined as the time from study enrollment to death.
Time frame: From date of study enrollment until the date of death, from any cause, assessed up to 24 months
Rate of Stable Disease
Rate of stable disease is defined as having a reading of stable disease or better per RECIST 1.1 criteria.
Time frame: At 3 months after targeted therapy initiation
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