Primary Outcomes

Description: as determined by investigator

Description: as determined by an independent central review board blinded to study treatment

Secondary Outcomes

Other Outcomes

Description: samples taken at baseline, 6 weeks, 6 months, and at progression

Primary Outcomes

Description: For participants receiving at least one dose of study treatment, the ORR is defined as the best overall response recorded from the start of the treatment until disease progression or recurrence as assessed over a 1-year period from the start of treatment. The frequency and percentages of patients with a best overall response rate of complete response (CR), partial response (PR), stable disease (SD), or progressive disease (PD) will be determined. We will test the hypothesis that the ORR is greater than the null hypothesis of 10% using the Fisher's exact test.

Secondary Outcomes

Description: The DR for Complete Response (CR) and Partial Response (PR) will be measured from the date that the best response is first recorded until the date that PD is documented. For patients who continue treatment post progression, the date of Disease Progression (PD) documentation will be used for analysis. The DR will be summarized using descriptive statistics (N, mean, standard deviation, minimum, and maximum).

Description: DCR will be defined as the percentage of patients who have achieved CR, PR, or SD for at least 12 weeks. The DCR will be summarized using descriptive statistics (N, mean, standard deviation, minimum, and maximum).

Description: PFS will be calculated as 1+ the number of days from the first dose of study drugs to documented radiographic progression or death due to any cause over a period of 1 year. For patients who continue treatment post-progression, the date of radiographic progression will be used for PFS analysis. For patients who continue treatment post-progression, the date of radiographic progression will be used for PFS analysis. The Kaplan-Meier analysis will be used to calculate the median PFS with 95% confidence interval.

Description: OS will be calculated as 1+ the number of days from the first dose of study drugs to death due to any cause over a period of 1 year. The Kaplan-Meier analysis will be used to calculate the median OS with 95% confidence interval.

Primary Outcomes

Description: ≤1 out of 6 at highest dose level below the maximal administered dose. If 0 of these 3 additional participants experience a dose limiting toxicity (DLT) (1 of 6), proceed to the next dose level. If 1 or more of the 3 additional participants experience DLT (2 of 6), then dose escalation is stopped, and this dose is declared the maximal administered dose (highest dose administered). Three (3) additional participants will be entered at the next lowest dose level if only 3 participants were treated previously at that dose.

Secondary Outcomes

Description: defined as the best overall response recorded from the start of the treatment until disease progression from the start of treatment. The frequency and percentages of patients with a best overall response rate of complete response (CR), partial response (PR), stable disease (SD), or progressive disease (PD) will be determined based on RECIST 1.1 criteria. We will compute a 95% confidence interval using a binomial distribution.

Description: The DR for CR and PR will be measured from the date that the best response if first recorded until the date that PD is documented over the period of 2 years. For patients who continue treatment post-progression, the date of PD documentation will be used for analysis. The DR will be summarized using descriptive statistics (N, mean, standard deviation, minimum, and maximum)

Description: The depth of response will be assessed by RECIST 1.1 criteria. The DOR will be summarized using descriptive statistics (N, mean, standard deviation, minimum, and maximum).

Description: Defined as the percentage of patients who have achieved CR, PR, or SD for at least 12 weeks. The DCR will be summarized using descriptive statistics (N, mean, standard deviation, minimum, and maximum).

Description: PFS will be calculated as 1+ the number of days from the first dose of alisertib to documented radiographic progression or death due to any cause over a period of 2 years. For patients who continue treatment post-progression, the date of radiographic progression will be used for PFS analysis. The Kaplan-Meier analysis will be used to calculate the mean PFS with 95% confidence interval.

Description: OS will be calculated as 1+ the number of days from the first dose of alisertib to death due to any cause over a period of 2 years. The Kaplan-Meier analysis will be used to calculate the mean OS with 95% confidence interval.

Description: Defined as the percentage of patients who have achieved CR, PR, or SD in the CNS for at least 12 weeks. The CNS disease control rate will be summarized using descriptive statistics (N, mean, standard deviation, minimum, and maximum).

Description: Pre-treatment tumor biopsy formalin-fixed paraffin-embedded (FFPE) samples will be stained for TPX2 expression by IHC. TPX2 IHC staining will be scored using the following scale: 0, 0-10% of tissue stained positive; 1, 10-20% stained positive; 2, 20-40% stained positive; 3, 40-70% stained positive; and 4, > 70% positive cells. The sum of staining score index (intensity + extent) will be designated as follows: 0-2, negative expression; 3-4, strong expression. The IHC score will be generated from three different areas of the slides and an average score will be calculated for each sample. We will determine whether there is a difference in TPX2 staining between responders and non-responders to alisertib + osimertinib treatment by the Fisher's exact test.

Description: Plasma will be collected to measure the drug concentrations at the indicated time points and area under curve (AUC) 0-24 hours. The area under the curve (AUC) is the definite integral in a plot of drug concentration in blood plasma vs. time

Description: Plasma will be collected to measure the drug concentrations at the indicated time points and Cmax will be calculated. It is a standard measurement in pharmacokinetics

Description: Plasma will be collected to measure the drug concentrations at the indicated time points and Tmax will be calculated. It is a standard measurement in pharmacokinetics