Alisertib in Adults With Nonhematological Malignancies, Followed by Alisertib in Lung, Breast, Head and Neck or Gastroesophageal Malignancies

Toxicity according to National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE), version 4.0. DLT defined as any of the following considered related to alisertib by investigator: Grade 4 neutropenia (absolute neutrophil count \<500 cells/cubic meter \[cells/mm\^3\]) for \>7 days; Grade 4 neutropenia with coincident fever; Grade 4 thrombocytopenia (platelets \<25,000 cells/mm3) for \>7 days; Platelet count \<10,000 cells/mm3; Grade 3 thrombocytopenia with clinically significant bleeding; Delay in initiation of the subsequent therapy cycle by \>7 days due to treatment-related toxicity; \>=Grade 3 nonhematological toxicity except \>=Grade 3 nausea/emesis occurred in the absence of optimal antiemetic therapy; \>=Grade 3 diarrhea occurred in the absence of optimal supportive therapy with loperamide/comparable antidiarrheal; Grade 3 fatigue for \<1 week; Other Grade 3 nonhematological toxicity that could be safely, reliably controlled to \<=Grade 2 with appropriate treatment.

Time frame: Phase 1: Cycle 1 Day 1 to Cycle 2 Day 21

Population: DLT-Evaluable population: all participants in the Phase 1 portion of the study who either experienced DLT during Cycle 1 or completed at least 85% of the planned doses of alisertib and had sufficient follow-up data to allow the investigators and sponsor to determine whether DLT occurred.

Percentage of participants with objective response based assessment of complete response (CR) or partial response (PR) according to Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST). CR was defined as complete disappearance of all target lesions and non-target disease, with the exception of nodal disease. All nodes, both target and non-target, must decrease to normal (short axis less than \[\<\] 10 millimeter \[mm\]). No new lesions. PR was defined as greater than or equal to (\>=) 30 percent (%) decrease under baseline of the sum of diameters of all target lesions. The short axis was used in the sum for target nodes, while the longest diameter was used in the sum for all other target lesions. No unequivocal progression of non-target disease. No new lesions.

Time frame: Baseline until complete response or partial response, assessed every 2 cycles up to end of study (up to 50 cycles)

Population: Response-Evaluable population included all participants with measurable disease who received at least 1 dose of alisertib and had at least 1 post-baseline response assessment.

Area under the plasma concentration-time curve during a dosing interval, where tau is the length of the dosing interval.

Time frame: Days 1 and 7: predose, 30 minutes, 1, 2, 3, 4, 6, 8, and 12 hours postdose

Population: PK-Evaluable population included all participants who had sufficient dosing data and alisertib concentration-time data to permit calculation of alisertib PK parameters in Phase 1 where Days 1 and 7 assessment were available.

Maximum observed plasma concentration (Cmax) is the peak plasma concentration of a drug after administration, obtained directly from the plasma concentration-time curve.

Time frame: Days 1 and 7: predose, 30 minutes, 1, 2, 3, 4, 6, 8, and 12 hours post-dose

Population: Pharmacokinetic (PK)-Evaluable population included all participants who had sufficient dosing data and alisertib concentration-time data to permit calculation of alisertib PK parameters in Phase 1 where Days 1 and 7 assessment were available.

Peak to trough ratio was estimated as a ratio of Cmax at Day 7 and the minimum observed plasma concentration (Ctrough) of alisertib at Day 7. Cmax is the peak plasma concentration of a drug after administration, obtained directly from the plasma concentration-time curve. Ctrough is the minimum plasma concentration of a drug after administration, obtained directly from the plasma concentration-time curve.

Time frame: Day 7: predose, 30 minutes, 1, 2, 3, 4, 6, 8, and 12 hours postdose

Population: PK-Evaluable population included all participants who had sufficient dosing data and alisertib concentration-time data to permit calculation of alisertib PK parameters in Phase 1 where Days 1 and 7 assessment were available.

Rac was estimated as a ratio of AUC (0-tau) at Day 7 and AUC (0-tau) at Day 1. Area under the plasma concentration-time curve during a dosing interval, where tau is the length of the dosing interval.

Time frame: Days 1 and 7: predose, 30 minutes, 1, 2, 3, 4, 6, 8, and 12 hours postdose

Population: PK-Evaluable population included all participants who had sufficient dosing data and alisertib concentration-time data to permit calculation of alisertib PK parameters in Phase 1 where Days 1 and 7 assessment were available.

CL/F is apparent clearance of the drug from the plasma, calculated as the drug dose divided AUC(0-tau), expressed in liter per hour (L/hr).

Time frame: Day 7: predose, 30 minutes, 1, 2, 3, 4, 6, 8, and 12 hours postdose

Population: PK-Evaluable population included all participants who had sufficient dosing data and alisertib concentration-time data to permit calculation of alisertib PK parameters in Phase 1 where Day 7 assessment was available.

Terminal phase elimination half-life (T1/2) is the time required for half of the drug to be eliminated from the plasma.

Time frame: Day 7: predose, 30 minutes, 1, 2, 3, 4, 6, 8, and 12 hours postdose

Population: PK-Evaluable population included all participants who had sufficient dosing data and alisertib concentration-time data to permit calculation of alisertib PK parameters in Phase 1 where Day 7 assessment was available.

Tmax: Time to reach the maximum plasma concentration (Cmax), equal to time (hours) to Cmax.

Time frame: Days 1 and 7: predose, 30 minutes, 1, 2, 3, 4, 6, 8, and 12 hours postdose

Population: PK-Evaluable population included all participants who had sufficient dosing data and alisertib concentration-time data to permit calculation of alisertib PK parameters in Phase 1 where Day 1 and Day 7 assessment were available.

Time in days from the first documentation of objective tumor response to objective tumor progression or death due to any cancer. Duration of tumor response=(the date of the first documentation of objective tumor progression or death due to cancer minus the date of the first CR or PR that was subsequently confirmed plus 1). CR: complete disappearance of all target lesions and non-target disease, except nodal disease; all nodes decreased to normal; no new lesions. PR: \>=30% decrease under baseline of the sum of diameters of all target lesions; no unequivocal progression of non-target disease; no new lesions. Tumor progression: \>=20% increase in the sum of diameters of target lesions, taking as reference the smallest sum on study (this includes the baseline sum if that is the smallest on study); absolute increase of \>=5 mm; appearance of \>=1 new lesions is also considered progression. DOR calculated for the subgroup of participants with objective response.

Time frame: Baseline up to Week 50

Population: Included a subset of response-evaluable population who had objective tumor response.

An adverse event (AE) is defined as any untoward medical occurrence in a clinical investigation participant administered a drug; it does not necessarily have to have a causal relationship with this treatment. An AE can therefore be any unfavorable and unintended sign (example, a clinically significant abnormal laboratory finding), symptom, or disease temporally associated with the use of a drug, whether or not it is considered related to the drug. A treatment-emergent adverse event (TEAE) is defined as an adverse event with an onset that occurs after receiving study drug. A serious adverse event (SAE) is an AE resulting in any of the following outcomes or deemed significant for any other reason: death; initial or prolonged inpatient hospitalization; life-threatening experience (immediate risk of dying); persistent or significant disability/incapacity; or congenital anomaly; or a medically important event.

Time frame: Baseline up to 30 days after the last dose of study drug

Population: Safety population included all participants who received any amount of alisertib.

PFS was defined as the time from randomization (or the first dose of study treatment for non-randomized studies) to the first documentation of objective tumor progression or to death due to any cause, whichever occurred first. Tumor progression as per RECIST 1.1 was defined as at least 20% increase in the sum of diameters of target lesions, taking as reference the smallest sum on study (this included the baseline sum if that is the smallest on study). In addition to the relative increase of 20%, the sum must also demonstrate an absolute increase of at least 5 mm. The appearance of 1or more new lesions is also considered progression.

Time frame: Baseline until progressive disease, assessed every 2 cycles up to end of study (up to 50 cycles)

Population: Safety population included all participants who received any amount of alisertib.

In SCLC,chemo-sensitive/resistant population were analyzed;in breast cancers,ER2 and ER2 status were analyzed.HR+ =estrogen receptor-positive or progesterone receptor-positive. HER+ =human epidermal growth factor receptor 2 (HER2). Triple negative =negative for estrogen receptors, progesterone receptors, and HER2.Clinical response according to RECIST version 1.1. CR:complete disappearance of all target lesions,non-target disease,except nodal disease;all nodes decrease to normal (short axis \<10 mm);no new lesions. PR:\>=30% decrease under baseline of the sum of diameters of all target lesions (SLD);short axis was used in the sum for target nodes,longest diameter used in the sum for all other target lesions;no unequivocal progression of non-target disease;no new lesions. Progressive Disease (PD): \>=20% rise in SLD from the smallest value on study;unequivocal progression of existing non-target lesions. Stable Disease (SD):Neither sufficient shrinkage for PR nor sufficient increase for PD.

Time frame: 12 months

Population: Response-Evaluable population. Data is reported only for SCLC and breast cancer cohorts becuase these cohorts showed clinical meaningful single agent activity, thus subgroup analysis were done to assess whether a particular subgroup of participants was more or less responsive to alisertib. Rest of the cohorts did not show meaningful activity.

Time in days from start of study treatment to first documentation of objective tumor progression. Tumor progression as per RECIST 1.1 was defined as at least 20% increase in the sum of diameters of target lesions, taking as reference the smallest sum on study (this includes the baseline sum if that is the smallest on study). In addition to the relative increase of 20%, the sum must also demonstrate an absolute increase of at least 5 mm. The appearance of 1or more new lesions is also considered progression.

Time frame: Baseline until disease progression, assessed every 2 cycles up to end of study (up to 50 cycles)

Population: Safety population included all participants who received any amount of alisertib.