A Study of Alisertib (MLN8237) in Adult East Asian Participants With Advanced Solid Tumors or Lymphomas

• Sponsor: Millennium Pharmaceuticals, Inc. (Industry)
• Overall Status: Completed
• CT.gov ID: NCT01512758
• Collaborator: (none)
• Enrollment: 36
• Location: 1
• Arms: 2
• Actual Duration (Months): 20
• Patients Per Site Per Month: 1.8

Study Details

Study Description

Brief Summary

The purpose of this study was to determine the safety profile, maximum tolerated dose (MTD), recommended Phase 2 dose (RP2D), and to characterize the pharmacokinetic (PK) profile of alisertib twice daily (BID) dosing for 7 days in East Asian participants with advanced solid tumors or lymphomas. The secondary objective was to describe any antitumor activity that may have been observed with alisertib treatment.

Condition or Disease	Intervention/Treatment	Phase
Advanced Solid Tumors; Lymphomas	Drug: Alisertib	Phase 1

Detailed Description

The drug being tested in this study is called alisertib (MLN8237). Alisertib is being tested to treat people who have advanced solid tumors or lymphomas for which standard curative or life-prolonging treatment did not exist or was no longer effective or tolerable. This study evaluated the safety and pharmacokinetic (PK) profile, and maximum tolerated dose (MTD) and recommended Phase 2 dose (RP2D) of alisertib, as well as any antitumor activity.

The study enrolled 36 patients. Participants were assigned to one of the two treatment groups and received:

• Alisertib 30 mg

• Alisertib 40 mg All participants took two enteric-coated tablets every 12 hours each day for 7 days followed by a 14-day rest period in a 21-day cycle for up to 16 cycles.

This multi-center trial is conducted in East Asia. The overall time to participate in this study was 24 months, unless it was determined that a participant would derive benefit from continued therapy beyond 24 months. Participants made multiple visits to the clinic, and were contacted up to a maximum of 30 days after last dose of study drug for a follow-up assessment.

Study Design

• Study Type: Interventional
• Actual Enrollment: 36 participants
• Allocation: Non-Randomized
• Intervention Model: Parallel Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: A Phase 1 Dose Escalation and Pharmacokinetic Study of Alisertib (MLN8237), an Aurora A Kinase Inhibitor, in Adult East Asian Patients With Advanced Solid Tumors or Lymphomas
• Actual Study Start Date: Feb 6, 2012
• Actual Primary Completion Date: Oct 8, 2013
• Actual Study Completion Date: Oct 8, 2013

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Alisertib 30 mg Alisertib 30 mg enteric-coated tablets (ECT), orally, twice a day (BID) for 7 days, followed by a 14-day rest period, in 21-day cycles until there is evidence of disease progression or unacceptable alisertib-related toxicities (up to 16 cycles). Cycles could be extended to 28-day cycles (with additional 7-day rest period) if all alisertib-related toxicities (except alopecia) were not resolved to less than Grade 2.	Drug: Alisertib; Alisertib enteric-coated tablets; Other Names: MLN8237
Experimental: Alisertib 40 mg Alisertib 40 mg ECT, orally, BID for 7 days, followed by a 14-day rest period, in 21-day cycles until there is evidence of disease progression or unacceptable alisertib-related toxicities (up to 7 cycles). Cycles could be extended to 28-day cycles (with additional 7-day rest period) if all alisertib-related toxicities (except alopecia) were not resolved to less than Grade 2.	Drug: Alisertib; Alisertib enteric-coated tablets; Other Names: MLN8237

Outcome Measures

Primary Outcome Measures

1. Maximum Tolerated Dose (MTD) and Recommended Phase 2 Dose (RP2D) [Treatment Cycle 1]

   MTD was defined as highest dose at which <2 participants experienced a dose-limiting toxicity (DLT). DLT was defined as any of the following events considered possibly related to therapy with alisertib by the investigator: 1. Grade 4 neutropenia (absolute neutrophil count <500 cells/mm^3) for >7 days; 2. Grade 4 neutropenia with fever (oral or ear temperature ≥38.5°C); 3. Grade 4 thrombocytopenia (platelets <25,000/mm^3) for >7 days; 4. Platelet count <10,000 cells/mm^3; 5. ≥Grade 3 thrombocytopenia with clinically significant bleeding; 6. Delay in initiation of subsequent cycle by >7 days due to treatment-related toxicity; 7. ≥Grade 3 nonhematological toxicity except following: a. ≥Grade 3 nausea and/or emesis in the absence of optimal antiemetic therapy; b. ≥Grade 3 diarrhea in the absence of optimal supportive therapy; c. Grade 3 fatigue lasting <1 week; d. Other Grade 3 nonhematological toxicity that can be safely and reliably controlled to ≤Grade 2 with appropriate treatment.

2. Number of Participants With Adverse Events and Serious Adverse Events [First dose to 30 days past last dose (Up to 12.1 Months)]

   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. A Serious Adverse Event (SAE) A serious is any experience that suggests a significant hazard, contraindication, side effect or precaution that: results in death, is life-threatening, required in-patient hospitalization or prolongation of existing hospitalization, results in persistent or significant disability/incapacity, is a congenital anomaly/birth defect or is medically significant.

3. Number of Participants With Abnormal Clinical Laboratory Values Reported as Adverse Events [First dose to 30 days past last dose (Up to 12.1 Months)]

   Laboratory AEs in the following system organ classes (SOCs) are reported: blood and lymphatic system disorders, investigations, and metabolism and nutrition disorders. An abnormal laboratory value was assessed as an AE if that value lead to discontinuation or delay in treatment, dose modification, therapeutic intervention, or was considered by the investigator to be a clinically significant change from baseline. A treatment¬-emergent adverse event (TEAE) is defined as an adverse event with an onset that occurs after receiving study drug.

4. Number of Participants With Clinically Significant Changes in Vital Signs Reported as Adverse Events [First dose to 30 days past last dose (Up to 12.1 Months)]

   Vital signs (blood pressure, pulse rate, and oral temperature) measurements were collected throughout the study.

5. Cmax: Maximum Observed Concentration for Alisertib [Cycle 1 Days 1 and 7 predose and at multiple time points (up to 12 hours) postdose]

6. Tmax: Time to First Occurrence of Cmax for Alisertib [Cycle 1 Days 1 and 7 predose and at multiple time points (up to 12 hours) postdose]

7. AUCτ: Area Under the Concentration-Time Curve From Time 0 to End of Dosing Interval (τ) for Alisertib [Cycle 1 Days 1 and 7 predose and at multiple time points (up to 12 hours) postdose]

8. Dose Normalized AUCτ: Area Under the Concentration-Time Curve From Time 0 to Time t for Alisertib [Cycle 1 Day 7 predose and at multiple time points (up to 12 hours) postdose]

   Dose normalized AUCτ was obtained using AUCτ divided by alisertib dose in milligrams.

9. T1/2: Terminal Half-Life for Alisertib [Cycle 1 Day 7 predose and at multiple time points (up to 12 hours) postdose]

10. Rac: Accumulation Ratio for Alisertib [Cycle 1 Day 7 predose and at multiple time points (up to 12 hours) postdose]

11. PTR: Peak Trough Ratio During a Dosing Interval, at Steady State for Alisertib [Cycle 1 Day 7 predose and at multiple time points (up to 12 hours) postdose]

12. CLss/F: Apparent Clearance After Extravascular Administration, at Steady State, Calculated Using AUCτ for Alisertib [Cycle 1 Day 7 predose and at multiple time points (up to 12 hours) postdose]

Secondary Outcome Measures

1. Best Overall Response Rate Based on Investigator Assessment [Baseline and every 2 cycles for up to 24 months or until progressive disease]

   Best overall response rate is defined as the percentage of participants with complete response (CR) and/or partial response (PR) as assessed by the Investigator using Lymphoma International Working Group (IWG) Criteria or Response Evaluation Criteria in Solid Tumors (RECIST) criteria 1.1 for target lesions and assessed by CT, PET or MRI. IWG criteria for CR is defined as the disappearance of all evidence of disease and PR is defined as regression of measurable disease and no new sites. RECIST response criteria is defined as: CR is defined as disappearance of all target lesions and PR is defined as 30% decrease in the sum of the longest diameter of target lesions.

2. Duration of Response [First documented response until disease progression; approximately 12 months]

   DOR is defined as the time from the date of first documentation of a CR response to the date of first documentation of PD according to IWG criteria or RECIST criteria 1.1. IWG PD is defined as PD is defined as any new lesion or increase by >50% of previously involved sites from nadir. RECIST PD is defined as unequivocal progression of existing non-target lesions.

3. Concentrations of Relevant Tumor Markers [Cycle 1, Day 1; at end of Cycle 2 and every 2 cycles thereafter; and at end treatment; approximately 12 months]

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years and Older
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria:

• Male or female East Asian participants 18 years or older

• Histologically or cytologically confirmed metastatic and/or advanced solid tumors or lymphomas for which no effective standard treatment is available

• Eastern Cooperative Oncology Group (ECOG) performance status 0 or 1

• Expected survival longer than 3 months from study enrollment

• Radiographically or clinically evaluable tumor

• Female participants who are post menopausal for at least 1 year, surgically sterile, or agree to practice 2 effective methods of contraception through 30 days after the last dose of study drug or agree to abstain from heterosexual intercourse

• Male participants who agree to practice effective barrier contraception through 6 months after the last dose of alisertib or agree to abstain from heterosexual intercourse

• Voluntary written consent

Exclusion Criteria:

• Female participants who are lactating or pregnant

• Treatment with any investigational products, systemic antineoplastic treatment, or antineoplastic treatment with glucocorticoids within 21 days preceding the first dose of alisertib

• Treatment with nitrosoureas, mitomycin C, rituximab, alemtuzumab, or other unconjugated antibody treatment within 42 days (21 days if clear evidence of progressive disease)

• Medical conditions requiring daily, chronic, or regular use of proton pump inhibitors or H2-receptor antagonists

• Treatment with radioimmunoconjugates such as ibritumomab tiuxetan or tositumomab within 56 days preceding first alisertib dose

• Major surgery within the 14 days preceding the first dose of alisertib

• Life-threatening or uncontrolled medical illness unrelated to cancer

• Known gastrointestinal (GI) disease or procedures that could interfere with the oral absorption or tolerance of alisertib

• Inability to swallow capsules

• Inadequate bone marrow or other organ function

• Diagnosed or treated for another malignancy within 2 years of first dose of alisertib, or previously diagnosed with another malignancy and have any radiographic or biochemical marker evidence of active disease. In the case of prior prostate cancer treated with radiotherapy, the prostate specific antigen (PSA) may be detectable, but must be < 1 ng/mL. Participants with completely resected basal cell carcinoma, squamous cell carcinoma of the skin, or in situ malignancy of any type are not excluded

• Other severe acute or chronic medical or psychiatric conditions, including uncontrolled diabetes, or laboratory abnormality

• Known or suspected human immunodeficiency virus (HIV) positive or hepatitis B surface antigen-positive status, or known or suspected active hepatitis C infection

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	National Cancer Centre	Tiong Bahru		Singapore	169610

Sponsors and Collaborators

• Millennium Pharmaceuticals, Inc.

Investigators

• Study Director: Medical Director Clinical Science, Millennium Pharmaceuticals, Inc.

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: Millennium Pharmaceuticals, Inc.
• ClinicalTrials.gov Identifier: NCT01512758
• Other Study ID Numbers: C14013; 1015004128; U1111-1187-6744
• First Posted: Jan 19, 2012
• Last Update Posted: Mar 15, 2019
• Last Verified: Nov 1, 2018

• Keywords provided by Millennium Pharmaceuticals, Inc.: East Asian Patients; Advanced solid tumors; Lymphomas; MLN8237; Alisertib; Aurora A Kinase Inhibitor; Drug therapy
• Additional relevant MeSH terms: Lymphoma

Study Results

Participant Flow

Recruitment Details	Participants took part in the study at 8 investigative sites in Singapore, Taiwan, Hong Kong, and South Korea from 06 February 2012 to 08 October 2013.
Pre-assignment Detail	Participants with a diagnosis of advanced solid tumors or lymphomas received alisertib 30 mg or 40 mg twice a day (BID) for 7 consecutive days followed by a 14-day rest period in 21-day cycles (28-day cycles with additional 7-day rest period if all alisertib-related toxicities [except alopecia] were not resolved to less than Grade 2).

Arm/Group Title	Alisertib 30 mg	Alisertib 40 mg
Arm/Group Description	Alisertib 30 mg enteric-coated tablets (ECT), orally, twice a day (BID) for 7 days, followed by a 14-day rest period, in 21-day cycles until there is evidence of disease progression or unacceptable alisertib-related toxicities (up to 16 cycles). Cycles could be extended to 28-day cycles (with additional 7-day rest period) if all alisertib-related toxicities (except alopecia) were not resolved to less than Grade 2.	Alisertib 40 mg ECT, orally, BID for 7 days, followed by a 14-day rest period, in 21-day cycles until there is evidence of disease progression or unacceptable alisertib-related toxicities (up to 7 cycles). Cycles could be extended to 28-day cycles (with additional 7-day rest period) if all alisertib-related toxicities (except alopecia) were not resolved to less than Grade 2.
Period Title: Overall Study
STARTED	30	6
COMPLETED	30	6
NOT COMPLETED	0	0

Baseline Characteristics

Arm/Group Title	Alisertib 30 mg	Alisertib 40 mg	Total
Arm/Group Description	Alisertib 30 mg enteric-coated tablets (ECT), orally, twice a day (BID) for 7 days, followed by a 14-day rest period, in 21-day cycles until there is evidence of disease progression or unacceptable alisertib-related toxicities (up to 16 cycles). Cycles could be extended to 28-day cycles (with additional 7-day rest period) if all alisertib-related toxicities (except alopecia) were not resolved to less than Grade 2.	Alisertib 40 mg ECT, orally, BID for 7 days, followed by a 14-day rest period, in 21-day cycles until there is evidence of disease progression or unacceptable alisertib-related toxicities (up to 7 cycles). Cycles could be extended to 28-day cycles (with additional 7-day rest period) if all alisertib-related toxicities (except alopecia) were not resolved to less than Grade 2.	Total of all reporting groups
Overall Participants	30	6	36
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	57.2 (9.52)	50.7 (18.25)	56.1 (11.35)
Sex: Female, Male (Count of Participants)
Female	11 36.7%	2 33.3%	13 36.1%
Male	19 63.3%	4 66.7%	23 63.9%
Race/Ethnicity, Customized (Count of Participants)
Asian (Chinese)	17 56.7%	5 83.3%	22 61.1%
Asian (Korean)	13 43.3%	0 0%	13 36.1%
Malay	0 0%	1 16.7%	1 2.8%
Race/Ethnicity, Customized (Count of Participants)
Not Hispanic or Latino	30 100%	6 100%	36 100%
Region of Enrollment (Count of Participants)
Singapore	4 13.3%	6 100%	10 27.8%
Taiwan	8 26.7%	0 0%	8 22.2%
Hong Kong	5 16.7%	0 0%	5 13.9%
Korea, Republic of	13 43.3%	0 0%	13 36.1%
Height (cm) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [cm]	162.5 (6.84)	161.9 (6.61)	162.4 (6.71)
Weight (kg) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [kg]	57.78 (9.255)	62.30 (11.714)	58.53 (9.669)
Body Surface Area (BSA) (m^2) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [m^2]	1.611 (0.1487)	1.667 (0.1613)	1.620 (0.1499)

Outcome Measures

1. Primary Outcome

Title	Maximum Tolerated Dose (MTD) and Recommended Phase 2 Dose (RP2D)
Description	MTD was defined as highest dose at which <2 participants experienced a dose-limiting toxicity (DLT). DLT was defined as any of the following events considered possibly related to therapy with alisertib by the investigator: 1. Grade 4 neutropenia (absolute neutrophil count <500 cells/mm^3) for >7 days; 2. Grade 4 neutropenia with fever (oral or ear temperature ≥38.5°C); 3. Grade 4 thrombocytopenia (platelets <25,000/mm^3) for >7 days; 4. Platelet count <10,000 cells/mm^3; 5. ≥Grade 3 thrombocytopenia with clinically significant bleeding; 6. Delay in initiation of subsequent cycle by >7 days due to treatment-related toxicity; 7. ≥Grade 3 nonhematological toxicity except following: a. ≥Grade 3 nausea and/or emesis in the absence of optimal antiemetic therapy; b. ≥Grade 3 diarrhea in the absence of optimal supportive therapy; c. Grade 3 fatigue lasting <1 week; d. Other Grade 3 nonhematological toxicity that can be safely and reliably controlled to ≤Grade 2 with appropriate treatment.
Time Frame	Treatment Cycle 1

Outcome Measure Data

Analysis Population Description

DLT-Evaluable population is defined as participants with a common race who had not used granulocyte colony-stimulating factor (G-CSF) in cycle 1, and either experienced DLT during Cycle 1 or received at least 85% of planned doses of alisertib and have sufficient follow up data to allow investigator and sponsor to determine whether a DLT occurred.

Arm/Group Title	Alisertib 30 mg or 40 mg
Arm/Group Description	Alisertib 30 mg or 40 mg enteric-coated tablets, orally, twice a day (BID) on Days 1 through 7, followed by a 14-day rest period, in a 21-day cycle (28-day cycle with additional 7-day rest period if all alisertib-related toxicities [except alopecia] were not resolved to less than Grade 2), for a maximum of 24 months or until there is evidence of disease progression or unacceptable treatment related toxicity (up to 16 cycles).
Measure Participants	8
Number [mg]	30

2. Primary Outcome

Title	Number of Participants With Adverse Events and Serious Adverse Events
Description	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. A Serious Adverse Event (SAE) A serious is any experience that suggests a significant hazard, contraindication, side effect or precaution that: results in death, is life-threatening, required in-patient hospitalization or prolongation of existing hospitalization, results in persistent or significant disability/incapacity, is a congenital anomaly/birth defect or is medically significant.
Time Frame	First dose to 30 days past last dose (Up to 12.1 Months)

Outcome Measure Data

Analysis Population Description

Safety Population is defined as all participants who received at least one dose of alisertib.

Arm/Group Title	Alisertib 30 mg	Alisertib 40 mg
Arm/Group Description	Alisertib 30 mg enteric-coated tablets (ECT), orally, twice a day (BID) for 7 days, followed by a 14-day rest period, in 21-day cycles until there is evidence of disease progression or unacceptable alisertib-related toxicities (up to 16 cycles). Cycles could be extended to 28-day cycles (with additional 7-day rest period) if all alisertib-related toxicities (except alopecia) were not resolved to less than Grade 2.	Alisertib 40 mg ECT, orally, BID for 7 days, followed by a 14-day rest period, in 21-day cycles until there is evidence of disease progression or unacceptable alisertib-related toxicities (up to 7 cycles). Cycles could be extended to 28-day cycles (with additional 7-day rest period) if all alisertib-related toxicities (except alopecia) were not resolved to less than Grade 2.
Measure Participants	30	6
AE	30 100%	6 100%
SAE	15 50%	4 66.7%

3. Primary Outcome

Title	Number of Participants With Abnormal Clinical Laboratory Values Reported as Adverse Events
Description	Laboratory AEs in the following system organ classes (SOCs) are reported: blood and lymphatic system disorders, investigations, and metabolism and nutrition disorders. An abnormal laboratory value was assessed as an AE if that value lead to discontinuation or delay in treatment, dose modification, therapeutic intervention, or was considered by the investigator to be a clinically significant change from baseline. A treatment¬-emergent adverse event (TEAE) is defined as an adverse event with an onset that occurs after receiving study drug.
Time Frame	First dose to 30 days past last dose (Up to 12.1 Months)

Outcome Measure Data

Analysis Population Description

Safety Population is defined as all participants who received at least one dose of alisertib.

Arm/Group Title	Alisertib 30 mg	Alisertib 40 mg
Arm/Group Description	Alisertib 30 mg enteric-coated tablets (ECT), orally, twice a day (BID) for 7 days, followed by a 14-day rest period, in 21-day cycles until there is evidence of disease progression or unacceptable alisertib-related toxicities (up to 16 cycles). Cycles could be extended to 28-day cycles (with additional 7-day rest period) if all alisertib-related toxicities (except alopecia) were not resolved to less than Grade 2.	Alisertib 40 mg ECT, orally, BID for 7 days, followed by a 14-day rest period, in 21-day cycles until there is evidence of disease progression or unacceptable alisertib-related toxicities (up to 7 cycles). Cycles could be extended to 28-day cycles (with additional 7-day rest period) if all alisertib-related toxicities (except alopecia) were not resolved to less than Grade 2.
Measure Participants	30	6
Neutropenia	19 63.3%	5 83.3%
Anaemia	9 30%	4 66.7%
Thrombocytopenia	6 20%	1 16.7%
Febrile neutropenia	4 13.3%	1 16.7%
Leukopenia	2 6.7%	2 33.3%
White blood cell count decreased	7 23.3%	0 0%
Aspartate aminotransferase increased	6 20%	0 0%
Neutrophil count decreased	4 13.3%	0 0%
Alanine aminotransferase increased	4 13.3%	0 0%
Platelet count decreased	3 10%	0 0%
Blood bilirubin increased	2 6.7%	0 0%
Haemoglobin decreased	1 3.3%	0 0%
Blood creatinine increased	0 0%	1 16.7%
Urine output decreased	1 3.3%	0 0%
Hypokalaemia	4 13.3%	3 50%
Hypercalcaemia	0 0%	1 16.7%
Hyponatraemia	1 3.3%	0 0%

4. Primary Outcome

Title	Number of Participants With Clinically Significant Changes in Vital Signs Reported as Adverse Events
Description	Vital signs (blood pressure, pulse rate, and oral temperature) measurements were collected throughout the study.
Time Frame	First dose to 30 days past last dose (Up to 12.1 Months)

Outcome Measure Data

Analysis Population Description

Safety Population is defined as all participants who received at least one dose of alisertib.

Arm/Group Title	Alisertib 30 mg	Alisertib 40 mg
Arm/Group Description	Alisertib 30 mg enteric-coated tablets (ECT), orally, twice a day (BID) for 7 days, followed by a 14-day rest period, in 21-day cycles until there is evidence of disease progression or unacceptable alisertib-related toxicities (up to 16 cycles). Cycles could be extended to 28-day cycles (with additional 7-day rest period) if all alisertib-related toxicities (except alopecia) were not resolved to less than Grade 2.	Alisertib 40 mg ECT, orally, BID for 7 days, followed by a 14-day rest period, in 21-day cycles until there is evidence of disease progression or unacceptable alisertib-related toxicities (up to 7 cycles). Cycles could be extended to 28-day cycles (with additional 7-day rest period) if all alisertib-related toxicities (except alopecia) were not resolved to less than Grade 2.
Measure Participants	30	6
Hypertension	1 3.3%	0 0%
Hypotension	1 3.3%	0 0%
Bradycardia	1 3.3%	0 0%
Pyrexia	8 26.7%	1 16.7%

5. Primary Outcome

Title	Cmax: Maximum Observed Concentration for Alisertib
Time Frame	Cycle 1 Days 1 and 7 predose and at multiple time points (up to 12 hours) postdose

Outcome Measure Data

Analysis Population Description

Pharmacokinetic (PK) Population is defined as all participants with sufficient dosing and PK concentration time data to reliably estimate PK parameters. "n" in the category is the number of participants with data available at the given time-point.

Arm/Group Title	Alisertib 30 mg	Alisertib 40 mg
Arm/Group Description	Alisertib 30 mg enteric-coated tablets (ECT), orally, twice a day (BID) for 7 days, followed by a 14-day rest period, in 21-day cycles until there is evidence of disease progression or unacceptable alisertib-related toxicities (up to 16 cycles). Cycles could be extended to 28-day cycles (with additional 7-day rest period) if all alisertib-related toxicities (except alopecia) were not resolved to less than Grade 2.	Alisertib 40 mg ECT, orally, BID for 7 days, followed by a 14-day rest period, in 21-day cycles until there is evidence of disease progression or unacceptable alisertib-related toxicities (up to 7 cycles). Cycles could be extended to 28-day cycles (with additional 7-day rest period) if all alisertib-related toxicities (except alopecia) were not resolved to less than Grade 2.
Measure Participants	30	6
Day 1	1442.5 (534.80)	1871.7 (429.62)
Day 7	3000.0 (1329.38)	3686.7 (885.45)

6. Primary Outcome

Title	Tmax: Time to First Occurrence of Cmax for Alisertib
Time Frame	Cycle 1 Days 1 and 7 predose and at multiple time points (up to 12 hours) postdose

Outcome Measure Data

Analysis Population Description

PK Population is defined as all participants with sufficient dosing and PK concentration time data to reliably estimate PK parameters. "n" in the category is the number of participants with data available at the given time-point.

Arm/Group Title	Alisertib 30 mg	Alisertib 40 mg
Arm/Group Description	Alisertib 30 mg enteric-coated tablets (ECT), orally, twice a day (BID) for 7 days, followed by a 14-day rest period, in 21-day cycles until there is evidence of disease progression or unacceptable alisertib-related toxicities (up to 16 cycles). Cycles could be extended to 28-day cycles (with additional 7-day rest period) if all alisertib-related toxicities (except alopecia) were not resolved to less than Grade 2.	Alisertib 40 mg ECT, orally, BID for 7 days, followed by a 14-day rest period, in 21-day cycles until there is evidence of disease progression or unacceptable alisertib-related toxicities (up to 7 cycles). Cycles could be extended to 28-day cycles (with additional 7-day rest period) if all alisertib-related toxicities (except alopecia) were not resolved to less than Grade 2.
Measure Participants	30	6
Day 1	3.0	2.0
Day 7	2.9	2.0

7. Primary Outcome

Title	AUCτ: Area Under the Concentration-Time Curve From Time 0 to End of Dosing Interval (τ) for Alisertib
Time Frame	Cycle 1 Days 1 and 7 predose and at multiple time points (up to 12 hours) postdose

Outcome Measure Data

Analysis Population Description

PK Population is defined as all participants with sufficient dosing and PK concentration time data to reliably estimate PK parameters. "n" in the category is the number of participants with data available at the given time-point.

Arm/Group Title	Alisertib 30 mg	Alisertib 40 mg
Arm/Group Description	Alisertib 30 mg enteric-coated tablets (ECT), orally, twice a day (BID) for 7 days, followed by a 14-day rest period, in 21-day cycles until there is evidence of disease progression or unacceptable alisertib-related toxicities (up to 16 cycles). Cycles could be extended to 28-day cycles (with additional 7-day rest period) if all alisertib-related toxicities (except alopecia) were not resolved to less than Grade 2.	Alisertib 40 mg ECT, orally, BID for 7 days, followed by a 14-day rest period, in 21-day cycles until there is evidence of disease progression or unacceptable alisertib-related toxicities (up to 7 cycles). Cycles could be extended to 28-day cycles (with additional 7-day rest period) if all alisertib-related toxicities (except alopecia) were not resolved to less than Grade 2.
Measure Participants	30	6
Day 1	9549.0 (4119.30)	11811.7 (2845.76)
Day 7	24377.9 (13261.61)	30683.3 (9575.68)

8. Primary Outcome

Title	Dose Normalized AUCτ: Area Under the Concentration-Time Curve From Time 0 to Time t for Alisertib
Description	Dose normalized AUCτ was obtained using AUCτ divided by alisertib dose in milligrams.
Time Frame	Cycle 1 Day 7 predose and at multiple time points (up to 12 hours) postdose

Outcome Measure Data

Analysis Population Description

PK Population is defined as all participants with sufficient dosing and PK concentration time data to reliably estimate PK parameters.

Arm/Group Title	Alisertib 30 mg	Alisertib 40 mg
Arm/Group Description	Alisertib 30 mg enteric-coated tablets (ECT), orally, twice a day (BID) for 7 days, followed by a 14-day rest period, in 21-day cycles until there is evidence of disease progression or unacceptable alisertib-related toxicities (up to 16 cycles). Cycles could be extended to 28-day cycles (with additional 7-day rest period) if all alisertib-related toxicities (except alopecia) were not resolved to less than Grade 2.	Alisertib 40 mg ECT, orally, BID for 7 days, followed by a 14-day rest period, in 21-day cycles until there is evidence of disease progression or unacceptable alisertib-related toxicities (up to 7 cycles). Cycles could be extended to 28-day cycles (with additional 7-day rest period) if all alisertib-related toxicities (except alopecia) were not resolved to less than Grade 2.
Measure Participants	28	6
Mean (Standard Deviation) [nM*hr/mg]	812.9 (441.90)	766.8 (238.88)

9. Primary Outcome

Title	T1/2: Terminal Half-Life for Alisertib
Time Frame	Cycle 1 Day 7 predose and at multiple time points (up to 12 hours) postdose

Outcome Measure Data

Analysis Population Description

PK Population is defined as all participants with sufficient dosing and PK concentration time data to reliably estimate PK parameters.

Arm/Group Title	Alisertib 30 mg	Alisertib 40 mg
Arm/Group Description	Alisertib 30 mg enteric-coated tablets (ECT), orally, twice a day (BID) for 7 days, followed by a 14-day rest period, in 21-day cycles until there is evidence of disease progression or unacceptable alisertib-related toxicities (up to 16 cycles). Cycles could be extended to 28-day cycles (with additional 7-day rest period) if all alisertib-related toxicities (except alopecia) were not resolved to less than Grade 2.	Alisertib 40 mg ECT, orally, BID for 7 days, followed by a 14-day rest period, in 21-day cycles until there is evidence of disease progression or unacceptable alisertib-related toxicities (up to 7 cycles). Cycles could be extended to 28-day cycles (with additional 7-day rest period) if all alisertib-related toxicities (except alopecia) were not resolved to less than Grade 2.
Measure Participants	24	6
Mean (Standard Deviation) [hr]	16.750 (8.1710)	14.795 (4.5715)

10. Primary Outcome

Title	Rac: Accumulation Ratio for Alisertib
Time Frame	Cycle 1 Day 7 predose and at multiple time points (up to 12 hours) postdose

Outcome Measure Data

Analysis Population Description

PK Population is defined as all participants with sufficient dosing and PK concentration time data to reliably estimate PK parameters.

Arm/Group Title	Alisertib 30 mg	Alisertib 40 mg
Arm/Group Description	Alisertib 30 mg enteric-coated tablets (ECT), orally, twice a day (BID) for 7 days, followed by a 14-day rest period, in 21-day cycles until there is evidence of disease progression or unacceptable alisertib-related toxicities (up to 16 cycles). Cycles could be extended to 28-day cycles (with additional 7-day rest period) if all alisertib-related toxicities (except alopecia) were not resolved to less than Grade 2.	Alisertib 40 mg ECT, orally, BID for 7 days, followed by a 14-day rest period, in 21-day cycles until there is evidence of disease progression or unacceptable alisertib-related toxicities (up to 7 cycles). Cycles could be extended to 28-day cycles (with additional 7-day rest period) if all alisertib-related toxicities (except alopecia) were not resolved to less than Grade 2.
Measure Participants	28	6
Mean (Standard Deviation) [ratio]	2.830 (1.2955)	2.690 (1.0638)

11. Primary Outcome

Title	PTR: Peak Trough Ratio During a Dosing Interval, at Steady State for Alisertib
Time Frame	Cycle 1 Day 7 predose and at multiple time points (up to 12 hours) postdose

Outcome Measure Data

Analysis Population Description

PK Population is defined as all participants with sufficient dosing and PK concentration time data to reliably estimate PK parameters.

Arm/Group Title	Alisertib 30 mg	Alisertib 40 mg
Arm/Group Description	Alisertib 30 mg enteric-coated tablets (ECT), orally, twice a day (BID) for 7 days, followed by a 14-day rest period, in 21-day cycles until there is evidence of disease progression or unacceptable alisertib-related toxicities (up to 16 cycles). Cycles could be extended to 28-day cycles (with additional 7-day rest period) if all alisertib-related toxicities (except alopecia) were not resolved to less than Grade 2.	Alisertib 40 mg ECT, orally, BID for 7 days, followed by a 14-day rest period, in 21-day cycles until there is evidence of disease progression or unacceptable alisertib-related toxicities (up to 7 cycles). Cycles could be extended to 28-day cycles (with additional 7-day rest period) if all alisertib-related toxicities (except alopecia) were not resolved to less than Grade 2.
Measure Participants	28	6
Mean (Standard Deviation) [ratio]	2.254 (0.6458)	2.207 (0.3946)

12. Primary Outcome

Title	CLss/F: Apparent Clearance After Extravascular Administration, at Steady State, Calculated Using AUCτ for Alisertib
Time Frame	Cycle 1 Day 7 predose and at multiple time points (up to 12 hours) postdose

Outcome Measure Data

Analysis Population Description

PK Population is defined as all participants with sufficient dosing and PK concentration time data to reliably estimate PK parameters.

Arm/Group Title	Alisertib 30 mg	Alisertib 40 mg
Arm/Group Description	Alisertib 30 mg enteric-coated tablets (ECT), orally, twice a day (BID) for 7 days, followed by a 14-day rest period, in 21-day cycles until there is evidence of disease progression or unacceptable alisertib-related toxicities (up to 16 cycles). Cycles could be extended to 28-day cycles (with additional 7-day rest period) if all alisertib-related toxicities (except alopecia) were not resolved to less than Grade 2.	Alisertib 40 mg ECT, orally, BID for 7 days, followed by a 14-day rest period, in 21-day cycles until there is evidence of disease progression or unacceptable alisertib-related toxicities (up to 7 cycles). Cycles could be extended to 28-day cycles (with additional 7-day rest period) if all alisertib-related toxicities (except alopecia) were not resolved to less than Grade 2.
Measure Participants	28	6
Mean (Standard Deviation) [L/hr]	2.9357 (1.37091)	2.8083 (1.20259)

13. Secondary Outcome

Title	Best Overall Response Rate Based on Investigator Assessment
Description	Best overall response rate is defined as the percentage of participants with complete response (CR) and/or partial response (PR) as assessed by the Investigator using Lymphoma International Working Group (IWG) Criteria or Response Evaluation Criteria in Solid Tumors (RECIST) criteria 1.1 for target lesions and assessed by CT, PET or MRI. IWG criteria for CR is defined as the disappearance of all evidence of disease and PR is defined as regression of measurable disease and no new sites. RECIST response criteria is defined as: CR is defined as disappearance of all target lesions and PR is defined as 30% decrease in the sum of the longest diameter of target lesions.
Time Frame	Baseline and every 2 cycles for up to 24 months or until progressive disease

Outcome Measure Data

Analysis Population Description

Safety Population is defined as all participants who received at least one dose of alisertib.

Arm/Group Title	Alisertib 30 mg	Alisertib 40 mg
Arm/Group Description	Alisertib 30 mg enteric-coated tablets (ECT), orally, twice a day (BID) for 7 days, followed by a 14-day rest period, in 21-day cycles until there is evidence of disease progression or unacceptable alisertib-related toxicities (up to 16 cycles). Cycles could be extended to 28-day cycles (with additional 7-day rest period) if all alisertib-related toxicities (except alopecia) were not resolved to less than Grade 2.	Alisertib 40 mg ECT, orally, BID for 7 days, followed by a 14-day rest period, in 21-day cycles until there is evidence of disease progression or unacceptable alisertib-related toxicities (up to 7 cycles). Cycles could be extended to 28-day cycles (with additional 7-day rest period) if all alisertib-related toxicities (except alopecia) were not resolved to less than Grade 2.
Measure Participants	30	6
CR	0 0%	0 0%
PR	3 10%	0 0%

14. Secondary Outcome

Title	Duration of Response
Description	DOR is defined as the time from the date of first documentation of a CR response to the date of first documentation of PD according to IWG criteria or RECIST criteria 1.1. IWG PD is defined as PD is defined as any new lesion or increase by >50% of previously involved sites from nadir. RECIST PD is defined as unequivocal progression of existing non-target lesions.
Time Frame	First documented response until disease progression; approximately 12 months

Outcome Measure Data

Analysis Population Description

Safety Population is defined as all participants who received at least one dose of alisertib. Participants with response were evaluated.

Arm/Group Title	Alisertib 30 mg	Alisertib 40 mg
Arm/Group Description	Alisertib 30 mg enteric-coated tablets (ECT), orally, twice a day (BID) for 7 days, followed by a 14-day rest period, in 21-day cycles until there is evidence of disease progression or unacceptable alisertib-related toxicities (up to 16 cycles). Cycles could be extended to 28-day cycles (with additional 7-day rest period) if all alisertib-related toxicities (except alopecia) were not resolved to less than Grade 2.	Alisertib 40 mg ECT, orally, BID for 7 days, followed by a 14-day rest period, in 21-day cycles until there is evidence of disease progression or unacceptable alisertib-related toxicities (up to 7 cycles). Cycles could be extended to 28-day cycles (with additional 7-day rest period) if all alisertib-related toxicities (except alopecia) were not resolved to less than Grade 2.
Measure Participants	1	0
Median (Full Range) [days]	169

15. Secondary Outcome

Title	Concentrations of Relevant Tumor Markers
Time Frame	Cycle 1, Day 1; at end of Cycle 2 and every 2 cycles thereafter; and at end treatment; approximately 12 months

Outcome Measure Data

Analysis Population Description

Data was not analyzed as per the change in planned analysis (protocol amendment).

Arm/Group Title	Alisertib 30 mg	Alisertib 40 mg
Arm/Group Description	Alisertib 30 mg enteric-coated tablets (ECT), orally, twice a day (BID) for 7 days, followed by a 14-day rest period, in 21-day cycles until there is evidence of disease progression or unacceptable alisertib-related toxicities (up to 16 cycles). Cycles could be extended to 28-day cycles (with additional 7-day rest period) if all alisertib-related toxicities (except alopecia) were not resolved to less than Grade 2.	Alisertib 40 mg ECT, orally, BID for 7 days, followed by a 14-day rest period, in 21-day cycles until there is evidence of disease progression or unacceptable alisertib-related toxicities (up to 7 cycles). Cycles could be extended to 28-day cycles (with additional 7-day rest period) if all alisertib-related toxicities (except alopecia) were not resolved to less than Grade 2.
Measure Participants	0	0

Adverse Events

Time Frame	First dose to 30 days past last dose (Up to 12.1 Months)
Adverse Event Reporting Description	At each visit the Investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment.
Arm/Group Title	Alisertib 30 mg		Alisertib 40 mg
Arm/Group Description	Alisertib 30 mg enteric-coated tablets (ECT), orally, twice a day (BID) for 7 days, followed by a 14-day rest period, in 21-day cycles until there is evidence of disease progression or unacceptable alisertib-related toxicities (up to 16 cycles). Cycles could be extended to 28-day cycles (with additional 7-day rest period) if all alisertib-related toxicities (except alopecia) were not resolved to less than Grade 2.		Alisertib 40 mg ECT, orally, BID for 7 days, followed by a 14-day rest period, in 21-day cycles until there is evidence of disease progression or unacceptable alisertib-related toxicities (up to 7 cycles). Cycles could be extended to 28-day cycles (with additional 7-day rest period) if all alisertib-related toxicities (except alopecia) were not resolved to less than Grade 2.
All Cause Mortality
	Alisertib 30 mg		Alisertib 40 mg
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	/ (NaN)		/ (NaN)
Serious Adverse Events
	Alisertib 30 mg		Alisertib 40 mg
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	15/30 (50%)		4/6 (66.7%)
Blood and lymphatic system disorders
Febrile neutropenia	4/30 (13.3%)		1/6 (16.7%)
Anaemia	1/30 (3.3%)		1/6 (16.7%)
Leukopenia	1/30 (3.3%)		1/6 (16.7%)
Neutropenia	2/30 (6.7%)		3/6 (50%)
Gastrointestinal disorders
Stomatitis	3/30 (10%)		1/6 (16.7%)
Diarrhoea	2/30 (6.7%)		0/6 (0%)
Upper gastrointestinal haemorrhage	1/30 (3.3%)		0/6 (0%)
Small intestinal obstruction	1/30 (3.3%)		0/6 (0%)
Ascites	1/30 (3.3%)		0/6 (0%)
Haematochezia	1/30 (3.3%)		0/6 (0%)
General disorders
Pyrexia	1/30 (3.3%)		0/6 (0%)
Infections and infestations
Bacteraemia	1/30 (3.3%)		0/6 (0%)
Sepsis	1/30 (3.3%)		0/6 (0%)
Subcutaneous abscess	0/30 (0%)		1/6 (16.7%)
Urinary tract infection	1/30 (3.3%)		0/6 (0%)
Investigations
Platelet count decreased	1/30 (3.3%)		0/6 (0%)
Neutrophil count decreased	1/30 (3.3%)		0/6 (0%)
Metabolism and nutrition disorders
Hypokalaemia	0/30 (0%)		1/6 (16.7%)
Musculoskeletal and connective tissue disorders
Pain in extremity	1/30 (3.3%)		0/6 (0%)
Lower extremity mass	1/30 (3.3%)		0/6 (0%)
Axillary mass	1/30 (3.3%)		0/6 (0%)
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Cholangiocarcinoma	1/30 (3.3%)		0/6 (0%)
Cancer pain	0/30 (0%)		1/6 (16.7%)
Respiratory, thoracic and mediastinal disorders
Pneumonia aspiration	1/30 (3.3%)		0/6 (0%)
Pulmonary embolism	1/30 (3.3%)		0/6 (0%)
Other (Not Including Serious) Adverse Events
	Alisertib 30 mg		Alisertib 40 mg
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	30/30 (100%)		6/6 (100%)
Blood and lymphatic system disorders
Neutropenia	19/30 (63.3%)		3/6 (50%)
Anaemia	8/30 (26.7%)		3/6 (50%)
Thrombocytopenia	6/30 (20%)		1/6 (16.7%)
Leukopenia	2/30 (6.7%)		2/6 (33.3%)
Eye disorders
Vision blurred	2/30 (6.7%)		0/6 (0%)
Cataract	0/30 (0%)		1/6 (16.7%)
Gastrointestinal disorders
Diarrhoea	17/30 (56.7%)		3/6 (50%)
Stomatitis	16/30 (53.3%)		2/6 (33.3%)
Abdominal pain	6/30 (20%)		1/6 (16.7%)
Abdominal pain upper	7/30 (23.3%)		0/6 (0%)
Nausea	6/30 (20%)		1/6 (16.7%)
Vomiting	5/30 (16.7%)		1/6 (16.7%)
Oral pain	2/30 (6.7%)		2/6 (33.3%)
Constipation	3/30 (10%)		0/6 (0%)
Mouth ulceration	1/30 (3.3%)		2/6 (33.3%)
Abdominal discomfort	2/30 (6.7%)		0/6 (0%)
Haematochezia	2/30 (6.7%)		0/6 (0%)
Anal ulcer	0/30 (0%)		1/6 (16.7%)
Gingival pain	0/30 (0%)		1/6 (16.7%)
General disorders
Fatigue	12/30 (40%)		2/6 (33.3%)
Pyrexia	7/30 (23.3%)		1/6 (16.7%)
Asthenia	5/30 (16.7%)		0/6 (0%)
Oedema peripheral	3/30 (10%)		0/6 (0%)
Injection site pain	0/30 (0%)		1/6 (16.7%)
Hepatobiliary disorders
Hyperbilirubinaemia	2/30 (6.7%)		1/6 (16.7%)
Immune system disorders
Contrast media allergy	2/30 (6.7%)		0/6 (0%)
Infections and infestations
Upper respiratory tract infection	3/30 (10%)		0/6 (0%)
Nasopharyngitis	2/30 (6.7%)		0/6 (0%)
Injury, poisoning and procedural complications
Skin wound	0/30 (0%)		1/6 (16.7%)
Investigations
White blood cell count decreased	7/30 (23.3%)		0/6 (0%)
Aspartate aminotransferase increased	6/30 (20%)		0/6 (0%)
Alanine aminotransferase increased	4/30 (13.3%)		0/6 (0%)
Neutrophil count decreased	4/30 (13.3%)		0/6 (0%)
Platelet count decreased	3/30 (10%)		0/6 (0%)
Blood bilirubin increased	2/30 (6.7%)		0/6 (0%)
Blood creatinine increased	0/30 (0%)		1/6 (16.7%)
Metabolism and nutrition disorders
Decreased appetite	8/30 (26.7%)		0/6 (0%)
Hypokalaemia	4/30 (13.3%)		3/6 (50%)
Hypercalcaemia	0/30 (0%)		1/6 (16.7%)
Musculoskeletal and connective tissue disorders
Back pain	3/30 (10%)		1/6 (16.7%)
Pain in extremity	2/30 (6.7%)		0/6 (0%)
Nervous system disorders
Somnolence	4/30 (13.3%)		0/6 (0%)
Lethargy	0/30 (0%)		3/6 (50%)
Headache	2/30 (6.7%)		0/6 (0%)
Psychiatric disorders
Insomnia	4/30 (13.3%)		0/6 (0%)
Respiratory, thoracic and mediastinal disorders
Dyspnoea	3/30 (10%)		0/6 (0%)
Epistaxis	3/30 (10%)		0/6 (0%)
Cough	1/30 (3.3%)		1/6 (16.7%)
Productive cough	1/30 (3.3%)		1/6 (16.7%)
Skin and subcutaneous tissue disorders
Alopecia	14/30 (46.7%)		3/6 (50%)
Pruritus	7/30 (23.3%)		0/6 (0%)
Palmar-plantar erythrodysaesthesia syndrome	3/30 (10%)		3/6 (50%)
Rash maculo-papular	3/30 (10%)		3/6 (50%)
Skin hyperpigmentation	2/30 (6.7%)		2/6 (33.3%)
Dry skin	1/30 (3.3%)		1/6 (16.7%)
Pigmentation disorder	2/30 (6.7%)		0/6 (0%)

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

In general, Investigators may publish clinical data after the earlier of (i) publication by the Sponsor or (ii) 12 months following the abandonment, early termination or database lock; provided a copy of the publication provided to Sponsor at least 30 days ahead of publication, the Sponsor's confidential information is removed as may be requested by Sponsor and Investigator defers publication for up to 60 days in the event Sponsor provides notice that it intends to file a patent application.