A Phase 2 Trial of MLN8237 in Adult Participants With Acute Myelogenous Leukemia and High-Grade Myelodysplastic Syndrome
Study Details
Study Description
Brief Summary
This is an open-label, multicenter, phase 2 study of alisertib (MLN8237) in participants with acute myeloid leukemia (AML) or myelodysplastic syndrome (MDS).
| Condition or Disease | Intervention/Treatment | Phase |
|---|---|---|
| Phase 2 |
Detailed Description
The drug being tested in this study is called alisertib (MLN8237). Alisertib is being tested to treat people who have acute myeloid leukemia (AML) or high-grade myelodysplastic syndrome (MDS). This study looked at the antitumor activity in people who received alisertib.
The study enrolled 57 patients. Participants were categorized by disease sub-types AML and
MDS. Participants received:
• Alisertib 50 mg
All participants took alisertib capsules every 12 hours each day for 7 days followed by a 14-day rest period in 21-day cycles for approximately 26 cycles.
This multi-center trial was conducted in North America and France. The overall time to participate in this study was until there is evidence of disease progression or unacceptable treatment-related toxicity. The participant could continue treatment beyond 12 months if it was considered by the Sponsor and the Investigator that they would derive benefit from continued alisertib treatment. Participants had weekly blood work and clinic visits, with disease assessments every 2 cycles (ie. every 6 weeks) up to and including Cycle 16. Reduced visits (every 12 weeks) were conducted for participants tolerating treatment beyond Cycle 16 and for participants off treatment without disease progression.
Study Design
Arms and Interventions
| Arm | Intervention/Treatment |
|---|---|
| Experimental: Alisertib Alisertib 50 mg, capsules, orally, twice daily for 7 days, followed by 14-day washout period, in 21-day cycles until disease progression or unacceptable treatment-related toxicity (Up to 26 Cycles). |
Drug: Alisertib
Alisertib capsules
Other Names:
|
Outcome Measures
Primary Outcome Measures
- Best Overall Response Rate (ORR) Based on Investigator's Assessment [Baseline and every 2 cycles up to Cycle 16 (up to Month 12), from Cycle 17 every 4 cycles until disease progression, after end of treatment every 12 weeks for up to 12 Months (Approximately 2.4 years)]
Best ORR is defined as the number of participants with complete remission(CR) or partial remission(PR) assessed by the Investigator using modified AML/MDS International Working Group(IWG) Criteria. AML:CR=neutrophils >1x10^9/L, platelets >100x10^9/L, bone marrow blasts(BMB) <5%, transfusion independent, no extramedullary disease(EMD); CRi=BMB <5%, transfusion independent, no EMD; PR=neutrophils >1x10^9/L, platelets >100x10^9/L, BMB >50% decrease and 5% to 25%, blasts <5% with Auer rods; PRi=BMB >50% decrease and 5% to 25%. MDS:CR=bone marrow: ≤5% myeloblasts with normal maturation, peripheral blood: hemoglobin ≥11 g/dL, platelets ≥100x10^9/L, neutrophils ≥1.0x10^9/L, blasts 0%; PR=all CR criteria if abnormal before treatment except: BMB decreased by ≥50% over pretreatment but still >5%; PRi=BMB decreased by ≥50% over pretreatment but still >5%; Marrow CR=bone marrow: ≤5% myeloblasts and decrease by ≥50% over pretreatment, peripheral blood hematologic improvement responses noted.
Secondary Outcome Measures
- Progression Free Survival (PFS) [Baseline and every 2 cycles up to Cycle 16 (up to Month 12), from Cycle 17 every 4 cycles until disease progression, after end of treatment every 12 weeks for up to 12 Months (Approximately 2.4 years)]
PFS is defined as the time from the date of first study drug administration to the date of first documented progressive disease (PD) or death.
- Duration of Response (DOR) [Baseline and every 2 cycles up to Cycle 16 (up to Month 12), from Cycle 17 every 4 cycles until disease progression, after end of treatment every 12 weeks for up to 12 Months (Approximately 2.4 years)]
Duration of response is defined as the time from the date of first documentation of a response to the date of first documented PD.
- Best Overall Hematologic Improvement (HI) Response for Myelodysplastic Syndrome Based on Investigator Assessment [Baseline and every 2 cycles up to Cycle 16 (up to Month 12), from Cycle 17 every 4 cycles until disease progression, after end of treatment every 12 weeks for up to 12 Months (Approximately 2.4 years)]
Best overall HI response is defined as percentage of participants with response as assessed by Investigator based on IWG criteria: 1)Erythroid response (pretreatment,<11 g/dL): hemoglobin (Hgb) increase by ≥1.5 g/dL, relevant reduction of units of red blood cell (RBC) transfusions by absolute number of at least 4 RBC transfusions/8 weeks compared to pretreatment transfusion number in previous 8 weeks. Only RBC transfusions given for Hgb of ≤9.0 g/dL pretreatment will count in RBC transfusion response evaluation. 2)Platelet response (pretreatment,<100x10^9/L):Absolute increase of ≥30x10^9/L for participants starting->20x10^9/L platelets, increase <20x10^9/L to >20x10^9/L by at least 100%. 3)Neutrophil response (pretreatment,<1.0x10^9/L):At least 100% increase and an absolute increase >0.5x10^9/L. 4)Progression or relapse after HI:At least 1 of following: 50% decrement from maximum response levels in granulocytes or platelets, or reduction in Hgb by ≥1.5 g/dL, or transfusion dependence.
- Number of Participants With Adverse Events (AEs), Serious Adverse Events (SAEs) and Deaths [First dose of study drug to 30 days after last dose (Up to 18.9 months)]
An AE is defined as any untoward medical occurrence in a participant administered a pharmaceutical product; the untoward medical occurrence does not necessarily have a causal relationship with this treatment. A serious adverse event (SAE) is defined as any untoward medical occurrence that at any dose results in death, is life-threatening, requires inpatient hospitalization or prolongation of an existing hospitalization, results in persistent or significant disability or incapacity, is a congenital anomaly/birth defect or is a medically important event. Relationship of each AE to study drug was determined by the Investigator.
- Number of Participants With Abnormal Vital Signs Reported as Treatment-Emergent Adverse Events [First dose of study drug to 30 days after last dose (Up to 18.9 months)]
Vital signs measurements (blood pressure, heart rate, and oral temperature) were obtained throughout the study. A treatment-emergent adverse event (TEAE) is defined as an adverse event with an onset that occurs after receiving study drug.
- Number of Participants With Abnormal Laboratory Values Reported as Treatment-Emergent Adverse Events [First dose of study drug to 30 days after last dose (Up to 18.9 months)]
Abnormal Laboratory Values for Chemistry or Hematology tests that were assessed by the investigator to be Grade 3 or higher using the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE). Grade 3=severe, Grade 4=life threatening or disabling and Grade 5=Death. A treatment--emergent adverse event (TEAE) is defined as an adverse event with an onset that occurs after receiving study drug.
Eligibility Criteria
Criteria
Inclusion Criteria:
Each participants must meet all of the following inclusion criteria:
-
Male or female participants 18 years or older
-
Eligible diagnoses:
-
Acute myelogenous leukemia (except acute promyelocytic leukemia [APL]) with > 10% bone marrow or peripheral blood blasts; failed to achieve complete response (CR) or relapse after prior therapy, not candidates for potentially curative treatment. Untreated participants > 60 are eligible if not candidates for standard induction.
-
High-grade myelodysplastic syndrome (MDS), defined by all the following features: International Prognostic Scoring System (IPSS) Intermediate-2 or High Risk; > 10% blasts on bone marrow examination; treatment failure from, or not candidates for, standard therapies including demethylating agents, e.g. azacytidine or decitabine.
-
Eastern Cooperative Oncology Group performance status 0-2
-
Female participants:
-
Postmenopausal for at least one year
-
Surgically sterile, or
-
If childbearing potential, agree to practice two effective methods of contraception or abstain from heterosexual intercourse.
- Male participants:
-
Practice effective barrier contraception to one month after the last dose of study drug, or
-
Abstain from heterosexual intercourse.
-
Voluntary written consent
-
Participants on hydroxyurea may be included
Exclusion Criteria:
-
Pregnant or lactating females
-
Known human immunodeficiency virus (HIV) positive or acquired immune deficiency syndrome (AIDS) - related illness
-
Serious medical or psychiatric illness that could, in the investigator's opinion, potentially interfere with the protocol completion
-
Total bilirubin > 1.5 × the upper limit of normal (ULN)
-
Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) > 2.5 × the ULN. AST, ALT may be elevated to 5 x the ULN if reasonably ascribed to underlying hematological disorder.
-
Calculated creatinine clearance < 30 mL/minute
-
Antineoplastic or radiotherapy within 14 days preceding the first dose
-
Myocardial infarction within 6 months of enrollment or current history of New York Heart Association (NYHA) Class III or IV heart failure, uncontrolled angina, severe uncontrolled ventricular arrhythmias, or electrocardiographic evidence of acute ischemia
-
Major surgery 14 days prior to the first dose
-
Clinically uncontrolled central nervous system (CNS) involvement.
-
Inability to swallow capsules
-
History of uncontrolled sleep apnea or conditions that result in excessive daytime sleepiness, such as chronic lung disease
Contacts and Locations
Locations
| Site | City | State | Country | Postal Code | |
|---|---|---|---|---|---|
| 1 | Hematology and Oncology Associates of Northern New Jersey | Morristown | New Jersey | United States | 07962 |
Sponsors and Collaborators
- Millennium Pharmaceuticals, Inc.
Investigators
- Study Director: Medical Director Clinical Science, Takeda
Study Documents (Full-Text)
None provided.More Information
Publications
None provided.- C14005
- 2008-006977-34
- U1111-1187-6569
Study Results
Participant Flow
| Recruitment Details | Participants took part in the study at 19 investigative sites in France, Canada and the United States from 10 February 2009 to 04 July 2011. |
|---|---|
| Pre-assignment Detail | Participants with a diagnosis of acute myelogenous leukemia or myelodysplastic syndrome received 50 mg alisertib twice daily for 7 days in 21 day cycles. Results are reported according to lymphoma disease subtypes: acute myelogenous leukemia and myelodysplastic syndrome. |
| Arm/Group Title | Alisertib 50 mg (Acute Myeloid Leukemia) | Alisertib 50 mg (Myelodysplastic Syndrome) |
|---|---|---|
| Arm/Group Description | Participants with acute myeloid leukemia received alisertib 50 mg, capsules, orally, twice daily for 7 days, followed by 14-day washout period, in 21-day cycles until disease progression or unacceptable treatment-related toxicity (Up to 26 Cycles). | Participants with myelodysplastic syndrome received alisertib 50 mg, capsules, orally, twice daily for 7 days, followed by 14-day washout period, in 21-day cycles until disease progression or unacceptable treatment-related toxicity (Up to 6 Cycles). |
| Period Title: Overall Study | ||
| STARTED | 46 | 11 |
| COMPLETED | 0 | 0 |
| NOT COMPLETED | 46 | 11 |
Baseline Characteristics
| Arm/Group Title | Alisertib 50 mg (Acute Myeloid Leukemia) | Alisertib 50 mg (Myelodysplastic Syndrome) | Total |
|---|---|---|---|
| Arm/Group Description | Participants with acute myeloid leukemia received alisertib 50 mg, capsules, orally, twice daily for 7 days, followed by 14-day washout period, in 21-day cycles until disease progression or unacceptable treatment-related toxicity (Up to 26 Cycles). | Participants with myelodysplastic syndrome received alisertib 50 mg, capsules, orally, twice daily for 7 days, followed by 14-day washout period, in 21-day cycles until disease progression or unacceptable treatment-related toxicity (Up to 6 Cycles). | Total of all reporting groups |
| Overall Participants | 46 | 11 | 57 |
| Age (years) [Mean (Standard Deviation) ] | |||
| Mean (Standard Deviation) [years] |
71.9
(7.41)
|
69.5
(12.50)
|
71.4
(8.54)
|
| Age, Customized (participants) [Number] | |||
| <60 years |
4
8.7%
|
2
18.2%
|
6
10.5%
|
| ≥60 years |
42
91.3%
|
9
81.8%
|
51
89.5%
|
| Sex: Female, Male (Count of Participants) | |||
| Female |
22
47.8%
|
3
27.3%
|
25
43.9%
|
| Male |
24
52.2%
|
8
72.7%
|
32
56.1%
|
| Race/Ethnicity, Customized (participants) [Number] | |||
| Hispanic or Latino |
2
4.3%
|
0
0%
|
2
3.5%
|
| Not Hispanic or Latino |
34
73.9%
|
9
81.8%
|
43
75.4%
|
| Not Reported |
10
21.7%
|
2
18.2%
|
12
21.1%
|
| Race/Ethnicity, Customized (participants) [Number] | |||
| White |
36
78.3%
|
10
90.9%
|
46
80.7%
|
| Black or African American |
3
6.5%
|
0
0%
|
3
5.3%
|
| Asian |
1
2.2%
|
0
0%
|
1
1.8%
|
| Not Reported |
6
13%
|
1
9.1%
|
7
12.3%
|
| Region of Enrollment (participants) [Number] | |||
| United States |
33
71.7%
|
9
81.8%
|
42
73.7%
|
| France |
11
23.9%
|
2
18.2%
|
13
22.8%
|
| Canada |
2
4.3%
|
0
0%
|
2
3.5%
|
| Height (cm) [Mean (Standard Deviation) ] | |||
| Mean (Standard Deviation) [cm] |
165.8
(8.35)
|
171.4
(9.98)
|
167.0
(8.93)
|
| Weight (kg) [Mean (Standard Deviation) ] | |||
| Mean (Standard Deviation) [kg] |
73.7
(13.80)
|
80.4
(17.27)
|
75.0
(14.62)
|
| Baseline Body Surface Area (BSA) (m^2) [Mean (Standard Deviation) ] | |||
| Mean (Standard Deviation) [m^2] |
1.83
(0.203)
|
1.94
(0.262)
|
1.86
(0.219)
|
| Years Since Initial Diagnosis (years) [Mean (Standard Deviation) ] | |||
| Mean (Standard Deviation) [years] |
0.65
(0.793)
|
0.82
(0.780)
|
0.68
(0.787)
|
| Eastern Cooperative Oncology Group (ECOG) Performance Status (participants) [Number] | |||
| 0 |
9
19.6%
|
3
27.3%
|
12
21.1%
|
| 1 |
29
63%
|
8
72.7%
|
37
64.9%
|
| 2 |
8
17.4%
|
0
0%
|
8
14%
|
Outcome Measures
| Title | Best Overall Response Rate (ORR) Based on Investigator's Assessment |
|---|---|
| Description | Best ORR is defined as the number of participants with complete remission(CR) or partial remission(PR) assessed by the Investigator using modified AML/MDS International Working Group(IWG) Criteria. AML:CR=neutrophils >1x10^9/L, platelets >100x10^9/L, bone marrow blasts(BMB) <5%, transfusion independent, no extramedullary disease(EMD); CRi=BMB <5%, transfusion independent, no EMD; PR=neutrophils >1x10^9/L, platelets >100x10^9/L, BMB >50% decrease and 5% to 25%, blasts <5% with Auer rods; PRi=BMB >50% decrease and 5% to 25%. MDS:CR=bone marrow: ≤5% myeloblasts with normal maturation, peripheral blood: hemoglobin ≥11 g/dL, platelets ≥100x10^9/L, neutrophils ≥1.0x10^9/L, blasts 0%; PR=all CR criteria if abnormal before treatment except: BMB decreased by ≥50% over pretreatment but still >5%; PRi=BMB decreased by ≥50% over pretreatment but still >5%; Marrow CR=bone marrow: ≤5% myeloblasts and decrease by ≥50% over pretreatment, peripheral blood hematologic improvement responses noted. |
| Time Frame | Baseline and every 2 cycles up to Cycle 16 (up to Month 12), from Cycle 17 every 4 cycles until disease progression, after end of treatment every 12 weeks for up to 12 Months (Approximately 2.4 years) |
Outcome Measure Data
| Analysis Population Description |
|---|
| Response-Evaluable Population included all participants who received at least 1 dose of alisertib and had at least 1 post-baseline response assessment. In 2 participants disease transformed from MDS to AML. One participant is considered AML and one participant is considered MDS in the calculation, based on the timing of their transformation. |
| Arm/Group Title | Alisertib 50 mg (Acute Myeloid Leukemia) | Alisertib 50 mg (Myelodysplastic Syndrome) |
|---|---|---|
| Arm/Group Description | Participants with acute myeloid leukemia received alisertib 50 mg, capsules, orally, twice daily for 7 days, followed by 14-day washout period, in 21-day cycles until disease progression or unacceptable treatment-related toxicity (Up to 26 Cycles). | Participants with myelodysplastic syndrome received alisertib 50 mg, capsules, orally, twice daily for 7 days, followed by 14-day washout period, in 21-day cycles until disease progression or unacceptable treatment-related toxicity (Up to 6 Cycles). |
| Measure Participants | 35 | 10 |
| CR + PR |
6
13%
|
0
0%
|
| Complete Remission (CR + CRi + Marrow CRi) |
1
2.2%
|
0
0%
|
| Partial Remission (PR + PRi) |
5
10.9%
|
0
0%
|
| Stable Disease as Best Response |
17
37%
|
2
18.2%
|
| Title | Progression Free Survival (PFS) |
|---|---|
| Description | PFS is defined as the time from the date of first study drug administration to the date of first documented progressive disease (PD) or death. |
| Time Frame | Baseline and every 2 cycles up to Cycle 16 (up to Month 12), from Cycle 17 every 4 cycles until disease progression, after end of treatment every 12 weeks for up to 12 Months (Approximately 2.4 years) |
Outcome Measure Data
| Analysis Population Description |
|---|
| Response-Evaluable Population included all participants who received at least 1 dose of alisertib and had at least 1 post-baseline response assessment. For a participant that has not progressed and has not died, PFS is censored at the last response assessment that is SD or better. |
| Arm/Group Title | Alisertib 50 mg (Acute Myeloid Leukemia) | Alisertib 50 mg (Myelodysplastic Syndrome) |
|---|---|---|
| Arm/Group Description | Participants with acute myeloid leukemia received alisertib 50 mg, capsules, orally, twice daily for 7 days, followed by 14-day washout period, in 21-day cycles until disease progression or unacceptable treatment-related toxicity (Up to 26 Cycles). | Participants with myelodysplastic syndrome received alisertib 50 mg, capsules, orally, twice daily for 7 days, followed by 14-day washout period, in 21-day cycles until disease progression or unacceptable treatment-related toxicity (Up to 6 Cycles). |
| Measure Participants | 35 | 10 |
| Median (95% Confidence Interval) [days] |
55.0
|
38.0
|
| Title | Duration of Response (DOR) |
|---|---|
| Description | Duration of response is defined as the time from the date of first documentation of a response to the date of first documented PD. |
| Time Frame | Baseline and every 2 cycles up to Cycle 16 (up to Month 12), from Cycle 17 every 4 cycles until disease progression, after end of treatment every 12 weeks for up to 12 Months (Approximately 2.4 years) |
Outcome Measure Data
| Analysis Population Description |
|---|
| Response--Evaluable Population included all participants who had measurable disease, received at least 1 dose of alisertib, and had at least 1 post baseline response assessment. All responders were evaluated in this outcome measure. For a participant that has not progressed, DOR is censored at the last response assessment that is SD or better. |
| Arm/Group Title | Alisertib 50 mg (Acute Myeloid Leukemia) | Alisertib 50 mg (Myelodysplastic Syndrome) |
|---|---|---|
| Arm/Group Description | Participants with acute myeloid leukemia received alisertib 50 mg, capsules, orally, twice daily for 7 days, followed by 14-day washout period, in 21-day cycles until disease progression or unacceptable treatment-related toxicity (Up to 26 Cycles). | Participants with myelodysplastic syndrome received alisertib 50 mg, capsules, orally, twice daily for 7 days, followed by 14-day washout period, in 21-day cycles until disease progression or unacceptable treatment-related toxicity (Up to 6 Cycles). |
| Measure Participants | 6 | 0 |
| Median (95% Confidence Interval) [days] |
409.0
|
| Title | Best Overall Hematologic Improvement (HI) Response for Myelodysplastic Syndrome Based on Investigator Assessment |
|---|---|
| Description | Best overall HI response is defined as percentage of participants with response as assessed by Investigator based on IWG criteria: 1)Erythroid response (pretreatment,<11 g/dL): hemoglobin (Hgb) increase by ≥1.5 g/dL, relevant reduction of units of red blood cell (RBC) transfusions by absolute number of at least 4 RBC transfusions/8 weeks compared to pretreatment transfusion number in previous 8 weeks. Only RBC transfusions given for Hgb of ≤9.0 g/dL pretreatment will count in RBC transfusion response evaluation. 2)Platelet response (pretreatment,<100x10^9/L):Absolute increase of ≥30x10^9/L for participants starting->20x10^9/L platelets, increase <20x10^9/L to >20x10^9/L by at least 100%. 3)Neutrophil response (pretreatment,<1.0x10^9/L):At least 100% increase and an absolute increase >0.5x10^9/L. 4)Progression or relapse after HI:At least 1 of following: 50% decrement from maximum response levels in granulocytes or platelets, or reduction in Hgb by ≥1.5 g/dL, or transfusion dependence. |
| Time Frame | Baseline and every 2 cycles up to Cycle 16 (up to Month 12), from Cycle 17 every 4 cycles until disease progression, after end of treatment every 12 weeks for up to 12 Months (Approximately 2.4 years) |
Outcome Measure Data
| Analysis Population Description |
|---|
| Safety population was defined as all participants who received any amount of alisertib. |
| Arm/Group Title | Alisertib 50 mg (Myelodysplastic Syndrome) |
|---|---|
| Arm/Group Description | Participants with myelodysplastic syndrome received alisertib 50 mg, capsules, orally, twice daily for 7 days, followed by 14-day washout period, in 21-day cycles until disease progression or unacceptable treatment-related toxicity (Up to 6 Cycles). |
| Measure Participants | 11 |
| Erythroid Response |
0
0%
|
| Platelet Response |
0
0%
|
| Neutrophil Response |
0
0%
|
| Progression or Relapse |
0
0%
|
| Not Available |
91
197.8%
|
| Unable to Assess |
9
19.6%
|
| Title | Number of Participants With Adverse Events (AEs), Serious Adverse Events (SAEs) and Deaths |
|---|---|
| Description | An AE is defined as any untoward medical occurrence in a participant administered a pharmaceutical product; the untoward medical occurrence does not necessarily have a causal relationship with this treatment. A serious adverse event (SAE) is defined as any untoward medical occurrence that at any dose results in death, is life-threatening, requires inpatient hospitalization or prolongation of an existing hospitalization, results in persistent or significant disability or incapacity, is a congenital anomaly/birth defect or is a medically important event. Relationship of each AE to study drug was determined by the Investigator. |
| Time Frame | First dose of study drug to 30 days after last dose (Up to 18.9 months) |
Outcome Measure Data
| Analysis Population Description |
|---|
| Safety population was defined as all participants who received any amount of alisertib. |
| Arm/Group Title | Alisertib 50 mg (Acute Myeloid Leukemia) | Alisertib 50 mg (Myelodysplastic Syndrome) |
|---|---|---|
| Arm/Group Description | Participants with acute myeloid leukemia received alisertib 50 mg, capsules, orally, twice daily for 7 days, followed by 14-day washout period, in 21-day cycles until disease progression or unacceptable treatment-related toxicity (Up to 26 Cycles). | Participants with myelodysplastic syndrome received alisertib 50 mg, capsules, orally, twice daily for 7 days, followed by 14-day washout period, in 21-day cycles until disease progression or unacceptable treatment-related toxicity (Up to 6 Cycles). |
| Measure Participants | 46 | 11 |
| AE |
46
100%
|
11
100%
|
| SAE |
36
78.3%
|
8
72.7%
|
| Deaths |
20
43.5%
|
2
18.2%
|
| Title | Number of Participants With Abnormal Vital Signs Reported as Treatment-Emergent Adverse Events |
|---|---|
| Description | Vital signs measurements (blood pressure, heart rate, and oral temperature) were obtained throughout the study. 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 of study drug to 30 days after last dose (Up to 18.9 months) |
Outcome Measure Data
| Analysis Population Description |
|---|
| Safety population was defined as all participants who received any amount of alisertib. |
| Arm/Group Title | Alisertib 50 mg (Acute Myeloid Leukemia) | Alisertib 50 mg (Myelodysplastic Syndrome) |
|---|---|---|
| Arm/Group Description | Participants with acute myeloid leukemia received alisertib 50 mg, capsules, orally, twice daily for 7 days, followed by 14-day washout period, in 21-day cycles until disease progression or unacceptable treatment-related toxicity (Up to 26 Cycles). | Participants with myelodysplastic syndrome received alisertib 50 mg, capsules, orally, twice daily for 7 days, followed by 14-day washout period, in 21-day cycles until disease progression or unacceptable treatment-related toxicity (Up to 6 Cycles). |
| Measure Participants | 46 | 11 |
| Dyspnoea |
12
26.1%
|
2
18.2%
|
| Pyrexia |
10
21.7%
|
2
18.2%
|
| Hypotension |
8
17.4%
|
0
0%
|
| Atrial fibrillation |
4
8.7%
|
1
9.1%
|
| Tachycardia |
3
6.5%
|
0
0%
|
| Dyspnoea exertional |
2
4.3%
|
1
9.1%
|
| Hypertension |
1
2.2%
|
1
9.1%
|
| Supraventricular tachycardia |
2
4.3%
|
0
0%
|
| Weight decreased |
2
4.3%
|
0
0%
|
| Tachypnoea |
1
2.2%
|
0
0%
|
| Hyperthermia |
1
2.2%
|
0
0%
|
| Hypothermia |
1
2.2%
|
0
0%
|
| Bradycardia |
0
0%
|
1
9.1%
|
| Ventricular tachycardia |
1
2.2%
|
0
0%
|
| Title | Number of Participants With Abnormal Laboratory Values Reported as Treatment-Emergent Adverse Events |
|---|---|
| Description | Abnormal Laboratory Values for Chemistry or Hematology tests that were assessed by the investigator to be Grade 3 or higher using the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE). Grade 3=severe, Grade 4=life threatening or disabling and Grade 5=Death. 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 of study drug to 30 days after last dose (Up to 18.9 months) |
Outcome Measure Data
| Analysis Population Description |
|---|
| Safety population was defined as all participants who received any amount of alisertib. |
| Arm/Group Title | Alisertib 50 mg (Acute Myeloid Leukemia) | Alisertib 50 mg (Myelodysplastic Syndrome) |
|---|---|---|
| Arm/Group Description | Participants with acute myeloid leukemia received alisertib 50 mg, capsules, orally, twice daily for 7 days, followed by 14-day washout period, in 21-day cycles until disease progression or unacceptable treatment-related toxicity (Up to 26 Cycles). | Participants with myelodysplastic syndrome received alisertib 50 mg, capsules, orally, twice daily for 7 days, followed by 14-day washout period, in 21-day cycles until disease progression or unacceptable treatment-related toxicity (Up to 6 Cycles). |
| Measure Participants | 46 | 11 |
| Febrile neutropenia |
17
37%
|
4
36.4%
|
| Anaemia |
14
30.4%
|
3
27.3%
|
| Thrombocytopenia |
9
19.6%
|
2
18.2%
|
| Neutropenia |
5
10.9%
|
3
27.3%
|
| Leukopenia |
3
6.5%
|
2
18.2%
|
| Hypoalbuminaemia |
4
8.7%
|
0
0%
|
| Leukocytosis |
3
6.5%
|
0
0%
|
| Hypokalaemia |
3
6.5%
|
0
0%
|
| Hyponatraemia |
3
6.5%
|
0
0%
|
| Neutrophil count decreased |
3
6.5%
|
0
0%
|
| Hypocalcaemia |
2
4.3%
|
0
0%
|
| Clostridium difficile colitis |
2
4.3%
|
0
0%
|
| Febrile bone marrow aplasia |
1
2.2%
|
0
0%
|
| Hypoxia |
1
2.2%
|
0
0%
|
| Hyperkalaemia |
1
2.2%
|
0
0%
|
| Hypernatraemia |
1
2.2%
|
0
0%
|
| Hyperglycaemia |
1
2.2%
|
0
0%
|
| Hypoglycaemia |
1
2.2%
|
0
0%
|
| Hypomagnesaemia |
0
0%
|
1
9.1%
|
| Hypophospataemia |
1
2.2%
|
0
0%
|
| Alanine aminotransferase increased |
0
0%
|
1
9.1%
|
| Blood bilirubin increased |
1
2.2%
|
0
0%
|
| Oxygen saturation decreased |
1
2.2%
|
0
0%
|
| Blood culture positive |
1
2.2%
|
0
0%
|
| Blood magnesium decreased |
1
2.2%
|
0
0%
|
| Blood creatinine increased |
1
2.2%
|
0
0%
|
| White blood cell count decreased |
1
2.2%
|
0
0%
|
| Gilbert's syndrome |
1
2.2%
|
0
0%
|
| Lymphoedema |
1
2.2%
|
0
0%
|
| Platelet count decreased |
1
2.2%
|
0
0%
|
Adverse Events
| Time Frame | First dose of study drug to 30 days after last dose (Up to 18.9 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 50 mg (Acute Myeloid Leukemia) | Alisertib 50 mg (Myelodysplastic Syndrome) | ||
| Arm/Group Description | Participants with acute myeloid leukemia received alisertib 50 mg, capsules, orally, twice daily for 7 days, followed by 14-day washout period, in 21-day cycles until disease progression or unacceptable treatment-related toxicity (Up to 26 Cycles). | Participants with myelodysplastic syndrome received alisertib 50 mg, capsules, orally, twice daily for 7 days, followed by 14-day washout period, in 21-day cycles until disease progression or unacceptable treatment-related toxicity (Up to 6 Cycles). | ||
All Cause Mortality |
||||
| Alisertib 50 mg (Acute Myeloid Leukemia) | Alisertib 50 mg (Myelodysplastic Syndrome) | |||
| Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | |
| Total | / (NaN) | / (NaN) | ||
Serious Adverse Events |
||||
| Alisertib 50 mg (Acute Myeloid Leukemia) | Alisertib 50 mg (Myelodysplastic Syndrome) | |||
| Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | |
| Total | 36/46 (78.3%) | 8/11 (72.7%) | ||
| Blood and lymphatic system disorders | ||||
| Febrile neutropenia | 13/46 (28.3%) | 4/11 (36.4%) | ||
| Anaemia | 4/46 (8.7%) | 0/11 (0%) | ||
| Febrile bone marrow aplasia | 1/46 (2.2%) | 0/11 (0%) | ||
| Thrombocytopenia | 1/46 (2.2%) | 0/11 (0%) | ||
| Cardiac disorders | ||||
| Atrial fibrillation | 0/46 (0%) | 1/11 (9.1%) | ||
| Supraventricular tachycardia | 1/46 (2.2%) | 0/11 (0%) | ||
| Pericardial effusion | 1/46 (2.2%) | 0/11 (0%) | ||
| Myocardial infarction | 0/46 (0%) | 1/11 (9.1%) | ||
| Ear and labyrinth disorders | ||||
| Deafness unilateral | 1/46 (2.2%) | 0/11 (0%) | ||
| Gastrointestinal disorders | ||||
| Stomatitis | 2/46 (4.3%) | 1/11 (9.1%) | ||
| Gastrointestinal haemorrhage | 1/46 (2.2%) | 0/11 (0%) | ||
| Melaena | 1/46 (2.2%) | 0/11 (0%) | ||
| Diarrhoea | 1/46 (2.2%) | 0/11 (0%) | ||
| Abdominal pain | 1/46 (2.2%) | 0/11 (0%) | ||
| Constipation | 0/46 (0%) | 1/11 (9.1%) | ||
| Gastrointestinal inflammation | 0/46 (0%) | 1/11 (9.1%) | ||
| Dysphagia | 1/46 (2.2%) | 0/11 (0%) | ||
| Rectal haemorrhage | 1/46 (2.2%) | 0/11 (0%) | ||
| Mouth haemorrhage | 1/46 (2.2%) | 0/11 (0%) | ||
| Ascites | 1/46 (2.2%) | 0/11 (0%) | ||
| General disorders | ||||
| Disease progression | 4/46 (8.7%) | 1/11 (9.1%) | ||
| Fatigue | 1/46 (2.2%) | 1/11 (9.1%) | ||
| General physical health deterioration | 1/46 (2.2%) | 0/11 (0%) | ||
| Multi-organ failure | 0/46 (0%) | 1/11 (9.1%) | ||
| Asthenia | 1/46 (2.2%) | 0/11 (0%) | ||
| Hyperthermia | 1/46 (2.2%) | 0/11 (0%) | ||
| Pyrexia | 1/46 (2.2%) | 0/11 (0%) | ||
| Infections and infestations | ||||
| Sepsis | 5/46 (10.9%) | 2/11 (18.2%) | ||
| Pneumonia | 4/46 (8.7%) | 0/11 (0%) | ||
| Bacteraemia | 1/46 (2.2%) | 1/11 (9.1%) | ||
| Bacterial infection | 1/46 (2.2%) | 1/11 (9.1%) | ||
| Bacterial sepsis | 1/46 (2.2%) | 0/11 (0%) | ||
| Septic shock | 1/46 (2.2%) | 0/11 (0%) | ||
| Cellulitis | 1/46 (2.2%) | 0/11 (0%) | ||
| Gastrointestinal infection | 1/46 (2.2%) | 0/11 (0%) | ||
| Vulvovaginal mycotic infection | 1/46 (2.2%) | 0/11 (0%) | ||
| Serratia bacteraemia | 1/46 (2.2%) | 0/11 (0%) | ||
| Injury, poisoning and procedural complications | ||||
| Subdural haematoma | 1/46 (2.2%) | 0/11 (0%) | ||
| Hip fracture | 1/46 (2.2%) | 0/11 (0%) | ||
| Fall | 0/46 (0%) | 1/11 (9.1%) | ||
| Spinal compression fracture | 0/46 (0%) | 1/11 (9.1%) | ||
| Transfusion reaction | 1/46 (2.2%) | 0/11 (0%) | ||
| Metabolism and nutrition disorders | ||||
| Dehydration | 2/46 (4.3%) | 0/11 (0%) | ||
| Musculoskeletal and connective tissue disorders | ||||
| Arthritis | 1/46 (2.2%) | 0/11 (0%) | ||
| Arthralgia | 1/46 (2.2%) | 0/11 (0%) | ||
| Neck mass | 1/46 (2.2%) | 0/11 (0%) | ||
| Neoplasms benign, malignant and unspecified (incl cysts and polyps) | ||||
| Acute myeloid leukaemia | 5/46 (10.9%) | 0/11 (0%) | ||
| Nervous system disorders | ||||
| Cerebral haemorrhage | 1/46 (2.2%) | 0/11 (0%) | ||
| Haemorrhage intracranial | 1/46 (2.2%) | 0/11 (0%) | ||
| Depressed level of consciousness | 1/46 (2.2%) | 0/11 (0%) | ||
| Somnolence | 1/46 (2.2%) | 0/11 (0%) | ||
| Dizziness | 1/46 (2.2%) | 0/11 (0%) | ||
| Renal and urinary disorders | ||||
| Renal failure acute | 2/46 (4.3%) | 0/11 (0%) | ||
| Cystitis haemorrhagic | 1/46 (2.2%) | 0/11 (0%) | ||
| Respiratory, thoracic and mediastinal disorders | ||||
| Dyspnoea | 2/46 (4.3%) | 1/11 (9.1%) | ||
| Respiratory distress | 1/46 (2.2%) | 0/11 (0%) | ||
| Hypoxia | 1/46 (2.2%) | 0/11 (0%) | ||
| Respiratory failure | 1/46 (2.2%) | 0/11 (0%) | ||
| Vascular disorders | ||||
| Hypotension | 1/46 (2.2%) | 0/11 (0%) | ||
| Hypertension | 1/46 (2.2%) | 1/11 (9.1%) | ||
Other (Not Including Serious) Adverse Events |
||||
| Alisertib 50 mg (Acute Myeloid Leukemia) | Alisertib 50 mg (Myelodysplastic Syndrome) | |||
| Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | |
| Total | 45/46 (97.8%) | 11/11 (100%) | ||
| Blood and lymphatic system disorders | ||||
| Anaemia | 10/46 (21.7%) | 3/11 (27.3%) | ||
| Thrombocytopenia | 8/46 (17.4%) | 2/11 (18.2%) | ||
| Neutropenia | 5/46 (10.9%) | 3/11 (27.3%) | ||
| Febrile neutropenia | 6/46 (13%) | 0/11 (0%) | ||
| Leukopenia | 3/46 (6.5%) | 2/11 (18.2%) | ||
| Leukocytosis | 3/46 (6.5%) | 0/11 (0%) | ||
| Cardiac disorders | ||||
| Atrial fibrillation | 4/46 (8.7%) | 0/11 (0%) | ||
| Tachycardia | 3/46 (6.5%) | 0/11 (0%) | ||
| Bradycardia | 0/46 (0%) | 1/11 (9.1%) | ||
| Ear and labyrinth disorders | ||||
| Tinnitus | 3/46 (6.5%) | 0/11 (0%) | ||
| Eye disorders | ||||
| Vision blurred | 1/46 (2.2%) | 1/11 (9.1%) | ||
| Gastrointestinal disorders | ||||
| Diarrhoea | 21/46 (45.7%) | 2/11 (18.2%) | ||
| Nausea | 19/46 (41.3%) | 3/11 (27.3%) | ||
| Stomatitis | 13/46 (28.3%) | 4/11 (36.4%) | ||
| Vomiting | 8/46 (17.4%) | 2/11 (18.2%) | ||
| Dysphagia | 6/46 (13%) | 0/11 (0%) | ||
| Abdominal pain upper | 4/46 (8.7%) | 0/11 (0%) | ||
| Constipation | 3/46 (6.5%) | 1/11 (9.1%) | ||
| Gingival bleeding | 4/46 (8.7%) | 0/11 (0%) | ||
| Oral pain | 4/46 (8.7%) | 0/11 (0%) | ||
| Haemorrhoids | 2/46 (4.3%) | 1/11 (9.1%) | ||
| Proctalgia | 2/46 (4.3%) | 1/11 (9.1%) | ||
| Abdominal distension | 1/46 (2.2%) | 1/11 (9.1%) | ||
| Dyspepsia | 1/46 (2.2%) | 1/11 (9.1%) | ||
| Tongue ulceration | 1/46 (2.2%) | 1/11 (9.1%) | ||
| Anal fissure | 0/46 (0%) | 1/11 (9.1%) | ||
| Oral disorder | 0/46 (0%) | 1/11 (9.1%) | ||
| Abdominal pain | 11/46 (23.9%) | 2/11 (18.2%) | ||
| General disorders | ||||
| Fatigue | 15/46 (32.6%) | 5/11 (45.5%) | ||
| Oedema peripheral | 12/46 (26.1%) | 0/11 (0%) | ||
| Pyrexia | 9/46 (19.6%) | 2/11 (18.2%) | ||
| Asthenia | 8/46 (17.4%) | 1/11 (9.1%) | ||
| Chills | 6/46 (13%) | 1/11 (9.1%) | ||
| Axillary pain | 0/46 (0%) | 1/11 (9.1%) | ||
| Catheter site erythema | 0/46 (0%) | 1/11 (9.1%) | ||
| Non-cardiac chest pain | 0/46 (0%) | 1/11 (9.1%) | ||
| Hepatobiliary disorders | ||||
| Cholelithiasis | 0/46 (0%) | 1/11 (9.1%) | ||
| Infections and infestations | ||||
| Oral herpes | 4/46 (8.7%) | 1/11 (9.1%) | ||
| Cellulitis | 3/46 (6.5%) | 1/11 (9.1%) | ||
| Pneumonia | 3/46 (6.5%) | 0/11 (0%) | ||
| Bronchitis | 1/46 (2.2%) | 1/11 (9.1%) | ||
| Anal abscess | 0/46 (0%) | 1/11 (9.1%) | ||
| Aspergillosis | 0/46 (0%) | 1/11 (9.1%) | ||
| Nasopharyngitis | 0/46 (0%) | 1/11 (9.1%) | ||
| Oral candidiasis | 0/46 (0%) | 1/11 (9.1%) | ||
| Injury, poisoning and procedural complications | ||||
| Contusion | 2/46 (4.3%) | 3/11 (27.3%) | ||
| Excoriation | 0/46 (0%) | 1/11 (9.1%) | ||
| Investigations | ||||
| Neutrophil count decreased | 3/46 (6.5%) | 0/11 (0%) | ||
| Alanine aminotransferase increased | 0/46 (0%) | 1/11 (9.1%) | ||
| Metabolism and nutrition disorders | ||||
| Decreased appetite | 8/46 (17.4%) | 0/11 (0%) | ||
| Hypoalbuminaemia | 4/46 (8.7%) | 0/11 (0%) | ||
| Hypokalaemia | 3/46 (6.5%) | 0/11 (0%) | ||
| Hyponatraemia | 3/46 (6.5%) | 0/11 (0%) | ||
| Dehydration | 1/46 (2.2%) | 1/11 (9.1%) | ||
| Hypomagnesaemia | 0/46 (0%) | 1/11 (9.1%) | ||
| Musculoskeletal and connective tissue disorders | ||||
| Back pain | 3/46 (6.5%) | 2/11 (18.2%) | ||
| Neck pain | 3/46 (6.5%) | 0/11 (0%) | ||
| Pain in extremity | 3/46 (6.5%) | 0/11 (0%) | ||
| Arthralgia | 1/46 (2.2%) | 1/11 (9.1%) | ||
| Myalgia | 1/46 (2.2%) | 1/11 (9.1%) | ||
| Gouty arthritis | 0/46 (0%) | 1/11 (9.1%) | ||
| Nervous system disorders | ||||
| Somnolence | 11/46 (23.9%) | 2/11 (18.2%) | ||
| Headache | 5/46 (10.9%) | 2/11 (18.2%) | ||
| Balance disorder | 0/46 (0%) | 1/11 (9.1%) | ||
| Burning sensation | 0/46 (0%) | 1/11 (9.1%) | ||
| Depressed level of consciousness | 0/46 (0%) | 1/11 (9.1%) | ||
| Subdural hygroma | 0/46 (0%) | 1/11 (9.1%) | ||
| Dizziness | 4/46 (8.7%) | 2/11 (18.2%) | ||
| Psychiatric disorders | ||||
| Anxiety | 4/46 (8.7%) | 0/11 (0%) | ||
| Confusional state | 2/46 (4.3%) | 1/11 (9.1%) | ||
| Mental status changes | 0/46 (0%) | 1/11 (9.1%) | ||
| Psychotic disorder | 0/46 (0%) | 1/11 (9.1%) | ||
| Renal and urinary disorders | ||||
| Haematuria | 3/46 (6.5%) | 0/11 (0%) | ||
| Respiratory, thoracic and mediastinal disorders | ||||
| Cough | 9/46 (19.6%) | 3/11 (27.3%) | ||
| Epistaxis | 5/46 (10.9%) | 3/11 (27.3%) | ||
| Oropharyngeal pain | 3/46 (6.5%) | 3/11 (27.3%) | ||
| Pleural effusion | 4/46 (8.7%) | 0/11 (0%) | ||
| Dyspnoea exertional | 2/46 (4.3%) | 1/11 (9.1%) | ||
| Sneezing | 0/46 (0%) | 1/11 (9.1%) | ||
| Dyspnoea | 10/46 (21.7%) | 2/11 (18.2%) | ||
| Skin and subcutaneous tissue disorders | ||||
| Alopecia | 7/46 (15.2%) | 4/11 (36.4%) | ||
| Petechiae | 4/46 (8.7%) | 0/11 (0%) | ||
| Pruritus | 2/46 (4.3%) | 2/11 (18.2%) | ||
| Blood blister | 1/46 (2.2%) | 2/11 (18.2%) | ||
| Ecchymosis | 3/46 (6.5%) | 0/11 (0%) | ||
| Night sweats | 3/46 (6.5%) | 0/11 (0%) | ||
| Rash | 2/46 (4.3%) | 1/11 (9.1%) | ||
| Rash pruritic | 2/46 (4.3%) | 1/11 (9.1%) | ||
| Urticaria | 3/46 (6.5%) | 0/11 (0%) | ||
| Rash macular | 0/46 (0%) | 1/11 (9.1%) | ||
| Vascular disorders | ||||
| Hypotension | 7/46 (15.2%) | 0/11 (0%) | ||
Limitations/Caveats
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.
Results Point of Contact
| Name/Title | Medical Director |
|---|---|
| Organization | Takeda |
| Phone | +1-877-825-3327 |
| trialdisclosures@takeda.com |
- C14005
- 2008-006977-34
- U1111-1187-6569