Burkitt's Lymphoma, Diffuse Large B-Cell Lymphoma, Mantle Cell Lymphoma, Transformed Follicular Lymphoma
Conditions
Brief summary
This is a single-arm, open-label, multicenter, dose escalation, phase 1-2 study of alisertib (MLN8237) administered in patients with relapsed or refractory diffuse large B-cell lymphoma (DLBCL)/transformed follicular lymphoma (TFL) treated with rituximab and vincristine. The study has three parts as follows: Phase 1, Part 1: Safety lead-in cohort to evaluate alisertib (MLN8237) and rituximab. Phase 1, Part 2: Dose escalation cohort to evaluate alisertib (MLN8237) + Rituximab + Vincristine and determine Phase 2 dose. Patients with other types of B-cell lymphoma (including mantle cell or Burkitt's lymphoma may enroll in Parts 1 and 2. Phase 2: Alisertib (MLN8237) + Rituximab + Vincristine in patients with relapsed or refractory DLBCL or TFL at recommended Phase 2 dose. Note that in 2013 Sponsor decision was taken to not initiate the phase 2 portion of the trial, which would have investigated the triplet at the recommended phase 2 dose identified in part 2. This decision was based on reprioritization within the company and not on any clinical or safety outcomes observed.
Detailed description
The drug tested in this study was called alisertib. Alisertib was tested to treat people who have relapsed or refractory diffuse large B-cell lymphoma or other aggressive B-cell lymphomas. This study looked at safety, any anti-tumor effect, and it also determined a recommended dose of alisertib plus rituximab and alisertib plus rituximab and vincristine to take into further studies. Pharmacokinetic blood samples were studied to characterize any effects on the concentration of each of the drugs when administered together . The study enrolled 45 patients. Participants received the following treatments: Phase 1 * Alisertib 50 mg + rituximab in the Safety Lead-in * Alisertib 30 mg + rituximab + vincristine in the Dose Escalation * Alisertib 40 mg + rituximab + vincristine in the Dose Escalation * Alisertib 50 mg + rituximab + vincristine in the Dose Escalation All participants were asked to take one alisertib table twice a day for 7 days in each cycle for up to 8 cycles along with rituximab on Day 1 of each cycle; some patients also received vincristine on Day 1 and Day 8 of each cycle. All participants with documented disease response or stabilization could continue with alisertib single-agent therapy for an additional 2 years or more. This multi-center trial was conducted in the USA. The overall time to participate in this study was up to 5.2 years. Participants made multiple visits to the clinic, plus a final visit 30 days after receiving their last dose of study drug for a follow-up assessment.
Interventions
DRUGAlisertib (MLN8237)
Alisertib (MLN8237) enteric coated tablet (ECT).
DRUGRituximab
Rituximab IV infusion.
DRUGVincristine
Vincristine IV Infusion.
Sponsors
Millennium Pharmaceuticals, Inc.
Study design
Allocation
NON_RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Histologically confirmed diagnosis of diffuse large B-cell lymphoma (DLBCL)/transformed follicular lymphoma (TFL). Note: Patients with Mantle Cell or Burkitt's lymphoma may be eligible for enrollment to the safety lead-in and dose escalation cohorts, parts 1 & 2 only * Relapsed or refractory after at least 1 prior systemic treatment for aggressive lymphoma (including anthracycline unless contra-indicated). Relapse following an autologous stem cell transplant is allowed. * Relapsed after autologous stem cell transplantation or not be eligible for autologous stem cell transplantation or refuse autologous stem cell transplantation. Patients enrolled to the phase 2 part must have received prior rituximab. * Measurable disease as specified in study protocol * Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 2 * Female patients 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 alisertib (MLN8237) or agree to abstain from heterosexual intercourse. Patients should also use effective contraception for 12 months following the last dose of rituximab and 1 month following the last dose of alisertib (MLN8237. * Male patients who agree to practice effective barrier contraception through 4 months after the last dose of MLN8237 or agree to abstain from heterosexual intercourse * Voluntary written consent
Exclusion criteria
* Received more than 4 prior systemic treatment regimens for lymphoma * Known human immunodeficiency virus (HIV) positive or acquired immunodeficiency syndrome (AIDS)-related illness; hepatitis B virus, or hepatitis C virus; known history of Charcot-Marie-Tooth disease or polio * Autologous stem cell transplant less than 3 months prior to enrollment * Patients who have undergone allogeneic stem cell or organ transplantation any time * Systemic antineoplastic therapy, including glucocorticoids or treatment with an investigational agent within 14 days preceding the first dose of study drug treatment. Steroids are permitted for administration with rituximab to prevent or treat infusion reaction * Treatment with nitrosoureas, mitomycin C, rituximab, alemtuzumab, or other unconjugated antibody treatment within 42 days (21 days if clear evidence of progressive disease) prior to the first day of study drug treatment * Treatment with radioimmunoconjugates or toxin immunoconjugates, such as ibritumomab-tiuxetan, or tositumomab, within 12 weeks prior to the first day of study drug treatment * Radiotherapy within 21 days prior to the first dose of study drug treatment * Treatment with enzyme-inducing antiepileptic drugs, such as phenytoin, carbamazepine, or phenobarbital, or with rifampin, rifabutin, rifapentine, or St. John's wort, within 14 days prior to the first dose of alisertib (MLN8237) also not permitted during study * Cardiac status as described in protocol * Major surgery, serious infection, or infection requiring systemic antibiotic therapy within 14 days prior to the first dose of study treatment * History of hemorrhagic or thrombotic cerebrovascular event in the past 12 months * Clinically uncontrolled central nervous system involvement * Inability to receive IV rituximab or vincristine, or to swallow tablets or inability or unwillingness to avoid taking anything by mouth except for water and prescribed medications for 2 hours before and 1 hour after each dose of alisertib (MLN8237) * History of uncontrolled sleep apnea syndrome and other conditions that could result in excessive daytime sleepiness * Female patients who are lactating or pregnant * Serious medical or psychiatric illness or laboratory abnormality that could, in the investigator's opinion, potentially interfere with the completion of treatment according to the protocol * Clinically apparent ≥ Grade 2 neuropathy due to any cause in the 3 months prior to enrollment, or history of ≥ Grade 3 neuropathy related to vincristine at any time * Prior treatment with Aurora A-targeted agents, including alisertib (MLN8237) * Patients who have received myeloid growth factors or platelet transfusion within 14 days prior to the first dose of study treatment * Patients with known hypersensitivity to rituximab, vincristine (or vinca alkaloids), or their diluents
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants With Clinically Significant Vital Signs Findings (Treatment Related and Unrelated) [Phase 1] | First dose of alisertib through 30 days after the last dose of alisertib (Up to 5.2 Years) | Vital sign parameters: blood pressure, heart rate and temperature determined by the investigator to be clinically significant were reported as adverse events. |
| Number of Participants With Clinically Significant Changes in Electrocardiograms (ECGs) [Phase 1] | First dose of alisertib through 30 days after the last dose of alisertib (Up to 5.2 Years) | Abnormal ECGs findings determined by the investigator to be clinically significant were reported as adverse events. |
| Number of Participants With Clinically Significant Changes in Multigated Acquisition (MUGA)/ Echocardiogram (ECHO) [Phase 1] | First dose of alisertib through 30 days after the last dose of alisertib (Up to 5.2 Years) | Abnormal changes in MUGA and ECHO findings determined by the investigator to be clinically significant were reported as adverse events. |
| Number of Participants With Clinically Significant Changes in Physical Examination Findings [Phase 1] | First dose of alisertib through 30 days after the last dose of alisertib (Up to 5.2 Years) | Abnormal Physical Examination findings determined by the investigator to be clinically significant were reported as Adverse Events. |
| Number of Participants With Clinically Significant Laboratory Tests Reported as Adverse Events [Phase 1] | First dose of alisertib through 30 days after the last dose of alisertib (Up to 5.2 Years) | Abnormal treatment-emergent Chemistry and Hematology Laboratory values determined by the investigator to be clinically significant were reported as adverse events. |
| Number of Participants With Treatment-Emergent Adverse Events [Phase 1] | First dose of alisertib through 30 days after the last dose of alisertib (Up to 5.2 Years) | 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 treatment-emergent adverse event (TEAE) is defined as an adverse event with an onset that occurs after receiving study drug. |
| Overall Response Rate [Phase 2] | At the end of Cycle 2, at the end of every second treatment cycle until 6 months, then every 12 weeks thereafter, approximately 2 years | Overall Response Rate was defined as the percentage of participants with Complete Response (CR) or Partial Response (PR) as assessed by the investigator using International Working Group (IWG) Criteria. CR is defined as the disappearance of all evidence of disease and PR is defined as regression of measurable disease and no new sites. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants With Clinically Significant Changes in Multigated Acquisition (MUGA)/ Echocardiogram (ECHO) [Phase 2] | From screening period to 30 days after last dose of study drug, approximately 2 years | — |
| Number of Participants With Clinically Significant Laboratory Tests Reported as Adverse Events [Phase 2] | From screening period to 30 days after last dose of study drug, approximately 2 years | — |
| Cmax: Maximum Plasma Concentration for Alisertib | Cycle 1 Days 1 and 7 prior to morning alisertib dose and multiple time-points (up to 12 hours) post-dose | — |
| Tmax: Time to First Occurrence of Cmax fo Alisertib | Cycle 1 Days 1 and 7 prior to morning alisertib dose and multiple time-points (up to 12 hours) post-dose | — |
| Overall Response Rate as Assessed by the Investigator [Phase 1] | First dose of alisertib through 30 days after the last dose of alisertib (Up to 5.2 Years) | Overall Response Rate was defined as the percentage of participants with Complete Response (CR) or Partial Response (PR) as assessed by the investigator using International Working Group (IWG) Criteria. CR is defined as the disappearance of all evidence of disease and PR is defined as regression of measurable disease and no new sites. |
| Cmax: Maximum Plasma Concentration for Vincristine | Cycles 1 and 2 on Day 1 prior to injection of vincristine and multiple time-points (up to 72 hours) post-dose | — |
| AUCt: Area Under the Concentration-time Time Curve Over the Dosing Interval From Time 0 to Time t for Vincristine | Cycles 1 and 2 on Day 1 prior to injection of vincristine and multiple time-points (up to 72 hours) post-dose | — |
| AUC∞: Area Under the Concentration-time Curve From Time 0 to Infinity for Vincristine | Cycles 1 and 2 on Day 1 prior to injection of vincristine and multiple time-points (up to 72 hours) post-dose | — |
| T1/2: Terminal Disposition Phase Half-life for Vincristine | Cycles 1 and 2 on Day prior to injection of vincristine and multiple time-points (up to 72 hours) post-dose | — |
| AUCt: Area Under the Concentration Time Curve Over the Dosing Interval From Time 0 to Time t for Alisertib | Cycle 1 Days 1 and 7 prior to morning alisertib dose and multiple time-points (up to 12 hours) post-dose | — |
| Complete Response Rate [Phase 2] | Duration of study until disease progression, approximately 2 years | Complete response rate was defined as the percentage of participants with Complete Response (CR). CR was assessed by the investigator using International Working Group (IWG) Criteria. CR is defined as the disappearance of all evidence of disease. |
| Duration of Response (DOR) [Phase 2] | Duration of study until disease progression, approximately 2 years | DOR was defined as the time from the date of first documentation of a response to the date of first documentation of Progressive Disease (PD). |
| Progression Free Survival (PFS) [Phase 2] | Duration of study until disease progression, approximately 2 years | PFS was defined as the time from the date of first study drug administration to the date of first documentation of PD or death. |
| Number of Participants With Treatment-Emergent Adverse Events [Phase 2] | From screening period to 30 days after last dose of study drug, approximately 2 years | 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 treatment-emergent adverse event (TEAE) is defined as an adverse event with an onset that occurs after receiving study drug. |
| Number of Participants With Clinically Significant Vital Signs Findings [Phase 2] | From screening period to 30 days after last dose of study drug, approximately 2 years | Vital sign parameters: blood pressure, heart rate and temperature determined by the investigator to be clinically significant were reported as adverse events. |
| Number of Participants With Clinically Significant Changes in Electrocardiograms (ECGs) [Phase 2] | From screening period to 30 days after last dose of study drug, approximately 2 years | — |
Countries
Italy, Spain, United Kingdom, United States
Participant flow
Recruitment details
Participants took part in the Phase 1 portion of the study at 10 investigative sites in the United States from 09 August 2011 to 05 October 2016. The Phase 2 portion of the study was cancelled by the sponsor.
Pre-assignment details
Participants with a diagnosis of relapsed or refractory Diffuse Large B-cell lymphoma (DLBCL)/transformed Follicular lymphoma (TFL), Mantle Cell lymphoma, or Burkitt's Lymphoma were enrolled to receive alisertib open label at doses 30 mg, 40 mg or 50 mg.
Participants by arm
| Arm | Count |
|---|---|
| Safety Lead-in Alisertib 50 mg, enteric coated tablets (ECT), orally, twice daily (BID), on Days 1 to 7 followed by a 14-day rest period in 21-day cycles plus rituximab 375 mg/m\^2, intravenous (IV), infusion on Day 1 of each 21-day cycle for up to 8 cycles. Following 8 cycles of treatment (or early discontinuation of rituximab) all participants with documented disease response or stabilization may continue with alisertib single-agent therapy for up to 2 years. | 13 |
| Dose Escalation, Alisertib 30 mg Alisertib 30 mg, ECT, orally, BID, on Days 1 to 7 followed by a 14-day rest period plus rituximab 375 mg/m\^2, IV, infusion on Day 1, plus vincristine 1.4 mg/m\^2, IV (max 2 mg), on Days 1 and 8 in a 21-day cycle for up to 8 cycles. Following 8 cycles of treatment (or early discontinuation of rituximab and/or vincristine) all participants with documented disease response or stabilization may continue with alisertib single-agent therapy for up to 2 years. | 4 |
| Dose Escalation, Alisertib 40 mg Alisertib 40 mg, ECT, orally, BID, on Days 1 to 7 followed by a 14-day rest period plus rituximab 375 mg/m\^2, IV, infusion on Day 1 plus vincristine 1.4 mg/m\^2, IV (max 2 mg), on Days 1 and 8 in a 21-day cycle for up to 8 cycles. Following 8 cycles of treatment (or early discontinuation of rituximab and/or vincristine) all participants with documented disease response or stabilization may continue with alisertib single-agent therapy for up to 2 years. | 25 |
| Dose Escalation, Alisertib 50 mg Alisertib 50 mg, ECT, orally, BID, on Days 1 to 7 followed by a 14-day rest period plus rituximab 375 mg/m\^2, IV, infusion on Day 1 plus vincristine 1.4 mg/m\^2, IV (max 2 mg), on Days 1 and 8 in a 21-day cycle for up to 8 cycles. Following 8 cycles of treatment (or early discontinuation of rituximab and/or vincristine) all participants with documented disease response or stabilization may continue with alisertib single-agent therapy for up to 2 years. | 3 |
| Total | 45 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 | FG004 |
|---|---|---|---|---|---|---|
| Overall Study | Adverse Event | 0 | 1 | 5 | 1 | 0 |
| Overall Study | Progressive Disease | 10 | 3 | 11 | 1 | 0 |
| Overall Study | Symptomatic Deterioration | 2 | 0 | 4 | 0 | 0 |
| Overall Study | Withdrawal by Subject | 1 | 0 | 5 | 1 | 0 |
Baseline characteristics
| Characteristic | Dose Escalation, Alisertib 30 mg | Dose Escalation, Alisertib 40 mg | Dose Escalation, Alisertib 50 mg | Safety Lead-in | Total |
|---|---|---|---|---|---|
| Age, Continuous | 51.3 years STANDARD_DEVIATION 21.65 | 62.8 years STANDARD_DEVIATION 10.51 | 66.7 years STANDARD_DEVIATION 12.86 | 60.3 years STANDARD_DEVIATION 14.06 | 61.3 years STANDARD_DEVIATION 12.89 |
| Body Surface Area | 2.093 m^2 STANDARD_DEVIATION 0.31 | 1.940 m^2 STANDARD_DEVIATION 0.23 | 1.823 m^2 STANDARD_DEVIATION 0.21 | 1.815 m^2 STANDARD_DEVIATION 0.25 | 1.910 m^2 STANDARD_DEVIATION 0.25 |
| Height | 178.2 cm STANDARD_DEVIATION 7.15 | 168.4 cm STANDARD_DEVIATION 10.76 | 166.5 cm STANDARD_DEVIATION 5.32 | 167.9 cm STANDARD_DEVIATION 10.9 | 169.0 cm STANDARD_DEVIATION 10.44 |
| Race/Ethnicity, Customized Asian | 0 participants | 0 participants | 0 participants | 1 participants | 1 participants |
| Race/Ethnicity, Customized Black or African American | 0 participants | 2 participants | 0 participants | 0 participants | 2 participants |
| Race/Ethnicity, Customized Hispanic or Latino | 1 participants | 6 participants | 1 participants | 7 participants | 15 participants |
| Race/Ethnicity, Customized Not Hispanic or Latino | 3 participants | 19 participants | 2 participants | 6 participants | 30 participants |
| Race/Ethnicity, Customized Not Reported | 0 participants | 1 participants | 0 participants | 0 participants | 1 participants |
| Race/Ethnicity, Customized Other | 0 participants | 1 participants | 0 participants | 0 participants | 1 participants |
| Race/Ethnicity, Customized White | 4 participants | 21 participants | 3 participants | 12 participants | 40 participants |
| Region of Enrollment United States | 4 participants | 25 participants | 3 participants | 13 participants | 45 participants |
| Sex: Female, Male Female | 1 Participants | 10 Participants | 2 Participants | 3 Participants | 16 Participants |
| Sex: Female, Male Male | 3 Participants | 15 Participants | 1 Participants | 10 Participants | 29 Participants |
| Weight | 89.51 kg STANDARD_DEVIATION 23.89 | 82.21 kg STANDARD_DEVIATION 16.4 | 71.94 kg STANDARD_DEVIATION 14.55 | 70.98 kg STANDARD_DEVIATION 16.18 | 78.93 kg STANDARD_DEVIATION 17.46 |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk |
|---|---|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — | — / — | — / — |
| other Total, other adverse events | 13 / 13 | 4 / 4 | 25 / 25 | 3 / 3 |
| serious Total, serious adverse events | 6 / 13 | 1 / 4 | 12 / 25 | 3 / 3 |
Outcome results
Primary
Number of Participants With Clinically Significant Changes in Electrocardiograms (ECGs) [Phase 1]
Abnormal ECGs findings determined by the investigator to be clinically significant were reported as adverse events.
Time frame: First dose of alisertib through 30 days after the last dose of alisertib (Up to 5.2 Years)
Population: Safety Population was defined as all participants who receive any amount of alisertib.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Safety Lead-in | Number of Participants With Clinically Significant Changes in Electrocardiograms (ECGs) [Phase 1] | 0 participants |
| Dose Escalation, Alisertib 30 mg | Number of Participants With Clinically Significant Changes in Electrocardiograms (ECGs) [Phase 1] | 0 participants |
| Dose Escalation, Alisertib 40 mg | Number of Participants With Clinically Significant Changes in Electrocardiograms (ECGs) [Phase 1] | 0 participants |
| Dose Escalation, Alisertib 50 mg | Number of Participants With Clinically Significant Changes in Electrocardiograms (ECGs) [Phase 1] | 0 participants |
Primary
Number of Participants With Clinically Significant Changes in Multigated Acquisition (MUGA)/ Echocardiogram (ECHO) [Phase 1]
Abnormal changes in MUGA and ECHO findings determined by the investigator to be clinically significant were reported as adverse events.
Time frame: First dose of alisertib through 30 days after the last dose of alisertib (Up to 5.2 Years)
Population: Safety Population was defined as all participants who receive any amount of alisertib.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Safety Lead-in | Number of Participants With Clinically Significant Changes in Multigated Acquisition (MUGA)/ Echocardiogram (ECHO) [Phase 1] | 0 participants |
| Dose Escalation, Alisertib 30 mg | Number of Participants With Clinically Significant Changes in Multigated Acquisition (MUGA)/ Echocardiogram (ECHO) [Phase 1] | 0 participants |
| Dose Escalation, Alisertib 40 mg | Number of Participants With Clinically Significant Changes in Multigated Acquisition (MUGA)/ Echocardiogram (ECHO) [Phase 1] | 0 participants |
| Dose Escalation, Alisertib 50 mg | Number of Participants With Clinically Significant Changes in Multigated Acquisition (MUGA)/ Echocardiogram (ECHO) [Phase 1] | 0 participants |
Primary
Number of Participants With Clinically Significant Changes in Physical Examination Findings [Phase 1]
Abnormal Physical Examination findings determined by the investigator to be clinically significant were reported as Adverse Events.
Time frame: First dose of alisertib through 30 days after the last dose of alisertib (Up to 5.2 Years)
Population: Safety Population was defined as all participants who receive any amount of alisertib.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Safety Lead-in | Number of Participants With Clinically Significant Changes in Physical Examination Findings [Phase 1] | 0 participants |
| Dose Escalation, Alisertib 30 mg | Number of Participants With Clinically Significant Changes in Physical Examination Findings [Phase 1] | 0 participants |
| Dose Escalation, Alisertib 40 mg | Number of Participants With Clinically Significant Changes in Physical Examination Findings [Phase 1] | 2 participants |
| Dose Escalation, Alisertib 50 mg | Number of Participants With Clinically Significant Changes in Physical Examination Findings [Phase 1] | 2 participants |
Primary
Number of Participants With Clinically Significant Laboratory Tests Reported as Adverse Events [Phase 1]
Abnormal treatment-emergent Chemistry and Hematology Laboratory values determined by the investigator to be clinically significant were reported as adverse events.
Time frame: First dose of alisertib through 30 days after the last dose of alisertib (Up to 5.2 Years)
Population: Safety Population was defined as all participants who receive any amount of alisertib.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Safety Lead-in | Number of Participants With Clinically Significant Laboratory Tests Reported as Adverse Events [Phase 1] | Hypokalaemia | 5 participants |
| Safety Lead-in | Number of Participants With Clinically Significant Laboratory Tests Reported as Adverse Events [Phase 1] | Neutropenia | 7 participants |
| Safety Lead-in | Number of Participants With Clinically Significant Laboratory Tests Reported as Adverse Events [Phase 1] | Febrile neutropenia | 0 participants |
| Safety Lead-in | Number of Participants With Clinically Significant Laboratory Tests Reported as Adverse Events [Phase 1] | Leukopenia | 8 participants |
| Safety Lead-in | Number of Participants With Clinically Significant Laboratory Tests Reported as Adverse Events [Phase 1] | Lymphopenia | 2 participants |
| Safety Lead-in | Number of Participants With Clinically Significant Laboratory Tests Reported as Adverse Events [Phase 1] | Thrombocytopenia | 7 participants |
| Safety Lead-in | Number of Participants With Clinically Significant Laboratory Tests Reported as Adverse Events [Phase 1] | Anaemia | 6 participants |
| Safety Lead-in | Number of Participants With Clinically Significant Laboratory Tests Reported as Adverse Events [Phase 1] | Hyperkalaemia | 0 participants |
| Safety Lead-in | Number of Participants With Clinically Significant Laboratory Tests Reported as Adverse Events [Phase 1] | Hypomagnesaemia | 2 participants |
| Safety Lead-in | Number of Participants With Clinically Significant Laboratory Tests Reported as Adverse Events [Phase 1] | Hypermagnesaemia | 0 participants |
| Safety Lead-in | Number of Participants With Clinically Significant Laboratory Tests Reported as Adverse Events [Phase 1] | Hypocalcaemia | 2 participants |
| Safety Lead-in | Number of Participants With Clinically Significant Laboratory Tests Reported as Adverse Events [Phase 1] | Hypercalcaemia | 1 participants |
| Safety Lead-in | Number of Participants With Clinically Significant Laboratory Tests Reported as Adverse Events [Phase 1] | Hyperglycaemia | 1 participants |
| Safety Lead-in | Number of Participants With Clinically Significant Laboratory Tests Reported as Adverse Events [Phase 1] | Hypoalbuminaemia | 3 participants |
| Safety Lead-in | Number of Participants With Clinically Significant Laboratory Tests Reported as Adverse Events [Phase 1] | Hyponatraemia | 2 participants |
| Safety Lead-in | Number of Participants With Clinically Significant Laboratory Tests Reported as Adverse Events [Phase 1] | Hypernatraemia | 0 participants |
| Safety Lead-in | Number of Participants With Clinically Significant Laboratory Tests Reported as Adverse Events [Phase 1] | Hypophosphataemia | 1 participants |
| Safety Lead-in | Number of Participants With Clinically Significant Laboratory Tests Reported as Adverse Events [Phase 1] | Neutrophil count decreased | 1 participants |
| Safety Lead-in | Number of Participants With Clinically Significant Laboratory Tests Reported as Adverse Events [Phase 1] | Lymphocyte count decreased | 1 participants |
| Safety Lead-in | Number of Participants With Clinically Significant Laboratory Tests Reported as Adverse Events [Phase 1] | White blood cell count decreased | 0 participants |
| Safety Lead-in | Number of Participants With Clinically Significant Laboratory Tests Reported as Adverse Events [Phase 1] | Aspartate aminotransferase increased | 0 participants |
| Safety Lead-in | Number of Participants With Clinically Significant Laboratory Tests Reported as Adverse Events [Phase 1] | Alanine aminotransferase increased | 0 participants |
| Safety Lead-in | Number of Participants With Clinically Significant Laboratory Tests Reported as Adverse Events [Phase 1] | Blood bilirubin increased | 1 participants |
| Safety Lead-in | Number of Participants With Clinically Significant Laboratory Tests Reported as Adverse Events [Phase 1] | Platelet count decreased | 1 participants |
| Dose Escalation, Alisertib 30 mg | Number of Participants With Clinically Significant Laboratory Tests Reported as Adverse Events [Phase 1] | Platelet count decreased | 0 participants |
| Dose Escalation, Alisertib 30 mg | Number of Participants With Clinically Significant Laboratory Tests Reported as Adverse Events [Phase 1] | Hyperglycaemia | 1 participants |
| Dose Escalation, Alisertib 30 mg | Number of Participants With Clinically Significant Laboratory Tests Reported as Adverse Events [Phase 1] | Leukopenia | 2 participants |
| Dose Escalation, Alisertib 30 mg | Number of Participants With Clinically Significant Laboratory Tests Reported as Adverse Events [Phase 1] | Blood bilirubin increased | 0 participants |
| Dose Escalation, Alisertib 30 mg | Number of Participants With Clinically Significant Laboratory Tests Reported as Adverse Events [Phase 1] | Alanine aminotransferase increased | 0 participants |
| Dose Escalation, Alisertib 30 mg | Number of Participants With Clinically Significant Laboratory Tests Reported as Adverse Events [Phase 1] | Hypoalbuminaemia | 0 participants |
| Dose Escalation, Alisertib 30 mg | Number of Participants With Clinically Significant Laboratory Tests Reported as Adverse Events [Phase 1] | Hypomagnesaemia | 0 participants |
| Dose Escalation, Alisertib 30 mg | Number of Participants With Clinically Significant Laboratory Tests Reported as Adverse Events [Phase 1] | Hypophosphataemia | 0 participants |
| Dose Escalation, Alisertib 30 mg | Number of Participants With Clinically Significant Laboratory Tests Reported as Adverse Events [Phase 1] | Thrombocytopenia | 1 participants |
| Dose Escalation, Alisertib 30 mg | Number of Participants With Clinically Significant Laboratory Tests Reported as Adverse Events [Phase 1] | Hyponatraemia | 0 participants |
| Dose Escalation, Alisertib 30 mg | Number of Participants With Clinically Significant Laboratory Tests Reported as Adverse Events [Phase 1] | Febrile neutropenia | 0 participants |
| Dose Escalation, Alisertib 30 mg | Number of Participants With Clinically Significant Laboratory Tests Reported as Adverse Events [Phase 1] | Hypernatraemia | 0 participants |
| Dose Escalation, Alisertib 30 mg | Number of Participants With Clinically Significant Laboratory Tests Reported as Adverse Events [Phase 1] | Aspartate aminotransferase increased | 0 participants |
| Dose Escalation, Alisertib 30 mg | Number of Participants With Clinically Significant Laboratory Tests Reported as Adverse Events [Phase 1] | Hypermagnesaemia | 0 participants |
| Dose Escalation, Alisertib 30 mg | Number of Participants With Clinically Significant Laboratory Tests Reported as Adverse Events [Phase 1] | White blood cell count decreased | 0 participants |
| Dose Escalation, Alisertib 30 mg | Number of Participants With Clinically Significant Laboratory Tests Reported as Adverse Events [Phase 1] | Neutropenia | 2 participants |
| Dose Escalation, Alisertib 30 mg | Number of Participants With Clinically Significant Laboratory Tests Reported as Adverse Events [Phase 1] | Hyperkalaemia | 0 participants |
| Dose Escalation, Alisertib 30 mg | Number of Participants With Clinically Significant Laboratory Tests Reported as Adverse Events [Phase 1] | Hypocalcaemia | 0 participants |
| Dose Escalation, Alisertib 30 mg | Number of Participants With Clinically Significant Laboratory Tests Reported as Adverse Events [Phase 1] | Hypokalaemia | 0 participants |
| Dose Escalation, Alisertib 30 mg | Number of Participants With Clinically Significant Laboratory Tests Reported as Adverse Events [Phase 1] | Lymphocyte count decreased | 0 participants |
| Dose Escalation, Alisertib 30 mg | Number of Participants With Clinically Significant Laboratory Tests Reported as Adverse Events [Phase 1] | Anaemia | 3 participants |
| Dose Escalation, Alisertib 30 mg | Number of Participants With Clinically Significant Laboratory Tests Reported as Adverse Events [Phase 1] | Hypercalcaemia | 0 participants |
| Dose Escalation, Alisertib 30 mg | Number of Participants With Clinically Significant Laboratory Tests Reported as Adverse Events [Phase 1] | Lymphopenia | 2 participants |
| Dose Escalation, Alisertib 30 mg | Number of Participants With Clinically Significant Laboratory Tests Reported as Adverse Events [Phase 1] | Neutrophil count decreased | 0 participants |
| Dose Escalation, Alisertib 40 mg | Number of Participants With Clinically Significant Laboratory Tests Reported as Adverse Events [Phase 1] | Hypocalcaemia | 1 participants |
| Dose Escalation, Alisertib 40 mg | Number of Participants With Clinically Significant Laboratory Tests Reported as Adverse Events [Phase 1] | Hypokalaemia | 6 participants |
| Dose Escalation, Alisertib 40 mg | Number of Participants With Clinically Significant Laboratory Tests Reported as Adverse Events [Phase 1] | Hyperkalaemia | 1 participants |
| Dose Escalation, Alisertib 40 mg | Number of Participants With Clinically Significant Laboratory Tests Reported as Adverse Events [Phase 1] | Hypomagnesaemia | 5 participants |
| Dose Escalation, Alisertib 40 mg | Number of Participants With Clinically Significant Laboratory Tests Reported as Adverse Events [Phase 1] | Hypermagnesaemia | 0 participants |
| Dose Escalation, Alisertib 40 mg | Number of Participants With Clinically Significant Laboratory Tests Reported as Adverse Events [Phase 1] | Aspartate aminotransferase increased | 1 participants |
| Dose Escalation, Alisertib 40 mg | Number of Participants With Clinically Significant Laboratory Tests Reported as Adverse Events [Phase 1] | White blood cell count decreased | 0 participants |
| Dose Escalation, Alisertib 40 mg | Number of Participants With Clinically Significant Laboratory Tests Reported as Adverse Events [Phase 1] | Hypercalcaemia | 2 participants |
| Dose Escalation, Alisertib 40 mg | Number of Participants With Clinically Significant Laboratory Tests Reported as Adverse Events [Phase 1] | Hyperglycaemia | 2 participants |
| Dose Escalation, Alisertib 40 mg | Number of Participants With Clinically Significant Laboratory Tests Reported as Adverse Events [Phase 1] | Hypoalbuminaemia | 0 participants |
| Dose Escalation, Alisertib 40 mg | Number of Participants With Clinically Significant Laboratory Tests Reported as Adverse Events [Phase 1] | Alanine aminotransferase increased | 0 participants |
| Dose Escalation, Alisertib 40 mg | Number of Participants With Clinically Significant Laboratory Tests Reported as Adverse Events [Phase 1] | Hyponatraemia | 0 participants |
| Dose Escalation, Alisertib 40 mg | Number of Participants With Clinically Significant Laboratory Tests Reported as Adverse Events [Phase 1] | Hypernatraemia | 1 participants |
| Dose Escalation, Alisertib 40 mg | Number of Participants With Clinically Significant Laboratory Tests Reported as Adverse Events [Phase 1] | Platelet count decreased | 1 participants |
| Dose Escalation, Alisertib 40 mg | Number of Participants With Clinically Significant Laboratory Tests Reported as Adverse Events [Phase 1] | Hypophosphataemia | 1 participants |
| Dose Escalation, Alisertib 40 mg | Number of Participants With Clinically Significant Laboratory Tests Reported as Adverse Events [Phase 1] | Neutrophil count decreased | 3 participants |
| Dose Escalation, Alisertib 40 mg | Number of Participants With Clinically Significant Laboratory Tests Reported as Adverse Events [Phase 1] | Blood bilirubin increased | 0 participants |
| Dose Escalation, Alisertib 40 mg | Number of Participants With Clinically Significant Laboratory Tests Reported as Adverse Events [Phase 1] | Anaemia | 14 participants |
| Dose Escalation, Alisertib 40 mg | Number of Participants With Clinically Significant Laboratory Tests Reported as Adverse Events [Phase 1] | Neutropenia | 11 participants |
| Dose Escalation, Alisertib 40 mg | Number of Participants With Clinically Significant Laboratory Tests Reported as Adverse Events [Phase 1] | Lymphocyte count decreased | 0 participants |
| Dose Escalation, Alisertib 40 mg | Number of Participants With Clinically Significant Laboratory Tests Reported as Adverse Events [Phase 1] | Febrile neutropenia | 4 participants |
| Dose Escalation, Alisertib 40 mg | Number of Participants With Clinically Significant Laboratory Tests Reported as Adverse Events [Phase 1] | Leukopenia | 9 participants |
| Dose Escalation, Alisertib 40 mg | Number of Participants With Clinically Significant Laboratory Tests Reported as Adverse Events [Phase 1] | Lymphopenia | 1 participants |
| Dose Escalation, Alisertib 40 mg | Number of Participants With Clinically Significant Laboratory Tests Reported as Adverse Events [Phase 1] | Thrombocytopenia | 7 participants |
| Dose Escalation, Alisertib 50 mg | Number of Participants With Clinically Significant Laboratory Tests Reported as Adverse Events [Phase 1] | Blood bilirubin increased | 0 participants |
| Dose Escalation, Alisertib 50 mg | Number of Participants With Clinically Significant Laboratory Tests Reported as Adverse Events [Phase 1] | Aspartate aminotransferase increased | 2 participants |
| Dose Escalation, Alisertib 50 mg | Number of Participants With Clinically Significant Laboratory Tests Reported as Adverse Events [Phase 1] | Hyperkalaemia | 0 participants |
| Dose Escalation, Alisertib 50 mg | Number of Participants With Clinically Significant Laboratory Tests Reported as Adverse Events [Phase 1] | Anaemia | 2 participants |
| Dose Escalation, Alisertib 50 mg | Number of Participants With Clinically Significant Laboratory Tests Reported as Adverse Events [Phase 1] | Hypocalcaemia | 1 participants |
| Dose Escalation, Alisertib 50 mg | Number of Participants With Clinically Significant Laboratory Tests Reported as Adverse Events [Phase 1] | Hypermagnesaemia | 1 participants |
| Dose Escalation, Alisertib 50 mg | Number of Participants With Clinically Significant Laboratory Tests Reported as Adverse Events [Phase 1] | Thrombocytopenia | 3 participants |
| Dose Escalation, Alisertib 50 mg | Number of Participants With Clinically Significant Laboratory Tests Reported as Adverse Events [Phase 1] | Neutropenia | 2 participants |
| Dose Escalation, Alisertib 50 mg | Number of Participants With Clinically Significant Laboratory Tests Reported as Adverse Events [Phase 1] | Lymphopenia | 1 participants |
| Dose Escalation, Alisertib 50 mg | Number of Participants With Clinically Significant Laboratory Tests Reported as Adverse Events [Phase 1] | Hypomagnesaemia | 1 participants |
| Dose Escalation, Alisertib 50 mg | Number of Participants With Clinically Significant Laboratory Tests Reported as Adverse Events [Phase 1] | White blood cell count decreased | 1 participants |
| Dose Escalation, Alisertib 50 mg | Number of Participants With Clinically Significant Laboratory Tests Reported as Adverse Events [Phase 1] | Febrile neutropenia | 3 participants |
| Dose Escalation, Alisertib 50 mg | Number of Participants With Clinically Significant Laboratory Tests Reported as Adverse Events [Phase 1] | Alanine aminotransferase increased | 2 participants |
| Dose Escalation, Alisertib 50 mg | Number of Participants With Clinically Significant Laboratory Tests Reported as Adverse Events [Phase 1] | Hyponatraemia | 1 participants |
| Dose Escalation, Alisertib 50 mg | Number of Participants With Clinically Significant Laboratory Tests Reported as Adverse Events [Phase 1] | Lymphocyte count decreased | 0 participants |
| Dose Escalation, Alisertib 50 mg | Number of Participants With Clinically Significant Laboratory Tests Reported as Adverse Events [Phase 1] | Hypernatraemia | 0 participants |
| Dose Escalation, Alisertib 50 mg | Number of Participants With Clinically Significant Laboratory Tests Reported as Adverse Events [Phase 1] | Platelet count decreased | 1 participants |
| Dose Escalation, Alisertib 50 mg | Number of Participants With Clinically Significant Laboratory Tests Reported as Adverse Events [Phase 1] | Hypoalbuminaemia | 2 participants |
| Dose Escalation, Alisertib 50 mg | Number of Participants With Clinically Significant Laboratory Tests Reported as Adverse Events [Phase 1] | Hypokalaemia | 2 participants |
| Dose Escalation, Alisertib 50 mg | Number of Participants With Clinically Significant Laboratory Tests Reported as Adverse Events [Phase 1] | Hypophosphataemia | 1 participants |
| Dose Escalation, Alisertib 50 mg | Number of Participants With Clinically Significant Laboratory Tests Reported as Adverse Events [Phase 1] | Hyperglycaemia | 1 participants |
| Dose Escalation, Alisertib 50 mg | Number of Participants With Clinically Significant Laboratory Tests Reported as Adverse Events [Phase 1] | Hypercalcaemia | 0 participants |
| Dose Escalation, Alisertib 50 mg | Number of Participants With Clinically Significant Laboratory Tests Reported as Adverse Events [Phase 1] | Leukopenia | 3 participants |
| Dose Escalation, Alisertib 50 mg | Number of Participants With Clinically Significant Laboratory Tests Reported as Adverse Events [Phase 1] | Neutrophil count decreased | 1 participants |
Primary
Number of Participants With Clinically Significant Vital Signs Findings (Treatment Related and Unrelated) [Phase 1]
Vital sign parameters: blood pressure, heart rate and temperature determined by the investigator to be clinically significant were reported as adverse events.
Time frame: First dose of alisertib through 30 days after the last dose of alisertib (Up to 5.2 Years)
Population: Safety Population was defined as all participants who receive any amount of alisertib.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Safety Lead-in | Number of Participants With Clinically Significant Vital Signs Findings (Treatment Related and Unrelated) [Phase 1] | Hypotension | 0 participants |
| Safety Lead-in | Number of Participants With Clinically Significant Vital Signs Findings (Treatment Related and Unrelated) [Phase 1] | Orthostatic hypotension | 2 participants |
| Safety Lead-in | Number of Participants With Clinically Significant Vital Signs Findings (Treatment Related and Unrelated) [Phase 1] | Hypertension | 1 participants |
| Safety Lead-in | Number of Participants With Clinically Significant Vital Signs Findings (Treatment Related and Unrelated) [Phase 1] | Pyrexia | 3 participants |
| Dose Escalation, Alisertib 30 mg | Number of Participants With Clinically Significant Vital Signs Findings (Treatment Related and Unrelated) [Phase 1] | Orthostatic hypotension | 2 participants |
| Dose Escalation, Alisertib 30 mg | Number of Participants With Clinically Significant Vital Signs Findings (Treatment Related and Unrelated) [Phase 1] | Hypertension | 0 participants |
| Dose Escalation, Alisertib 30 mg | Number of Participants With Clinically Significant Vital Signs Findings (Treatment Related and Unrelated) [Phase 1] | Pyrexia | 0 participants |
| Dose Escalation, Alisertib 30 mg | Number of Participants With Clinically Significant Vital Signs Findings (Treatment Related and Unrelated) [Phase 1] | Hypotension | 0 participants |
| Dose Escalation, Alisertib 40 mg | Number of Participants With Clinically Significant Vital Signs Findings (Treatment Related and Unrelated) [Phase 1] | Hypertension | 0 participants |
| Dose Escalation, Alisertib 40 mg | Number of Participants With Clinically Significant Vital Signs Findings (Treatment Related and Unrelated) [Phase 1] | Orthostatic hypotension | 0 participants |
| Dose Escalation, Alisertib 40 mg | Number of Participants With Clinically Significant Vital Signs Findings (Treatment Related and Unrelated) [Phase 1] | Pyrexia | 2 participants |
| Dose Escalation, Alisertib 40 mg | Number of Participants With Clinically Significant Vital Signs Findings (Treatment Related and Unrelated) [Phase 1] | Hypotension | 3 participants |
| Dose Escalation, Alisertib 50 mg | Number of Participants With Clinically Significant Vital Signs Findings (Treatment Related and Unrelated) [Phase 1] | Pyrexia | 1 participants |
| Dose Escalation, Alisertib 50 mg | Number of Participants With Clinically Significant Vital Signs Findings (Treatment Related and Unrelated) [Phase 1] | Orthostatic hypotension | 0 participants |
| Dose Escalation, Alisertib 50 mg | Number of Participants With Clinically Significant Vital Signs Findings (Treatment Related and Unrelated) [Phase 1] | Hypotension | 1 participants |
| Dose Escalation, Alisertib 50 mg | Number of Participants With Clinically Significant Vital Signs Findings (Treatment Related and Unrelated) [Phase 1] | Hypertension | 0 participants |
Primary
Number of Participants With Treatment-Emergent Adverse Events [Phase 1]
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 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 alisertib through 30 days after the last dose of alisertib (Up to 5.2 Years)
Population: Safety Population was defined as all participants who receive any amount of alisertib.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Safety Lead-in | Number of Participants With Treatment-Emergent Adverse Events [Phase 1] | 13 participants |
| Dose Escalation, Alisertib 30 mg | Number of Participants With Treatment-Emergent Adverse Events [Phase 1] | 4 participants |
| Dose Escalation, Alisertib 40 mg | Number of Participants With Treatment-Emergent Adverse Events [Phase 1] | 25 participants |
| Dose Escalation, Alisertib 50 mg | Number of Participants With Treatment-Emergent Adverse Events [Phase 1] | 3 participants |
Primary
Overall Response Rate [Phase 2]
Overall Response Rate was defined as the percentage of participants with Complete Response (CR) or Partial Response (PR) as assessed by the investigator using International Working Group (IWG) Criteria. CR is defined as the disappearance of all evidence of disease and PR is defined as regression of measurable disease and no new sites.
Time frame: At the end of Cycle 2, at the end of every second treatment cycle until 6 months, then every 12 weeks thereafter, approximately 2 years
Population: The Phase 2 portion of the study was cancelled by the sponsor.
Secondary
AUC∞: Area Under the Concentration-time Curve From Time 0 to Infinity for Vincristine
Time frame: Cycles 1 and 2 on Day 1 prior to injection of vincristine and multiple time-points (up to 72 hours) post-dose
Population: Vincristine PK-evaluable population was defined as participants with sufficient dosing and concentration-time data to permit non-compartmental PK analysis. Safety Lead-in arm did not receive vincristine. Number analyzed is the number of participants with data available at the time-point. No data was collected for the alisertib 50 mg arm in Cycle 2.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Safety Lead-in | AUC∞: Area Under the Concentration-time Curve From Time 0 to Infinity for Vincristine | Cycle 1, Day 1 | 77.9 ng/mL*hr | Standard Deviation 11.25 |
| Safety Lead-in | AUC∞: Area Under the Concentration-time Curve From Time 0 to Infinity for Vincristine | Cycle 2, Day 1 | 69.0 ng/mL*hr | Standard Deviation 4.45 |
| Dose Escalation, Alisertib 30 mg | AUC∞: Area Under the Concentration-time Curve From Time 0 to Infinity for Vincristine | Cycle 1, Day 1 | 84.8 ng/mL*hr | Standard Deviation 36.21 |
| Dose Escalation, Alisertib 30 mg | AUC∞: Area Under the Concentration-time Curve From Time 0 to Infinity for Vincristine | Cycle 2, Day 1 | 82.7 ng/mL*hr | Standard Deviation 35.39 |
| Dose Escalation, Alisertib 40 mg | AUC∞: Area Under the Concentration-time Curve From Time 0 to Infinity for Vincristine | Cycle 1, Day 1 | 116.8 ng/mL*hr | Standard Deviation 44.95 |
Secondary
AUCt: Area Under the Concentration Time Curve Over the Dosing Interval From Time 0 to Time t for Alisertib
Time frame: Cycle 1 Days 1 and 7 prior to morning alisertib dose and multiple time-points (up to 12 hours) post-dose
Population: Alisertib PK-Evaluable Population was defined as all participants with sufficient dosing and alisertib concentration-time data to permit non-compartmental PK analysis. Number analyzed is the number of participants with data available at the given time-point.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Safety Lead-in | AUCt: Area Under the Concentration Time Curve Over the Dosing Interval From Time 0 to Time t for Alisertib | Day 1 | 10116.7 nanomoles/liter*hour (nmol/L*hr) | Standard Deviation 6683.97 |
| Safety Lead-in | AUCt: Area Under the Concentration Time Curve Over the Dosing Interval From Time 0 to Time t for Alisertib | Day 7 | 21812.5 nanomoles/liter*hour (nmol/L*hr) | Standard Deviation 13090.21 |
| Dose Escalation, Alisertib 30 mg | AUCt: Area Under the Concentration Time Curve Over the Dosing Interval From Time 0 to Time t for Alisertib | Day 7 | 12227.5 nanomoles/liter*hour (nmol/L*hr) | Standard Deviation 3480.09 |
| Dose Escalation, Alisertib 30 mg | AUCt: Area Under the Concentration Time Curve Over the Dosing Interval From Time 0 to Time t for Alisertib | Day 1 | 5817.5 nanomoles/liter*hour (nmol/L*hr) | Standard Deviation 2966.26 |
| Dose Escalation, Alisertib 40 mg | AUCt: Area Under the Concentration Time Curve Over the Dosing Interval From Time 0 to Time t for Alisertib | Day 1 | 8005.9 nanomoles/liter*hour (nmol/L*hr) | Standard Deviation 3251.32 |
| Dose Escalation, Alisertib 40 mg | AUCt: Area Under the Concentration Time Curve Over the Dosing Interval From Time 0 to Time t for Alisertib | Day 7 | 17996.0 nanomoles/liter*hour (nmol/L*hr) | Standard Deviation 11555.15 |
| Dose Escalation, Alisertib 50 mg | AUCt: Area Under the Concentration Time Curve Over the Dosing Interval From Time 0 to Time t for Alisertib | Day 1 | 13096.7 nanomoles/liter*hour (nmol/L*hr) | Standard Deviation 7453.39 |
| Dose Escalation, Alisertib 50 mg | AUCt: Area Under the Concentration Time Curve Over the Dosing Interval From Time 0 to Time t for Alisertib | Day 7 | 33800.0 nanomoles/liter*hour (nmol/L*hr) | Standard Deviation 16263.46 |
Secondary
AUCt: Area Under the Concentration-time Time Curve Over the Dosing Interval From Time 0 to Time t for Vincristine
Time frame: Cycles 1 and 2 on Day 1 prior to injection of vincristine and multiple time-points (up to 72 hours) post-dose
Population: Vincristine PK-evaluable population was defined as all participants with sufficient dosing and vincristine concentration-time data to permit non-compartmental PK analysis. Safety Lead-in arm did not receive vincristine Number analyzed is the number of participants with data available at the given time-point.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Safety Lead-in | AUCt: Area Under the Concentration-time Time Curve Over the Dosing Interval From Time 0 to Time t for Vincristine | Cycle 1, Day 1 | 69.8 ng/mL*hr | Standard Deviation 9.92 |
| Safety Lead-in | AUCt: Area Under the Concentration-time Time Curve Over the Dosing Interval From Time 0 to Time t for Vincristine | Cycle 2, Day 1 | 60.8 ng/mL*hr | Standard Deviation 2.26 |
| Dose Escalation, Alisertib 30 mg | AUCt: Area Under the Concentration-time Time Curve Over the Dosing Interval From Time 0 to Time t for Vincristine | Cycle 2, Day 1 | 72.8 ng/mL*hr | Standard Deviation 30.4 |
| Dose Escalation, Alisertib 30 mg | AUCt: Area Under the Concentration-time Time Curve Over the Dosing Interval From Time 0 to Time t for Vincristine | Cycle 1, Day 1 | 69.1 ng/mL*hr | Standard Deviation 33.24 |
| Dose Escalation, Alisertib 40 mg | AUCt: Area Under the Concentration-time Time Curve Over the Dosing Interval From Time 0 to Time t for Vincristine | Cycle 1, Day 1 | 104.1 ng/mL*hr | Standard Deviation 43.34 |
| Dose Escalation, Alisertib 40 mg | AUCt: Area Under the Concentration-time Time Curve Over the Dosing Interval From Time 0 to Time t for Vincristine | Cycle 2, Day 1 | 72.2 ng/mL*hr | Standard Deviation 32.6 |
Secondary
Cmax: Maximum Plasma Concentration for Alisertib
Time frame: Cycle 1 Days 1 and 7 prior to morning alisertib dose and multiple time-points (up to 12 hours) post-dose
Population: Alisertib Pharmacokinetic (PK)-Evaluable Population was defined as all participants with sufficient dosing and alisertib concentration-time data to permit non-compartmental PK analysis. Number analyzed is the number of participants with data available at the given time-point.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Safety Lead-in | Cmax: Maximum Plasma Concentration for Alisertib | Day 1 | 1624.1 nanoMolar (nM) | Standard Deviation 929.68 |
| Safety Lead-in | Cmax: Maximum Plasma Concentration for Alisertib | Day 7 | 2915.8 nanoMolar (nM) | Standard Deviation 1537.03 |
| Dose Escalation, Alisertib 30 mg | Cmax: Maximum Plasma Concentration for Alisertib | Day 7 | 1672.5 nanoMolar (nM) | Standard Deviation 183.92 |
| Dose Escalation, Alisertib 30 mg | Cmax: Maximum Plasma Concentration for Alisertib | Day 1 | 893.3 nanoMolar (nM) | Standard Deviation 350.03 |
| Dose Escalation, Alisertib 40 mg | Cmax: Maximum Plasma Concentration for Alisertib | Day 1 | 1159.7 nanoMolar (nM) | Standard Deviation 391.78 |
| Dose Escalation, Alisertib 40 mg | Cmax: Maximum Plasma Concentration for Alisertib | Day 7 | 2223.3 nanoMolar (nM) | Standard Deviation 1217.22 |
| Dose Escalation, Alisertib 50 mg | Cmax: Maximum Plasma Concentration for Alisertib | Day 1 | 1746.7 nanoMolar (nM) | Standard Deviation 594.75 |
| Dose Escalation, Alisertib 50 mg | Cmax: Maximum Plasma Concentration for Alisertib | Day 7 | 3670.0 nanoMolar (nM) | Standard Deviation 1541.49 |
Secondary
Cmax: Maximum Plasma Concentration for Vincristine
Time frame: Cycles 1 and 2 on Day 1 prior to injection of vincristine and multiple time-points (up to 72 hours) post-dose
Population: Vincristine PK-evaluable population was defined as all participants with sufficient dosing and vincristine concentration-time data to permit non-compartmental PK analysis. Safety Lead-in arm did not receive vincristine. Number analyzed is the number of participants with data available at the given time-point.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Safety Lead-in | Cmax: Maximum Plasma Concentration for Vincristine | Cycle 1, Day 1 | 132.2 ng/mL | Standard Deviation 54.57 |
| Safety Lead-in | Cmax: Maximum Plasma Concentration for Vincristine | Cycle 2, Day 1 | 113.9 ng/mL | Standard Deviation 53.86 |
| Dose Escalation, Alisertib 30 mg | Cmax: Maximum Plasma Concentration for Vincristine | Cycle 1, Day 1 | 105.4 ng/mL | Standard Deviation 78.93 |
| Dose Escalation, Alisertib 30 mg | Cmax: Maximum Plasma Concentration for Vincristine | Cycle 2, Day 1 | 124.4 ng/mL | Standard Deviation 157.7 |
| Dose Escalation, Alisertib 40 mg | Cmax: Maximum Plasma Concentration for Vincristine | Cycle 1, Day 1 | 158.4 ng/mL | Standard Deviation 67.94 |
| Dose Escalation, Alisertib 40 mg | Cmax: Maximum Plasma Concentration for Vincristine | Cycle 2, Day 1 | 122.3 ng/mL | Standard Deviation 36.42 |
Secondary
Complete Response Rate [Phase 2]
Complete response rate was defined as the percentage of participants with Complete Response (CR). CR was assessed by the investigator using International Working Group (IWG) Criteria. CR is defined as the disappearance of all evidence of disease.
Time frame: Duration of study until disease progression, approximately 2 years
Population: Phase 2 portion of the study was cancelled by the sponsor.
Secondary
Duration of Response (DOR) [Phase 2]
DOR was defined as the time from the date of first documentation of a response to the date of first documentation of Progressive Disease (PD).
Time frame: Duration of study until disease progression, approximately 2 years
Population: Phase 2 portion of the study was cancelled by the sponsor.
Secondary
Number of Participants With Clinically Significant Changes in Electrocardiograms (ECGs) [Phase 2]
Time frame: From screening period to 30 days after last dose of study drug, approximately 2 years
Population: Phase 2 portion of the study was cancelled by the sponsor.
Secondary
Number of Participants With Clinically Significant Changes in Multigated Acquisition (MUGA)/ Echocardiogram (ECHO) [Phase 2]
Time frame: From screening period to 30 days after last dose of study drug, approximately 2 years
Population: Phase 2 portion of the study was cancelled by the sponsor.
Secondary
Number of Participants With Clinically Significant Laboratory Tests Reported as Adverse Events [Phase 2]
Time frame: From screening period to 30 days after last dose of study drug, approximately 2 years
Population: Phase 2 portion of the study was cancelled by the sponsor.
Secondary
Number of Participants With Clinically Significant Vital Signs Findings [Phase 2]
Vital sign parameters: blood pressure, heart rate and temperature determined by the investigator to be clinically significant were reported as adverse events.
Time frame: From screening period to 30 days after last dose of study drug, approximately 2 years
Population: Phase 2 portion of the study was cancelled by the sponsor.
Secondary
Number of Participants With Treatment-Emergent Adverse Events [Phase 2]
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 treatment-emergent adverse event (TEAE) is defined as an adverse event with an onset that occurs after receiving study drug.
Time frame: From screening period to 30 days after last dose of study drug, approximately 2 years
Population: Phase 2 portion of the study was cancelled by the sponsor.
Secondary
Overall Response Rate as Assessed by the Investigator [Phase 1]
Overall Response Rate was defined as the percentage of participants with Complete Response (CR) or Partial Response (PR) as assessed by the investigator using International Working Group (IWG) Criteria. CR is defined as the disappearance of all evidence of disease and PR is defined as regression of measurable disease and no new sites.
Time frame: First dose of alisertib through 30 days after the last dose of alisertib (Up to 5.2 Years)
Population: Response-Evaluable Population was defined as all participants with measurable disease who received at least 1 dose of alisertib and had at least 1 post-baseline response assessment.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Safety Lead-in | Overall Response Rate as Assessed by the Investigator [Phase 1] | 25 percentage of participants |
| Dose Escalation, Alisertib 30 mg | Overall Response Rate as Assessed by the Investigator [Phase 1] | 33 percentage of participants |
| Dose Escalation, Alisertib 40 mg | Overall Response Rate as Assessed by the Investigator [Phase 1] | 45 percentage of participants |
| Dose Escalation, Alisertib 50 mg | Overall Response Rate as Assessed by the Investigator [Phase 1] | 50 percentage of participants |
Secondary
Progression Free Survival (PFS) [Phase 2]
PFS was defined as the time from the date of first study drug administration to the date of first documentation of PD or death.
Time frame: Duration of study until disease progression, approximately 2 years
Population: The Phase 2 portion of the study was cancelled by the sponsor.
Secondary
T1/2: Terminal Disposition Phase Half-life for Vincristine
Time frame: Cycles 1 and 2 on Day prior to injection of vincristine and multiple time-points (up to 72 hours) post-dose
Population: Vincristine PK-evaluable population was defined as participants with sufficient dosing and concentration-time data to permit non-compartmental PK analysis. Safety Lead-in arm did not receive vincristine. Number analyzed is the number of participants with data available at the time-point. No data was collected for the alisertib 50 mg arm in Cycle 2.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Safety Lead-in | T1/2: Terminal Disposition Phase Half-life for Vincristine | Cycle 1, Day 1 | 20.2 nanogram/milliliter (ng/mL) | Standard Deviation 5.04 |
| Safety Lead-in | T1/2: Terminal Disposition Phase Half-life for Vincristine | Cycle 2, Day 1 | 19.9 nanogram/milliliter (ng/mL) | Standard Deviation 0.92 |
| Dose Escalation, Alisertib 30 mg | T1/2: Terminal Disposition Phase Half-life for Vincristine | Cycle 1, Day 1 | 20.0 nanogram/milliliter (ng/mL) | Standard Deviation 5.89 |
| Dose Escalation, Alisertib 30 mg | T1/2: Terminal Disposition Phase Half-life for Vincristine | Cycle 2, Day 1 | 20.2 nanogram/milliliter (ng/mL) | Standard Deviation 4.66 |
| Dose Escalation, Alisertib 40 mg | T1/2: Terminal Disposition Phase Half-life for Vincristine | Cycle 1, Day 1 | 25.6 nanogram/milliliter (ng/mL) | Standard Deviation 4.55 |
Secondary
Tmax: Time to First Occurrence of Cmax fo Alisertib
Time frame: Cycle 1 Days 1 and 7 prior to morning alisertib dose and multiple time-points (up to 12 hours) post-dose
Population: Alisertib PK-Evaluable Population was defined as all participants with sufficient dosing and alisertib concentration-time data to permit non-compartmental PK analysis. Number analyzed is the number of participants with data available at the given time-point.
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Safety Lead-in | Tmax: Time to First Occurrence of Cmax fo Alisertib | Day 7 | 2.0 hours (hr) |
| Safety Lead-in | Tmax: Time to First Occurrence of Cmax fo Alisertib | Day 1 | 3.0 hours (hr) |
| Dose Escalation, Alisertib 30 mg | Tmax: Time to First Occurrence of Cmax fo Alisertib | Day 1 | 3.5 hours (hr) |
| Dose Escalation, Alisertib 30 mg | Tmax: Time to First Occurrence of Cmax fo Alisertib | Day 7 | 3.1 hours (hr) |
| Dose Escalation, Alisertib 40 mg | Tmax: Time to First Occurrence of Cmax fo Alisertib | Day 7 | 3.1 hours (hr) |
| Dose Escalation, Alisertib 40 mg | Tmax: Time to First Occurrence of Cmax fo Alisertib | Day 1 | 3.0 hours (hr) |
| Dose Escalation, Alisertib 50 mg | Tmax: Time to First Occurrence of Cmax fo Alisertib | Day 7 | 2.5 hours (hr) |
| Dose Escalation, Alisertib 50 mg | Tmax: Time to First Occurrence of Cmax fo Alisertib | Day 1 | 6.1 hours (hr) |