Back to resultsMLN8237 in Patients With Relapsed or Refractory Aggressive B-Cell Lymphoma Treated With Rituximab +/- Vincristine
Primary Purpose
Diffuse Large B-Cell Lymphoma, Transformed Follicular Lymphoma, Mantle Cell Lymphoma
Status
Completed
Phase
Phase 1
Locations
International
Study Type
Interventional
Intervention
Alisertib (MLN8237)
Rituximab
Vincristine
Sponsored by
About this trial
This is an interventional treatment trial for Diffuse Large B-Cell Lymphoma
Eligibility Criteria
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
Sites / Locations
Arms of the Study
Arm 1
Arm 2
Arm 3
Arm 4
Arm 5
Arm Type
Experimental
Experimental
Experimental
Experimental
Experimental
Arm Label
Safety Lead-in
Dose Escalation, Alisertib 30 mg
Dose Escalation, Alisertib 40 mg
Dose Escalation, Alisertib 50 mg
Phase 2: Alisertib
Arm Description
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.
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 (max 2 mg), IV, 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.
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 2mg), 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.
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 2mg), 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.
Phase 2: Alisertib (MLN8237) at the Recommended Phase 2 Dose, ECT orally twice/day on Days 1-7 & rituximab as an IV infusion on Day 1 & vincristine IV on Days 1 & 8 in a 21 Day cycle for up to 8 cycles was planned but not conducted.
Outcomes
Primary Outcome Measures
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.
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.
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.
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.
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.
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.
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.
Secondary Outcome Measures
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.
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.
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).
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.
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.
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.
Number of Participants With Clinically Significant Changes in Electrocardiograms (ECGs) [Phase 2]
Number of Participants With Clinically Significant Changes in Multigated Acquisition (MUGA)/ Echocardiogram (ECHO) [Phase 2]
Number of Participants With Clinically Significant Laboratory Tests Reported as Adverse Events [Phase 2]
Cmax: Maximum Plasma Concentration for Alisertib
Tmax: Time to First Occurrence of Cmax fo Alisertib
AUCt: Area Under the Concentration Time Curve Over the Dosing Interval From Time 0 to Time t for Alisertib
Cmax: Maximum Plasma Concentration for Vincristine
AUCt: Area Under the Concentration-time Time Curve Over the Dosing Interval From Time 0 to Time t for Vincristine
AUC∞: Area Under the Concentration-time Curve From Time 0 to Infinity for Vincristine
T1/2: Terminal Disposition Phase Half-life for Vincristine
Full Information
NCT ID
NCT01397825
First Posted
July 17, 2011
Last Updated
February 27, 2018
Sponsor
Millennium Pharmaceuticals, Inc.
1. Study Identification
Unique Protocol Identification Number
NCT01397825
Brief Title
MLN8237 in Patients With Relapsed or Refractory Aggressive B-Cell Lymphoma Treated With Rituximab +/- Vincristine
Official Title
A Multicenter, Phase 1-2 Study of MLN8237, an Oral Aurora A Kinase Inhibitor, in Patients With Relapsed or Refractory Aggressive B-Cell Lymphoma Treated With Rituximab and Vincristine
Study Type
Interventional
2. Study Status
Record Verification Date
February 2018
Overall Recruitment Status
Completed
Study Start Date
August 9, 2011 (Actual)
Primary Completion Date
February 5, 2015 (Actual)
Study Completion Date
October 5, 2016 (Actual)
3. Sponsor/Collaborators
Responsible Party, by Official Title
Sponsor
Name of the Sponsor
Millennium Pharmaceuticals, Inc.
4. Oversight
Studies a U.S. FDA-regulated Drug Product
Yes
Studies a U.S. FDA-regulated Device Product
No
Data Monitoring Committee
No
5. Study Description
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.
6. Conditions and Keywords
Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Diffuse Large B-Cell Lymphoma, Transformed Follicular Lymphoma, Mantle Cell Lymphoma, Burkitt's Lymphoma
7. Study Design
Primary Purpose
Treatment
Study Phase
Phase 1, Phase 2
Interventional Study Model
Parallel Assignment
Masking
None (Open Label)
Allocation
Non-Randomized
Enrollment
45 (Actual)
8. Arms, Groups, and Interventions
Arm Title
Safety Lead-in
Arm Type
Experimental
Arm Description
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.
Arm Title
Dose Escalation, Alisertib 30 mg
Arm Type
Experimental
Arm Description
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 (max 2 mg), IV, 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.
Arm Title
Dose Escalation, Alisertib 40 mg
Arm Type
Experimental
Arm Description
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 2mg), 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.
Arm Title
Dose Escalation, Alisertib 50 mg
Arm Type
Experimental
Arm Description
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 2mg), 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.
Arm Title
Phase 2: Alisertib
Arm Type
Experimental
Arm Description
Phase 2: Alisertib (MLN8237) at the Recommended Phase 2 Dose, ECT orally twice/day on Days 1-7 & rituximab as an IV infusion on Day 1 & vincristine IV on Days 1 & 8 in a 21 Day cycle for up to 8 cycles was planned but not conducted.
Intervention Type
Drug
Intervention Name(s)
Alisertib (MLN8237)
Intervention Description
Alisertib (MLN8237) enteric coated tablet (ECT).
Intervention Type
Drug
Intervention Name(s)
Rituximab
Intervention Description
Rituximab IV infusion.
Intervention Type
Drug
Intervention Name(s)
Vincristine
Intervention Description
Vincristine IV Infusion.
Primary Outcome Measure Information:
Title
Number of Participants With Clinically Significant Vital Signs Findings (Treatment Related and Unrelated) [Phase 1]
Description
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)
Title
Number of Participants With Clinically Significant Changes in Electrocardiograms (ECGs) [Phase 1]
Description
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)
Title
Number of Participants With Clinically Significant Changes in Multigated Acquisition (MUGA)/ Echocardiogram (ECHO) [Phase 1]
Description
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)
Title
Number of Participants With Clinically Significant Changes in Physical Examination Findings [Phase 1]
Description
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)
Title
Number of Participants With Clinically Significant Laboratory Tests Reported as Adverse Events [Phase 1]
Description
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)
Title
Number of Participants With Treatment-Emergent Adverse Events [Phase 1]
Description
An Adverse Event (AE) is defined as any untoward medical occurrence in a clinical investigation participant administered a drug; it does not necessarily have to have a causal relationship with this treatment. A 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)
Title
Overall Response Rate [Phase 2]
Description
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
Secondary Outcome Measure Information:
Title
Overall Response Rate as Assessed by the Investigator [Phase 1]
Description
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)
Title
Complete Response Rate [Phase 2]
Description
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
Title
Duration of Response (DOR) [Phase 2]
Description
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
Title
Progression Free Survival (PFS) [Phase 2]
Description
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
Title
Number of Participants With Treatment-Emergent Adverse Events [Phase 2]
Description
An Adverse Event (AE) is defined as any untoward medical occurrence in a clinical investigation participant administered a drug; it does not necessarily have to have a causal relationship with this treatment. A 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
Title
Number of Participants With Clinically Significant Vital Signs Findings [Phase 2]
Description
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
Title
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
Title
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
Title
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
Title
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
Title
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
Title
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
Title
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
Title
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
Title
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
Title
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
10. Eligibility
Sex
All
Minimum Age & Unit of Time
18 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
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
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Medical Monitor
Organizational Affiliation
Millennium Pharmaceuticals, Inc.
Official's Role
Study Director
Facility Information:
City
Tucson
State/Province
Arizona
Country
United States
City
Beverly Hills
State/Province
California
Country
United States
City
Burbank
State/Province
California
Country
United States
City
Miami
State/Province
Florida
Country
United States
City
Lexington
State/Province
Kentucky
Country
United States
City
Worcester
State/Province
Massachusetts
Country
United States
City
New York
State/Province
New York
Country
United States
City
Rochester
State/Province
New York
Country
United States
City
Chapel Hill
State/Province
North Carolina
Country
United States
City
Philadelphia
State/Province
Pennsylvania
Country
United States
City
Germantown
State/Province
Tennessee
Country
United States
City
Memphis
State/Province
Tennessee
Country
United States
City
Houston
State/Province
Texas
Country
United States
City
San Antonio
State/Province
Texas
Country
United States
City
Burlington
State/Province
Vermont
Country
United States
City
Orbassano
State/Province
Torino
Country
Italy
City
Genova
Country
Italy
City
Palermo
Country
Italy
City
Roma
Country
Italy
City
Madrid
Country
Spain
City
Sevilla
Country
Spain
City
Aberdeen
State/Province
Grampian Region
Country
United Kingdom
City
London
State/Province
Greater London
Country
United Kingdom
City
Southampton
State/Province
Hampshire
Country
United Kingdom
City
Birmingham
State/Province
West Midlands
Country
United Kingdom
12. IPD Sharing Statement
Citations:
PubMed Identifier
30082475
Citation
Kelly KR, Friedberg JW, Park SI, McDonagh K, Hayslip J, Persky D, Ruan J, Puvvada S, Rosen P, Iyer SP, Stefanovic A, Bernstein SH, Weitman S, Karnad A, Monohan G, VanderWalde A, Mena R, Schmelz M, Spier C, Groshen S, Venkatakrishnan K, Zhou X, Sheldon-Waniga E, Leonard EJ, Mahadevan D. Phase I Study of the Investigational Aurora A Kinase Inhibitor Alisertib plus Rituximab or Rituximab/Vincristine in Relapsed/Refractory Aggressive B-cell Lymphoma. Clin Cancer Res. 2018 Dec 15;24(24):6150-6159. doi: 10.1158/1078-0432.CCR-18-0286. Epub 2018 Aug 6.
Results Reference
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MLN8237 in Patients With Relapsed or Refractory Aggressive B-Cell Lymphoma Treated With Rituximab +/- Vincristine
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