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.
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.
Study Type
INTERVENTIONAL
Allocation
NON_RANDOMIZED
Purpose
TREATMENT
Masking
NONE
Enrollment
45
Alisertib (MLN8237) enteric coated tablet (ECT).
Rituximab IV infusion.
Vincristine IV Infusion.
Unnamed facility
Tucson, Arizona, United States
Unnamed facility
Beverly Hills, California, United States
Unnamed facility
Burbank, California, United States
Unnamed facility
Miami, Florida, United States
Unnamed facility
Lexington, Kentucky, United States
Unnamed facility
Worcester, Massachusetts, United States
Unnamed facility
New York, New York, United States
Unnamed facility
Rochester, New York, United States
Unnamed facility
Chapel Hill, North Carolina, United States
Unnamed facility
Philadelphia, Pennsylvania, United States
...and 15 more locations
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)
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)
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)
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)
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)
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)
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
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)
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
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
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
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
Number of Participants With Clinically Significant Vital Signs Findings [Phase 2]
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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
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
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
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
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
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
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
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
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
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
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