MLN8237 in Patients With Relapsed or Refractory Aggressive B-Cell Lymphoma Treated With Rituximab +/- Vincristine

Study Overview
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Brief Summary
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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
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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.

Official Title
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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

Conditions
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Diffuse Large B-Cell Lymphoma, Transformed Follicular Lymphoma, Mantle Cell Lymphoma, Burkitt's Lymphoma

Intervention / Treatment
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* Drug: Alisertib (MLN8237)
* Drug: Rituximab
* Drug: Vincristine


Participation Criteria
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Eligibility Criteria
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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

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Safety Lead-in<br>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. | Drug: Alisertib (MLN8237)<br>* Alisertib (MLN8237) enteric coated tablet (ECT).<br>Drug: Rituximab<br>* Rituximab IV infusion.<br>|
| Experimental: Dose Escalation, Alisertib 30 mg<br>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. | Drug: Alisertib (MLN8237)<br>* Alisertib (MLN8237) enteric coated tablet (ECT).<br>Drug: Rituximab<br>* Rituximab IV infusion.<br>Drug: Vincristine<br>* Vincristine IV Infusion.<br>|
| Experimental: Dose Escalation, Alisertib 40 mg<br>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. | Drug: Alisertib (MLN8237)<br>* Alisertib (MLN8237) enteric coated tablet (ECT).<br>Drug: Rituximab<br>* Rituximab IV infusion.<br>Drug: Vincristine<br>* Vincristine IV Infusion.<br>|
| Experimental: Dose Escalation, Alisertib 50 mg<br>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. | Drug: Alisertib (MLN8237)<br>* Alisertib (MLN8237) enteric coated tablet (ECT).<br>Drug: Rituximab<br>* Rituximab IV infusion.<br>Drug: Vincristine<br>* Vincristine IV Infusion.<br>|
| Experimental: Phase 2: Alisertib<br>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. | Drug: Alisertib (MLN8237)<br>* Alisertib (MLN8237) enteric coated tablet (ECT).<br>Drug: Rituximab<br>* Rituximab IV infusion.<br>Drug: Vincristine<br>* Vincristine IV Infusion.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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. | 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. | 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. | 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. | 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. | 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. | 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. | 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 Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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. | 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. | 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). | 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. | 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. | 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] | Vital sign parameters: blood pressure, heart rate and temperature determined by the investigator to be clinically significant were reported as adverse events. | 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] |  | 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] |  | 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 | 
| 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 | 
| 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 |