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

Phase 1

Completed

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

Interventions: Drug: Alisertib (MLN8237)
Drug: Rituximab
Drug: Vincristine

Registration Number: NCT01397825

Lead Sponsor: Millennium Pharmaceuticals, Inc.

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.

Recruitment & Eligibility

Status: COMPLETED

Sex: All

Target Recruitment: 45

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

Exclusion Criteria

Not provided

Study & Design

Study Type: INTERVENTIONAL

Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
Dose Escalation, Alisertib 50 mg	Alisertib (MLN8237)	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.
Safety Lead-in	Alisertib (MLN8237)	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.
Dose Escalation, Alisertib 30 mg	Alisertib (MLN8237)	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.
Dose Escalation, Alisertib 30 mg	Rituximab	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.
Dose Escalation, Alisertib 40 mg	Alisertib (MLN8237)	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.
Phase 2: Alisertib	Alisertib (MLN8237)	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.
Phase 2: Alisertib	Rituximab	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.
Phase 2: Alisertib	Vincristine	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.
Safety Lead-in	Rituximab	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.
Dose Escalation, Alisertib 30 mg	Vincristine	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.
Dose Escalation, Alisertib 40 mg	Rituximab	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.
Dose Escalation, Alisertib 50 mg	Vincristine	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.
Dose Escalation, Alisertib 40 mg	Vincristine	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.
Dose Escalation, Alisertib 50 mg	Rituximab	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.

Primary Outcome Measures

Name	Time	Method
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 Outcome Measures

Name	Time	Method
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
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.
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.
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.
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).
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
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
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