Neoplasms

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Rituximab

Vincristine

Antineoplastic Agents, Immunological

Immunologic Factors

Tubulin Modulators

Antimitotic Agents

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.

Alisertib (MLN8237) enteric coated tablet (ECT).

Alisertib (MLN8237)

Medical Monitor

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.

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

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

Vital sign parameters: blood pressure, heart rate and temperature determined by the investigator to be clinically significant were reported as adverse events.

Abnormal ECGs findings determined by the investigator to be clinically significant were reported as adverse events.

Abnormal changes in MUGA and ECHO findings determined by the investigator to be clinically significant were reported as adverse events.

Abnormal Physical Examination findings determined by the investigator to be clinically significant were reported as Adverse Events.

Abnormal treatment-emergent Chemistry and Hematology Laboratory values determined by the investigator to be clinically significant were reported as adverse events.

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 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 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.

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).

PFS was defined as the time from the date of first study drug administration to the date of first documentation of PD or death.

Millennium Pharmaceuticals, Inc.

At each visit the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment.

Safety Lead-in

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.

Dose Escalation, Alisertib 30 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.

Dose Escalation, Alisertib 40 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.

Dose Escalation, Alisertib 50 mg

Total

Age, Continuous

Sex: Female, Male

Hispanic or Latino

Not Hispanic or Latino

Race/Ethnicity, Customized

White

Black or African American

Asian

Other

Not Reported

United States

Region of Enrollment

Height

Weight

Body surface area (m\^²)=square root \[height (cm)×weight (kg)/3600\].

Body Surface Area

Safety Population was defined as all participants who receive any amount of alisertib.

The Phase 2 portion of the study was cancelled by the sponsor; this was an administrative decision not based on any clinical or safety outcomes.

Medical Director

Hypotension

Orthostatic hypotension

Hypertension

Pyrexia

Number of Participants With Clinically Significant Vital Signs Findings (Treatment Related and Unrelated) [Phase 1]

Number of Participants With Clinically Significant Changes in Electrocardiograms (ECGs) [Phase 1]

Number of Participants With Clinically Significant Changes in Multigated Acquisition (MUGA)/ Echocardiogram (ECHO) [Phase 1]

Number of Participants With Clinically Significant Changes in Physical Examination Findings [Phase 1]

Anaemia

Neutropenia

Febrile neutropenia

Leukopenia

Lymphopenia

Thrombocytopenia

Hypokalaemia

Hyperkalaemia

Hypomagnesaemia

Hypermagnesaemia

Hypocalcaemia

Hypercalcaemia

Hyperglycaemia

Hypoalbuminaemia

Hyponatraemia

Hypernatraemia

Hypophosphataemia

Neutrophil count decreased

Lymphocyte count decreased

White blood cell count decreased

Aspartate aminotransferase increased

Alanine aminotransferase increased

Blood bilirubin increased

Platelet count decreased

Number of Participants With Clinically Significant Laboratory Tests Reported as Adverse Events [Phase 1]

Number of Participants With Treatment-Emergent Adverse Events [Phase 1]

Phase 2: Alisertib

The Phase 2 portion of the study was cancelled by the sponsor.

Overall Response Rate [Phase 2]

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.

Overall Response Rate as Assessed by the Investigator [Phase 1]

Phase 2 portion of the study was cancelled by the sponsor.

Complete Response Rate [Phase 2]

Duration of Response (DOR) [Phase 2]

Progression Free Survival (PFS) [Phase 2]

Number of Participants With Treatment-Emergent Adverse Events [Phase 2]

Number of Participants With Clinically Significant Vital Signs Findings [Phase 2]

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]

Day 1

Day 7

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.

Cmax: Maximum Plasma Concentration for Alisertib

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.

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

Cycle 1, Day 1

Cycle 2, Day 1

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.

Cmax: Maximum Plasma Concentration for Vincristine

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.

AUCt: Area Under the Concentration-time Time Curve Over the Dosing Interval From Time 0 to Time t for Vincristine

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.

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization	Link
MLN8237 in Patients With Relapsed or Refractory Aggressive B-Cell Lymphoma Treated With Rituximab +/- Vincristine	NCT01397825	Diffuse Large B... Transformed Fol... Mantle Cell Lym... Burkitt's Lymph...	Alisertib (MLN8... Rituximab Vincristine	18 Years -	Takeda
MLN8237 in Patients With Relapsed or Refractory Aggressive B-Cell Lymphoma Treated With Rituximab +/- Vincristine	NCT01397825	Diffuse Large B... Transformed Fol... Mantle Cell Lym... Burkitt's Lymph...	Alisertib (MLN8... Rituximab Vincristine	18 Years -	Takeda

Spots Global Cancer Trial Database for alisertib (mln8237)