Clinical trial NCT01397825: 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
Overall status: COMPLETED
Phase: PHASE1
PHASE2
Conditions: Diffuse Large B-Cell Lymphoma
Transformed Follicular Lymphoma
Mantle Cell Lymphoma
Burkitt's Lymphoma
Lead sponsor: Takeda
Sponsor class: INDUSTRY
First posted: 2011-07-20
Enrollment: 45
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NON_RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

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.

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

Primary outcomes:
measure: Number of Participants With Clinically Significant Vital Signs Findings (Treatment Related and Unrelated) [Phase 1]
timeFrame: First dose of alisertib through 30 days after the last dose of alisertib (Up to 5.2 Years)
measure: Number of Participants With Clinically Significant Changes in Electrocardiograms (ECGs) [Phase 1]
timeFrame: First dose of alisertib through 30 days after the last dose of alisertib (Up to 5.2 Years)
measure: Number of Participants With Clinically Significant Changes in Multigated Acquisition (MUGA)/ Echocardiogram (ECHO) [Phase 1]
timeFrame: First dose of alisertib through 30 days after the last dose of alisertib (Up to 5.2 Years)
measure: Number of Participants With Clinically Significant Changes in Physical Examination Findings [Phase 1]
timeFrame: First dose of alisertib through 30 days after the last dose of alisertib (Up to 5.2 Years)
measure: Number of Participants With Clinically Significant Laboratory Tests Reported as Adverse Events [Phase 1]
timeFrame: First dose of alisertib through 30 days after the last dose of alisertib (Up to 5.2 Years)
measure: Number of Participants With Treatment-Emergent Adverse Events [Phase 1]
timeFrame: First dose of alisertib through 30 days after the last dose of alisertib (Up to 5.2 Years)
measure: Overall Response Rate [Phase 2]
timeFrame: 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 outcomes:
measure: Overall Response Rate as Assessed by the Investigator [Phase 1]
timeFrame: First dose of alisertib through 30 days after the last dose of alisertib (Up to 5.2 Years)
measure: Complete Response Rate [Phase 2]
timeFrame: Duration of study until disease progression, approximately 2 years
measure: Duration of Response (DOR) [Phase 2]
timeFrame: Duration of study until disease progression, approximately 2 years
measure: Progression Free Survival (PFS) [Phase 2]
timeFrame: Duration of study until disease progression, approximately 2 years
measure: Number of Participants With Treatment-Emergent Adverse Events [Phase 2]
timeFrame: From screening period to 30 days after last dose of study drug, approximately 2 years
measure: Number of Participants With Clinically Significant Vital Signs Findings [Phase 2]
timeFrame: From screening period to 30 days after last dose of study drug, approximately 2 years
measure: Number of Participants With Clinically Significant Changes in Electrocardiograms (ECGs) [Phase 2]
timeFrame: From screening period to 30 days after last dose of study drug, approximately 2 years
measure: Number of Participants With Clinically Significant Changes in Multigated Acquisition (MUGA)/ Echocardiogram (ECHO) [Phase 2]
timeFrame: From screening period to 30 days after last dose of study drug, approximately 2 years
measure: Number of Participants With Clinically Significant Laboratory Tests Reported as Adverse Events [Phase 2]
timeFrame: From screening period to 30 days after last dose of study drug, approximately 2 years
measure: Cmax: Maximum Plasma Concentration for Alisertib
timeFrame: Cycle 1 Days 1 and 7 prior to morning alisertib dose and multiple time-points (up to 12 hours) post-dose
measure: Tmax: Time to First Occurrence of Cmax fo Alisertib
timeFrame: Cycle 1 Days 1 and 7 prior to morning alisertib dose and multiple time-points (up to 12 hours) post-dose
measure: AUCt: Area Under the Concentration Time Curve Over the Dosing Interval From Time 0 to Time t for Alisertib
timeFrame: Cycle 1 Days 1 and 7 prior to morning alisertib dose and multiple time-points (up to 12 hours) post-dose
measure: Cmax: Maximum Plasma Concentration for Vincristine
timeFrame: Cycles 1 and 2 on Day 1 prior to injection of vincristine and multiple time-points (up to 72 hours) post-dose
measure: AUCt: Area Under the Concentration-time Time Curve Over the Dosing Interval From Time 0 to Time t for Vincristine
timeFrame: Cycles 1 and 2 on Day 1 prior to injection of vincristine and multiple time-points (up to 72 hours) post-dose
measure: AUC∞: Area Under the Concentration-time Curve From Time 0 to Infinity for Vincristine
timeFrame: Cycles 1 and 2 on Day 1 prior to injection of vincristine and multiple time-points (up to 72 hours) post-dose
measure: T1/2: Terminal Disposition Phase Half-life for Vincristine
timeFrame: Cycles 1 and 2 on Day prior to injection of vincristine and multiple time-points (up to 72 hours) post-dose
Other outcomes:
Locations:
city: Tucson
country: United States
state: Arizona
city: Beverly Hills
country: United States
state: California
city: Burbank
country: United States
state: California
city: Miami
country: United States
state: Florida
city: Lexington
country: United States
state: Kentucky
city: Worcester
country: United States
state: Massachusetts
city: New York
country: United States
state: New York
city: Rochester
country: United States
state: New York
city: Chapel Hill
country: United States
state: North Carolina
city: Philadelphia
country: United States
state: Pennsylvania
city: Germantown
country: United States
state: Tennessee
city: Memphis
country: United States
state: Tennessee
city: Houston
country: United States
state: Texas
city: San Antonio
country: United States
state: Texas
city: Burlington
country: United States
state: Vermont
city: Orbassano
country: Italy
state: Torino
city: Genova
country: Italy
city: Palermo
country: Italy
city: Roma
country: Italy
city: Madrid
country: Spain
city: Sevilla
country: Spain
city: Aberdeen
country: United Kingdom
state: Grampian Region
city: London
country: United Kingdom
state: Greater London
city: Southampton
country: United Kingdom
state: Hampshire
city: Birmingham
country: United Kingdom
state: West Midlands
Study officials:
affiliation: Millennium Pharmaceuticals, Inc.
name: Medical Monitor
role: STUDY_DIRECTOR
References:
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.