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

NCT01397825 | Completed Phase 1 Results FDA Drug

• 4 other identifiers: C140112011-000609-32U1111-1181-033312/NE/0268
• Study Type: interventional
• Target: 45
• Locations: 4 countries
• Sites: 25

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.

Conditions

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

Outcome Measures

Primary Outcomes (7)

• 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 Outcomes (16)

• 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)

• Complete Response Rate [Phase 2]

  Duration of study until disease progression, approximately 2 years

• Duration of Response (DOR) [Phase 2]

  Duration of study until disease progression, approximately 2 years

• Progression Free Survival (PFS) [Phase 2]

  Duration of study until disease progression, approximately 2 years

• 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

Study Arms (5)

Safety Lead-in

EXPERIMENTAL

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); Drug: Rituximab

Dose Escalation, Alisertib 30 mg

EXPERIMENTAL

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); Drug: Rituximab; Drug: Vincristine

Dose Escalation, Alisertib 40 mg

EXPERIMENTAL

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); Drug: Rituximab; Drug: Vincristine

Dose Escalation, Alisertib 50 mg

EXPERIMENTAL

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); Drug: Rituximab; Drug: Vincristine

Phase 2: Alisertib

EXPERIMENTAL

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); Drug: Rituximab; Drug: Vincristine

Interventions

Alisertib (MLN8237) DRUG

Alisertib (MLN8237) enteric coated tablet (ECT).

Dose Escalation, Alisertib 30 mg; Dose Escalation, Alisertib 40 mg; Dose Escalation, Alisertib 50 mg; Phase 2: Alisertib; Safety Lead-in

Rituximab DRUG

Rituximab IV infusion.

Dose Escalation, Alisertib 30 mg; Dose Escalation, Alisertib 40 mg; Dose Escalation, Alisertib 50 mg; Phase 2: Alisertib; Safety Lead-in

Vincristine DRUG

Vincristine IV Infusion.

Dose Escalation, Alisertib 30 mg; Dose Escalation, Alisertib 40 mg; Dose Escalation, Alisertib 50 mg; Phase 2: Alisertib

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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

You may not qualify if:

• 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

Sponsors & Collaborators

• Millennium Pharmaceuticals, Inc.: lead

Study Sites (25)

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Tucson, Arizona, United States

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Beverly Hills, California, United States

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Burbank, California, United States

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Miami, Florida, United States

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Lexington, Kentucky, United States

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Worcester, Massachusetts, United States

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New York, New York, United States

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Rochester, New York, United States

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Chapel Hill, North Carolina, United States

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Philadelphia, Pennsylvania, United States

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Germantown, Tennessee, United States

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Memphis, Tennessee, United States

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Houston, Texas, United States

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San Antonio, Texas, United States

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Burlington, Vermont, United States

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Orbassano, Torino, Italy

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Genova, Italy

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Palermo, Italy

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Roma, Italy

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Madrid, Spain

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Seville, Spain

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Aberdeen, Grampian Region, United Kingdom

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London, Greater London, United Kingdom

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Southampton, Hampshire, United Kingdom

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Birmingham, West Midlands, United Kingdom

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Related Publications (1)

• 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.

  PMID: 30082475 DERIVED

MeSH Terms

Conditions

Lymphoma, Large B-Cell, Diffuse; Lymphoma, Mantle-Cell; Burkitt Lymphoma

Interventions

MLN 8237; Rituximab; Vincristine

Condition Hierarchy (Ancestors)

Lymphoma, B-Cell; Lymphoma, Non-Hodgkin; Lymphoma; Neoplasms by Histologic Type; Neoplasms; Lymphoproliferative Disorders; Lymphatic Diseases; Hemic and Lymphatic Diseases; Immunoproliferative Disorders; Immune System Diseases; Epstein-Barr Virus Infections; Herpesviridae Infections; DNA Virus Infections; Virus Diseases; Infections; Tumor Virus Infections

Intervention Hierarchy (Ancestors)

Antibodies, Monoclonal, Murine-Derived; Antibodies, Monoclonal; Antibodies; Immunoglobulins; Immunoproteins; Blood Proteins; Proteins; Amino Acids, Peptides, and Proteins; Serum Globulins; Globulins; Vinca Alkaloids; Secologanin Tryptamine Alkaloids; Indole Alkaloids; Alkaloids; Heterocyclic Compounds; Indoles; Heterocyclic Compounds, 2-Ring; Heterocyclic Compounds, Fused-Ring; Indolizidines; Indolizines

Limitations and Caveats

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.

Results Point of Contact

• Title: Medical Director
• Organization: Takeda

trialdisclosures@takeda.com

+1-877-825-3327

Study Officials

• Medical Monitor

  Millennium Pharmaceuticals, Inc.

  STUDY DIRECTOR

Publication Agreements

• PI is Sponsor Employee: No
• Restriction Type: OTHER
• Restrictive Agreement: Yes

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NON RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: July 17, 2011
• First Posted: July 20, 2011
• Study Start: August 9, 2011
• Primary Completion: February 5, 2015
• Study Completion: October 5, 2016
• Last Updated: March 27, 2018
• Results First Posted: March 27, 2018

Record last verified: 2018-02

Locations

IT (4); GB (4); US (15); ES (2)