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

This study is ongoing, but not recruiting participants.
Sponsor:
Information provided by (Responsible Party):
Millennium Pharmaceuticals, Inc.
ClinicalTrials.gov Identifier:
NCT01397825
First received: July 17, 2011
Last updated: January 20, 2014
Last verified: January 2014
  Purpose

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:

Part 1, Phase 1: Safety lead-in cohort to evaluate alisertib (MLN8237) and rituximab.

Part 2, Phase 1: 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.


Condition Intervention Phase
Diffuse Large B-Cell Lymphoma
Transformed Follicular Lymphoma
Mantle Cell Lymphoma
Burkitt's Lymphoma
Drug: Alisertib (MLN8237) + Rituximab + Vincristine
Phase 1
Phase 2

Study Type: Interventional
Study Design: Intervention Model: Single Group Assignment
Masking: Open Label
Primary Purpose: Treatment
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

Resource links provided by NLM:


Further study details as provided by Millennium Pharmaceuticals, Inc.:

Primary Outcome Measures:
  • Recommended phase 2 dose and schedule of alisertib (MLN8237) in combination with rituximab based on safety and tolerability (phase 1, part 1) [ Time Frame: From the screening period to 30 days after the last dose of alisertib (MLN8237), approximately 6 months ] [ Designated as safety issue: Yes ]
    Vital signs, electrocardiograms (ECGs), multigated acquisition (MUGA)/ echocardiogram (ECHO), physical examination, laboratory tests, and adverse events

  • Recommended phase 2 dose and schedule of alisertib (MLN8237) in combination with rituximab and vincristine based on safety and tolerability (phase 1, part 2) [ Time Frame: From the screening period to 30 days after the last dose of alisertib (MLN8237), approximately 6 months ] [ Designated as safety issue: Yes ]
    Vital signs, electrocardiograms (ECGs), multigated acquisition (MUGA)/ echocardiogram (ECHO), physical examination, laboratory tests, and adverse events

  • Number of patients with overall response (phase 2) [ Time Frame: 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 ] [ Designated as safety issue: No ]
    Complete response + partial response


Secondary Outcome Measures:
  • Number of patients with overall response (phase 1, part 1) [ Time Frame: 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 ] [ Designated as safety issue: No ]
    Complete response + partial response

  • Number of patients with overall response (phase 1, part 1 & 2) [ Time Frame: 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 ] [ Designated as safety issue: No ]
    Complete response + partial response

  • Number of patients with complete response, duration of response, and progression free survival (phase 2) [ Time Frame: Duration of study until disease progression, approximately 2 years ] [ Designated as safety issue: No ]
  • Number of adverse events and results of vital signs, electrocardiograms (ECGs), multigated acquisition (MUGA)/ echocardiogram (ECHO), physical examination and laboratory tests (phase 2) [ Time Frame: From screening period to 30 days after last dose of study drug, approximately 2 years ] [ Designated as safety issue: Yes ]
    Safety and tolerability of alisertib (MLN8237) treatment

  • Maximum plasma concentration (Cmax) (phase 1, parts 1&2) [ Time Frame: Cycle 1 Day 1 and Day 7, then Day 8 of each treatment cycle, approximately 6 months ] [ Designated as safety issue: No ]
    Pharmacokinetic parameters of alisertib (MLN8237)

  • Time to maximum plasma concentration (Tmax) (phase 1, parts 1&2) [ Time Frame: Cycle 1 Day 1 and Day 7, then Day 8 of each treatment cycle, approximately 6 months ] [ Designated as safety issue: No ]
    Pharmacokinetic parameters of alisertib (MLN8237)

  • Area under the plasma concentration versus time curve over the dosing interval (AUC0-τ) (phase 1, parts 1&2) [ Time Frame: Cycle 1 Day 1 and Day 7, then Day 8 of each treatment cycle, approximately 6 months ] [ Designated as safety issue: No ]
    Pharmacokinetic parameters of alisertib (MLN8237)

  • Maximum plasma concentration (phase 1, part 2) [ Time Frame: Days 1-4 of Cycle 2 ] [ Designated as safety issue: No ]
    Pharmacokinetic parameters of vincristine

  • Area under the plasma concentration vs time curve from time zero to the time of last quantifiable concentration (phase 1, part 2) [ Time Frame: Days 1-4 of Cycle 2 ] [ Designated as safety issue: No ]
    Pharmacokinetic parameters of vincristine

  • Area under the plasma concentration vs time curve from time zero to infinity (phase 1, part 2) [ Time Frame: Days 1-4 of Cycle 2 ] [ Designated as safety issue: No ]
    Pharmacokinetic parameters of vincristine

  • Half-life of vincristine (phase 1, part 2) [ Time Frame: Days 1-4 of Cycle 2 ] [ Designated as safety issue: No ]
    Pharmacokinetic parameters of vincristine


Enrollment: 43
Study Start Date: August 2011
Estimated Study Completion Date: June 2014
Estimated Primary Completion Date: March 2014 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: Alisertib (MLN8237) + Rituximab + Vincristine Drug: Alisertib (MLN8237) + Rituximab + Vincristine

Phase 1, Part 1: Safety lead-in cohort combining alisertib (MLN8237) as an enteric coated tablet (ECT) orally twice/day Days 1-7 & rituximab as an intravenous (IV) infusion on Day 1 in a 21 Day cycle for up to 8 cycles

Phase 1, Part 2: Alisertib (MLN8237) as an ECT orally twice/day Days 1-7 & rituximab as an IV infusion on Day 1 & vincristine IV Days 1 & 8 in a 21 Day cycle for up to 8 cycles

Phase 2: Alisertib (MLN8237) as an ECT orally twice/day Days 1-7 & rituximab as an IV infusion on Day 1 & vincristine IV Days 1 & 8 in a 21 Day cycle for up to 8 cycles

Following 8 cycles of treatment (or early discontinuation of rituximab) all patients with documented disease response or stabilization may continue with alisertib (MLN8237) single-agent therapy up to 2 years


  Eligibility

Ages Eligible for Study:   18 Years and older
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
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
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT01397825

Locations
United States, Arizona
Arizona Cancer Center
Tucson, Arizona, United States, 85724
U Arizona Cancer Center
Tucson, Arizona, United States, 78229
United States, California
Providence Health Services
Beverly Hills, California, United States, 90211
United States, Florida
University of Miami
Miami, Florida, United States, 33136
United States, Kentucky
Univ. of Kentucky Chandler Medical Center, Hematology/Oncology/BMT CRP, Markey Cancer Center
Lexington, Kentucky, United States, 40536
United States, Massachusetts
University of Massachusets Memorial Medical Center
Worcester, Massachusetts, United States, 1655
United States, New York
Weill Cornell Medical College/New York-Presbyterian Hospital
New York, New York, United States, 10065
University of Rochester
Rochester, New York, United States, 14642
United States, North Carolina
Division of Hematology-Oncology, UNC Chapel Hill Lineberger Comprehensive Cancer Center
Chapel Hill, North Carolina, United States, 27599
United States, Tennessee
The West Clinic
Memphis, Tennessee, United States, 38120
United States, Texas
The Methodist Cancer Center
Houston, Texas, United States, 77030
University of Texas Health Science Center at San Antonio
San Antonio, Texas, United States, 78229
Sponsors and Collaborators
Millennium Pharmaceuticals, Inc.
Investigators
Study Director: Medical Monitor Millennium Pharmaceuticals, Inc.
  More Information

No publications provided

Responsible Party: Millennium Pharmaceuticals, Inc.
ClinicalTrials.gov Identifier: NCT01397825     History of Changes
Other Study ID Numbers: C14011, 2011-000609-32
Study First Received: July 17, 2011
Last Updated: January 20, 2014
Health Authority: United States: Food and Drug Administration
European Union: European Medicines Agency
United Kingdom: Medicines and Healthcare Products Regulatory Agency
Italy: Ministry of Health
Spain: Ministry of Health

Additional relevant MeSH terms:
Burkitt Lymphoma
Lymphoma
Lymphoma, Non-Hodgkin
Lymphoma, Follicular
Lymphoma, B-Cell
Lymphoma, Large B-Cell, Diffuse
Lymphoma, Mantle-Cell
Epstein-Barr Virus Infections
Herpesviridae Infections
DNA Virus Infections
Virus Diseases
Tumor Virus Infections
Neoplasms by Histologic Type
Neoplasms
Neoplasms, Experimental
Lymphoproliferative Disorders
Lymphatic Diseases
Immunoproliferative Disorders
Immune System Diseases
Vincristine
Rituximab
Antineoplastic Agents, Phytogenic
Antineoplastic Agents
Therapeutic Uses
Pharmacologic Actions
Tubulin Modulators
Antimitotic Agents
Mitosis Modulators
Molecular Mechanisms of Pharmacological Action
Immunologic Factors

ClinicalTrials.gov processed this record on August 28, 2014