Alisertib, Bortezomib, and Rituximab in Treating Patients With Relapsed or Refractory Mantle Cell Lymphoma or B-Cell Low Grade Non-Hodgkin Lymphoma

This study is currently recruiting participants.
Verified March 2014 by National Cancer Institute (NCI)
Sponsor:
Information provided by (Responsible Party):
National Cancer Institute (NCI)
ClinicalTrials.gov Identifier:
NCT01695941
First received: September 26, 2012
Last updated: April 4, 2014
Last verified: March 2014
  Purpose

This phase I trial studies the side effects and best dose of alisertib and bortezomib when given together with rituximab in treating patients with relapsed or refractory mantle cell lymphoma or B-cell low grade non-Hodgkin lymphoma. Alisertib and bortezomib may stop the growth of cancer cells by blocking some of the enzymes needed for cell growth. Monoclonal antibodies, such as rituximab, can block cancer growth in different ways. Some block the ability of cancer cells to grow and spread. Others find cancer cells and help kill them or carry cancer-killing substances to them. Giving alisertib and bortezomib together with rituximab may kill more cancer cells.


Condition Intervention Phase
Extranodal Marginal Zone B-cell Lymphoma of Mucosa-associated Lymphoid Tissue
Nodal Marginal Zone B-cell Lymphoma
Recurrent Adult Diffuse Small Cleaved Cell Lymphoma
Recurrent Grade 1 Follicular Lymphoma
Recurrent Grade 2 Follicular Lymphoma
Recurrent Mantle Cell Lymphoma
Recurrent Marginal Zone Lymphoma
Recurrent Small Lymphocytic Lymphoma
Refractory Hairy Cell Leukemia
Splenic Marginal Zone Lymphoma
Waldenström Macroglobulinemia
Drug: alisertib
Drug: bortezomib
Biological: rituximab
Other: laboratory biomarker analysis
Phase 1

Study Type: Interventional
Study Design: Endpoint Classification: Safety Study
Intervention Model: Single Group Assignment
Masking: Open Label
Primary Purpose: Treatment
Official Title: A Phase I Study of MLN8237 in Combination With Bortezomib and Rituximab in Relapsed and Refractory Mantle Cell and Low Grade Non-Hodgkin Lymphoma

Resource links provided by NLM:


Further study details as provided by National Cancer Institute (NCI):

Primary Outcome Measures:
  • Recommended phase II dose of alisertib and bortezomib when combined with rituximab, defined as the highest dose level at which < 33% of the dose cohort experience a dose limiting toxicity (DLT) [ Time Frame: 21 days ] [ Designated as safety issue: Yes ]
    Adverse events will be graded using the National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) v4.0. Toxicities will be described by intensity at each dose level.


Secondary Outcome Measures:
  • Overall response rate (ORR) (complete response and partial response) [ Time Frame: Up to 30 days post-treatment ] [ Designated as safety issue: No ]
    ORR will be summarized descriptively.

  • Progression free survival (PFS) [ Time Frame: From time of study entry to the first documentation of tumor progression or death due to any cause, whichever comes first, assessed up to 30 days post-treatment ] [ Designated as safety issue: No ]
    Kaplan-Meier methodology will be used to summarize estimate median PFS for patients in all treatment groups.

  • Duration of response (DOR) [ Time Frame: From time of documentation of a response to treatment to the first documentation of documentation of tumor progression or death due to any cause whichever comes first, assessed up to 30 days post-treatment ] [ Designated as safety issue: No ]
    Kaplan-Meier methodology will be used to summarize estimate median DOR for patients in all treatment groups.

  • Overall survival [ Time Frame: From time of randomization to the date of death due to any cause, assessed up to 30 days post-treatment ] [ Designated as safety issue: No ]

Estimated Enrollment: 24
Study Start Date: August 2012
Estimated Primary Completion Date: August 2015 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: Treatment (alisertib, bortezomib, and rituximab)

Patients receive alisertib PO BID on days 1-7; bortezomib SC on days 1, 8, and 15; and rituximab IV on day 1. Treatment repeats every 28 days* in the absence of disease progression or unacceptable toxicity.

Note: *After 8 courses, treatment with rituximab repeats once every 3 courses (12 weeks) in the absence of disease progression or unacceptable toxicity.

Drug: alisertib
Given PO
Other Names:
  • Aurora A kinase inhibitor MLN8237
  • MLN8237
Drug: bortezomib
Given SC
Other Names:
  • LDP 341
  • MLN341
  • VELCADE
Biological: rituximab
Given IV
Other Names:
  • IDEC-C2B8
  • IDEC-C2B8 monoclonal antibody
  • Mabthera
  • MOAB IDEC-C2B8
  • Rituxan
Other: laboratory biomarker analysis
Correlative studies

Detailed Description:

PRIMARY OBJECTIVES:

I. To determine the recommended phase II dose of MLN8237 (alisertib) and bortezomib when combined with rituximab in patients with relapsed/refractory mantle cell and B-cell low grade non-Hodgkin lymphoma.

SECONDARY OBJECTIVES:

I. To describe the rate of overall response (complete response and partial response) for patients with relapsed/refractory mantle cell and B-cell low grade non-Hodgkin lymphoma treated with the combination of MLN8237 plus bortezomib and rituximab.

TERTIARY OBJECTIVES:

I. To evaluate the clinical significance of Aurora A over-expression and the proliferative index in initial tumor biopsy specimens from patients with relapsed/refractory mantle cell and B-cell low grade non-Hodgkin lymphoma treated with the combination of MLN8237 plus bortezomib and rituximab.

II. To evaluate and compare in paired biopsy specimens pre-treatment and on day 8: apoptosis and G2M arrest and the expression level of cell cycle related proteins including: cyclin D1, p53, BIM-1, p27, p21, noxa, puma and survivin.

OUTLINE: This is a dose-escalation study of alisertib and bortezomib.

Patients receive alisertib orally (PO) twice daily (BID) on days 1-7; bortezomib subcutaneously (SC) on days 1, 8, and 15; and rituximab intravenously (IV) on day 1. Treatment repeats every 28 days* in the absence of disease progression or unacceptable toxicity.

Note: *After 8 courses, treatment with rituximab repeats once every 3 courses (12 weeks) in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed up for 30 days.

  Eligibility

Ages Eligible for Study:   18 Years and older
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • Patients must have histologically confirmed relapsed or refractory mantle cell lymphoma or low grade B-cell non-Hodgkin lymphoma (NHL); patients with evidence of transformation to a high grade histology will not be eligible
  • Measurable or evaluable disease, as defined in 2008 Revised Response Criteria for Malignant Lymphoma; baseline scans used for measurement should be obtained within 30 days of registration, and baseline bone marrow biopsy and/or aspiration should be obtained with 90 days of registration
  • Patients may have received one or more lines of prior chemotherapy with/without rituximab (including high dose therapy plus stem cell transplant which is counted as one regimen); prior bortezomib is allowed; patients must not have received bortezomib in the past 6 months
  • Patients with human immunodeficiency virus (HIV) who are not receiving cytochrome p450 inhibitors, and who have a minimum of 300+ cluster of differentiation 4+ (CD4+) cells/mm^3, an undetectable viral load, and no history of acquired immune deficiency syndrome (AIDS) indicator conditions
  • Patients must be able to take oral medication and to maintain a fast as required for 2 hours before and 1 hour after MLN8237 administration
  • Eastern Cooperative Oncology Group (ECOG) performance status 0, 1, or 2 (Karnofsky >= 60%)
  • Leukocytes >= 3,000/mcL
  • Absolute neutrophil count >= 1,500/mcL
  • Platelets >= 75,000/mcL
  • Total bilirubin within normal institutional limits (may be elevated if direct bilirubin normal)
  • Aspartate aminotransferase (AST) (serum glutamic oxaloacetic transaminase [SGOT])/alanine aminotransferase (ALT) (serum glutamic pyruvate transaminase [SGPT]) < 3 X institutional upper limit of normal
  • Creatinine within normal institutional limits OR creatinine clearance >= 60 mL/min/1.73 m^2 for patients with creatinine levels above institutional normal
  • Women of child-bearing potential and men must agree to use adequate contraception (hormonal or barrier method of birth control; abstinence) prior to study entry and for the duration of study participation; should a woman become pregnant or suspect she is pregnant while she or her partner is participating in this study, she should inform her treating physician immediately; men treated on this protocol must also agree to use adequate contraception prior to the study, for the duration of study participation, and 4 months after completion of MLN8237 administration
  • Ability to understand and the willingness to sign a written informed consent document

Exclusion Criteria:

  • Patients who have had chemotherapy or radiotherapy within 4 weeks (6 weeks for nitrosoureas or mitomycin C, 3 weeks for rituximab) prior to entering the study or those who have not recovered from adverse events due to agents administered more than 4 weeks earlier
  • Patients who are receiving any other investigational agents
  • Patients with known brain metastases should be excluded from this clinical trial
  • History of allergic reactions attributed to compounds of similar chemical or biologic composition to MLN8237, bortezomib or rituximab
  • Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, or psychiatric illness/social situations that would limit compliance with study requirements
  • Known history of uncontrolled sleep apnea syndrome and other conditions that could result in excessive daytime sleepiness, such as severe chronic obstructive pulmonary disease; requirement for supplemental oxygen; or any conditions that could result in excessive toxicity associated with the benzodiazepine-like effects of MLN8237
  • Inability to swallow oral medication or to maintain a fast as required for 2 hours before and 1 hour after MLN8237 administration or any condition that would modify small bowel absorption of oral medications, including malabsorption, or resection of pancreas or upper bowel
  • Pregnant women are excluded from this study; breastfeeding should be discontinued if the mother is treated with MLN8237
  • HIV-positive patients on combination antiretroviral therapy which include cytochrome p450 inhibitors are ineligible; patients with CD4 counts less than 300 CD4+ cells/mm3 and or a high viral load are at increased risk of lethal infections when treated with marrow-suppressive therapy, and are ineligible
  • Grade 2 or greater neuropathy
  • The following agents are not permitted while patients are taking MLN8237, and should be discontinued at prior to registration if patients are taking them:

    • Patients must stop using the proton pump inhibitor (PPI) for at least 4 days prior to the first dose of MLN8237; administration of PPI while on study is not permitted
    • Histamine-2 (H2) receptor antagonists are not permitted from the day prior through to the end of MLN8237 dosing, except as required for premedication for rituximab; constant dosing of H2 blockers is not permitted
    • Antacid preparations are not permitted for 2 hours before or 2 hours after administration of MLN8237
    • Administration of pancreatic enzymes is not permitted at any time while on study
    • Co-administration of enzyme-inducing antiepileptic drugs, rifampin, rifabutin, rifapentine or St. John's wort is not permitted
    • Concurrent bisphosphonate therapy is allowed if it was started before study entry and is maintained at recommended dosing intervals; if bisphosphonate therapy is initiated after study entry, bone lesions will not be considered evaluable for disease response
    • Patients must be willing not drive, operate dangerous tools or machinery, or engage in any other potentially hazardous activity that requires full alertness and coordination if they experience sedation; if a patient experiences excessive sedation believed to be related to MLN8237, treatment with MLN8237 should be interrupted
    • Patients must be willing to limit alcohol consumption to no more than 1 standard unit of alcohol (12 oz beer [350 mL], 1.5 oz [45 mL] of 80- proof alcohol, or one 6-oz [175 mL] glass of wine per day during the study and for 30 days from the last dose of MLN8237; minimize the use of agents with central nervous system (CNS) effects
    • Benzodiazepine use is discouraged but not prohibited
  Contacts and Locations
Please refer to this study by its ClinicalTrials.gov identifier: NCT01695941

Locations
United States, New York
Montefiore Medical Center Recruiting
Bronx, New York, United States, 10467-2490
Contact: Joseph A. Sparano    718-405-8404    jsparano@montefiore.org   
Principal Investigator: Joseph A. Sparano         
New York University Langone Medical Center Recruiting
New York, New York, United States, 10016
Contact: Catherine S. Diefenbach    212-731-5670    catherine.diefenbach@nyumc.org   
Principal Investigator: Catherine S. Diefenbach         
Sponsors and Collaborators
Investigators
Principal Investigator: Catherine Diefenbach Montefiore Medical Center
  More Information

No publications provided

Responsible Party: National Cancer Institute (NCI)
ClinicalTrials.gov Identifier: NCT01695941     History of Changes
Other Study ID Numbers: NCI-2012-01712, NCI-2012-01712, CDR0000740877, S12-02028, S12-02028, 9086, P30CA013330
Study First Received: September 26, 2012
Last Updated: April 4, 2014
Health Authority: United States: Food and Drug Administration

Additional relevant MeSH terms:
Leukemia
Leukemia, Lymphocytic, Chronic, B-Cell
Leukemia, Hairy Cell
Lymphoma
Lymphoma, Follicular
Lymphoma, Non-Hodgkin
Waldenstrom Macroglobulinemia
Lymphoma, B-Cell
Lymphoma, B-Cell, Marginal Zone
Lymphoma, Mantle-Cell
Neoplasms by Histologic Type
Neoplasms
Leukemia, B-Cell
Leukemia, Lymphoid
Lymphoproliferative Disorders
Lymphatic Diseases
Immunoproliferative Disorders
Immune System Diseases
Neoplasms, Plasma Cell
Hemostatic Disorders
Vascular Diseases
Cardiovascular Diseases
Paraproteinemias
Blood Protein Disorders
Hematologic Diseases
Hemorrhagic Disorders
Antibodies, Monoclonal
Rituximab
Bortezomib
Immunologic Factors

ClinicalTrials.gov processed this record on April 15, 2014