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Trial record 46 of 59 for:    MLN8237

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

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details.
ClinicalTrials.gov Identifier: NCT01695941
Recruitment Status : Active, not recruiting
First Posted : September 28, 2012
Last Update Posted : August 13, 2019
Sponsor:
Information provided by (Responsible Party):
National Cancer Institute (NCI)

Tracking Information
First Submitted Date  ICMJE September 26, 2012
First Posted Date  ICMJE September 28, 2012
Last Update Posted Date August 13, 2019
Actual Study Start Date  ICMJE August 31, 2012
Actual Primary Completion Date May 29, 2018   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: February 15, 2018)
  • Recommended phase II dose of alisertib when combined with bortezomib and rituximab, defined as the highest dose level at which < 33% of the dose cohort experience a dose limiting toxicity (DLT) [ Time Frame: 21 days ]
    Graded using the National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) version 5.0. Toxicities will be described by intensity at each dose level.
  • Recommended phase II dose of bortezomib when combined with alisertib and rituximab, defined as the highest dose level at which < 33% of the dose cohort experience a dose limiting toxicity (DLT) [ Time Frame: 21 days ]
    Graded using the NCI CTCAE version 5.0. Toxicities will be described by intensity at each dose level.
Original Primary Outcome Measures  ICMJE
 (submitted: September 26, 2012)
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 ]
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.
Change History Complete list of historical versions of study NCT01695941 on ClinicalTrials.gov Archive Site
Current Secondary Outcome Measures  ICMJE
 (submitted: September 26, 2012)
  • Overall response rate (ORR) (complete response and partial response) [ Time Frame: Up to 30 days post-treatment ]
    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 ]
    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 ]
    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 ]
Original Secondary Outcome Measures  ICMJE Same as current
Current Other Pre-specified Outcome Measures
 (submitted: April 2, 2015)
Aurora A expression measured from patient biopsy specimens [ Time Frame: Up to day 8 (course 1) ]
Statistical techniques such as T-tests for bivariate analyses and logistic regression modeling for multivariable analyses will be applied to assess the association between initial Aurora A expression measured from patient biopsy specimens with response to therapy and other clinical outcomes. In patients who consent to biopsy, findings will be reported descriptively since these analyses will be viewed as exploratory in nature.
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE Alisertib, Bortezomib, and Rituximab in Treating Patients With Relapsed or Refractory Mantle Cell Lymphoma or B-cell Low Grade Non-Hodgkin Lymphoma
Official Title  ICMJE A Phase I Study of MLN8237 in Combination With Bortezomib and Rituximab in Relapsed and Refractory Mantle Cell and Low Grade Non-Hodgkin Lymphoma
Brief Summary This phase I trial studies the side effects and best dose of alisertib and bortezomib when given together with rituximab in treating patients with mantle cell lymphoma or B-cell low grade non-Hodgkin lymphoma that has returned after a period of improvement (relapsed) or does not respond to treatment (refractory). 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, may interfere with the ability of cancer cells to grow and spread. Giving alisertib and bortezomib together with rituximab may be a better treatment for relapsed or refractory mantle cell lymphoma or B-cell low grade non-Hodgkin lymphoma.
Detailed Description

PRIMARY OBJECTIVES:

I. To determine the recommended phase II dose of alisertib (MLN8237) 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.

TRANSLATIONAL 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.

Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 1
Study Design  ICMJE Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Condition  ICMJE
  • Recurrent B-Cell Non-Hodgkin Lymphoma
  • Recurrent Mantle Cell Lymphoma
  • Refractory B-Cell Non-Hodgkin Lymphoma
  • Refractory Mantle Cell Lymphoma
Intervention  ICMJE
  • Drug: Alisertib
    Given PO
    Other Names:
    • Aurora A Kinase Inhibitor MLN8237
    • MLN-8237
    • MLN8237
  • Drug: Bortezomib
    Given SC
    Other Names:
    • [(1R)-3-Methyl-1-[[(2S)-1-oxo-3-phenyl-2-[(pyrazinylcarbonyl)amino]propyl]amino]butyl]boronic Acid
    • LDP 341
    • MLN341
    • PS-341
    • PS341
    • Velcade
  • Other: Laboratory Biomarker Analysis
    Correlative studies
  • Biological: Rituximab
    Given IV
    Other Names:
    • ABP 798
    • BI 695500
    • C2B8 Monoclonal Antibody
    • Chimeric Anti-CD20 Antibody
    • CT-P10
    • IDEC-102
    • IDEC-C2B8
    • IDEC-C2B8 Monoclonal Antibody
    • MabThera
    • Monoclonal Antibody IDEC-C2B8
    • PF-05280586
    • Rituxan
    • Rituximab ABBS
    • Rituximab Biosimilar ABP 798
    • Rituximab Biosimilar BI 695500
    • Rituximab Biosimilar CT-P10
    • Rituximab Biosimilar GB241
    • Rituximab Biosimilar IBI301
    • Rituximab Biosimilar JHL1101
    • Rituximab Biosimilar PF-05280586
    • Rituximab Biosimilar RTXM83
    • Rituximab Biosimilar SAIT101
    • rituximab biosimilar TQB2303
    • rituximab-abbs
    • RTXM83
    • Truxima
Study Arms  ICMJE 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.

Interventions:
  • Drug: Alisertib
  • Drug: Bortezomib
  • Other: Laboratory Biomarker Analysis
  • Biological: Rituximab
Publications * Not Provided

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Active, not recruiting
Actual Enrollment  ICMJE
 (submitted: September 26, 2012)
24
Original Estimated Enrollment  ICMJE Same as current
Study Completion Date  ICMJE Not Provided
Actual Primary Completion Date May 29, 2018   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

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+ 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 (obtained within 30 days of registration)
  • Absolute neutrophil count >= 1,500/mcL (obtained within 30 days of registration)
  • Platelets >= 75,000/mcL or >= 50,000/mcL with documented bone marrow involvement (obtained within 30 days of registration)
  • Total bilirubin within normal institutional limits (may be elevated if direct bilirubin normal) (obtained within 30 days of registration)
  • Aspartate aminotransferase (AST) (serum glutamic oxaloacetic transaminase [SGOT])/alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT]) < 3 X institutional upper limit of normal (obtained within 30 days of registration)
  • Creatinine within normal institutional limits OR creatinine clearance >= 60 mL/min/1.73 m^2 for patients with creatinine levels above institutional normal (obtained within 30 days of registration)
  • 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/mm^3 and or a high viral load 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 excessive 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
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 18 Years and older   (Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE Contact information is only displayed when the study is recruiting subjects
Listed Location Countries  ICMJE United States
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT01695941
Other Study ID Numbers  ICMJE NCI-2012-01712
NCI-2012-01712 ( Registry Identifier: CTRP (Clinical Trial Reporting Program) )
S12-02028
CDR0000740877
P9086
9086 ( Other Identifier: Montefiore Medical Center - Moses Campus )
9086 ( Other Identifier: CTEP )
P30CA013330 ( U.S. NIH Grant/Contract )
Has Data Monitoring Committee No
U.S. FDA-regulated Product Not Provided
IPD Sharing Statement  ICMJE Not Provided
Responsible Party National Cancer Institute (NCI)
Study Sponsor  ICMJE National Cancer Institute (NCI)
Collaborators  ICMJE Not Provided
Investigators  ICMJE
Principal Investigator: Catherine S Diefenbach Montefiore Medical Center - Moses Campus
PRS Account National Cancer Institute (NCI)
Verification Date April 2019

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP