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Alisertib and Romidepsin in Treating Patients With Relapsed or Refractory B-Cell or T-Cell Lymphomas

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: NCT01897012
Recruitment Status : Completed
First Posted : July 11, 2013
Last Update Posted : January 28, 2019
Sponsor:
Information provided by (Responsible Party):
National Cancer Institute (NCI)

Tracking Information
First Submitted Date  ICMJE July 8, 2013
First Posted Date  ICMJE July 11, 2013
Last Update Posted Date January 28, 2019
Actual Study Start Date  ICMJE July 17, 2013
Actual Primary Completion Date October 31, 2018   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: September 18, 2018)
  • Incidence of adverse events as graded by the National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) version 5.0 (utilized for adverse event reporting beginning April 1, 2018) [ Time Frame: Up to 4 weeks post-treatment ]
  • Maximum tolerated dose graded according to NCI CTCAE version 5.0 [ Time Frame: Up to 28 days ]
    Maximum tolerated dose is defined as the highest dose level at which 6 patients have been treated with fewer than 2 instances of dose-limiting toxicities.
Original Primary Outcome Measures  ICMJE
 (submitted: July 8, 2013)
MTD, defined as the highest dose level at which 6 patients have been treated with fewer than 2 instances of dose limiting toxicity (DLT), graded according to the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) v4.0 [ Time Frame: Up to 21 days ]
Change History
Current Secondary Outcome Measures  ICMJE
 (submitted: September 18, 2018)
  • Overall response rate [ Time Frame: Up to 4 weeks post-treatment ]
    Point estimates along with 95% confidence intervals will be provided.
  • Complete response [ Time Frame: Up to 4 weeks post-treatment ]
    Point estimates along with 95% confidence intervals will be provided.
Original Secondary Outcome Measures  ICMJE
 (submitted: July 8, 2013)
  • ORR [ Time Frame: Up to 24 weeks ]
    Point estimates along with 95% confidence intervals will be provided.
  • CR [ Time Frame: Up to 24 weeks ]
    Point estimates along with 95% confidence intervals will be provided.
Current Other Pre-specified Outcome Measures
 (submitted: September 28, 2015)
  • Aurora A kinase expression intensity, assessed by immunohistochemistry [ Time Frame: Baseline ]
    Will be correlated with response.
  • Change in gene expression profiles [ Time Frame: Baseline to up to 28 days (course 1) ]
    Will be correlated with response.
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE Alisertib and Romidepsin in Treating Patients With Relapsed or Refractory B-Cell or T-Cell Lymphomas
Official Title  ICMJE A Phase 1 Trial of MLN8237 Plus Romidepsin for Relapsed/Refractory Aggressive B-Cell and T-Cell Lymphomas
Brief Summary This phase I trial studies the side effects and best dose of alisertib and romidepsin in treating patients with B-cell or T-cell lymphomas that have returned after a period of improvement (relapsed) or have not responded to treatment (refractory). Alisertib and romidepsin may stop the growth of cancer cells by blocking some of the enzymes needed for cell growth.
Detailed Description

PRIMARY OBJECTIVES:

I. To assess the safety profile of alisertib (MLN8237) plus romidepsin. II. To determine the maximum tolerated dose (MTD), if reached, of MLN8237 administered in combination with romidepsin.

SECONDARY OBJECTIVES:

I. To evaluate objective response rate (ORR) and complete response (CR) of the combined regimen.

II. To assess whether higher levels of expression of aurora kinase A correlate with outcomes.

III. To determine if this combination results in downregulation of targets of v-myc myelocytomatosis viral oncogene homolog (avian) (C-Myc) in C-Myc positive patients, induces mitotic catastrophe, changes immune system or other host responses, or upregulates markers for apoptosis.

OUTLINE: This is a dose-escalation study.

Patients receive alisertib orally (PO) twice daily (BID) on days 1-7 (dose levels 1-4) or days 1-3, 8-10, and 15-17 (dose levels 5-8). Patients also receive romidepsin intravenously (IV) over 4 hours on days 1 and 8 (dose levels 1-4) or 2, 9, and 16 (dose levels 5-8). Treatment repeats every 21 days (dose levels 1-4) or 28 days (dose levels 5-8) for up to 8 courses in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed up for 4 weeks.

Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 1
Study Design  ICMJE Allocation: N/A
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Condition  ICMJE
  • MYC Positive
  • Recurrent B-Cell Non-Hodgkin Lymphoma
  • Recurrent Burkitt Lymphoma
  • Recurrent Diffuse Large B-Cell Lymphoma
  • Recurrent Follicular Lymphoma
  • Recurrent High Grade B-Cell Lymphoma With MYC and BCL2 or BCL6 Rearrangements
  • Recurrent Hodgkin Lymphoma
  • Recurrent Mantle Cell Lymphoma
  • Recurrent Mature T- and NK-Cell Non-Hodgkin Lymphoma
  • Refractory B-Cell Non-Hodgkin Lymphoma
  • Refractory Burkitt Lymphoma
  • Refractory Diffuse Large B-Cell Lymphoma
  • Refractory Follicular Lymphoma
  • Refractory High Grade B-Cell Lymphoma With MYC and BCL2 or BCL6 Rearrangements
  • Refractory Hodgkin Lymphoma
  • Refractory Mantle Cell Lymphoma
  • Refractory Mature T-Cell and NK-Cell Non-Hodgkin Lymphoma
Intervention  ICMJE
  • Drug: Alisertib
    Given PO
    Other Names:
    • Aurora A Kinase Inhibitor MLN8237
    • MLN-8237
    • MLN8237
  • Other: Laboratory Biomarker Analysis
    Correlative studies
  • Drug: Romidepsin
    Given IV
    Other Names:
    • Antibiotic FR 901228
    • Depsipeptide
    • FK228
    • FR901228
    • Istodax
    • N-[(3S,4E)-3-Hydroxy-7-mercapto-1-oxo-4-heptenyl]-D-valyl-D-cysteinyl-(2Z)-2-amino-2-butenoyl-L-valine, (4->1) Lactone, Cyclic
Study Arms  ICMJE Experimental: Treatment (alisertib, romidepsin)
Patients receive alisertib PO BID on days 1-7 (dose levels 1-4) or days 1-3, 8-10, and 15-17 (dose levels 5-8). Patients also receive romidepsin IV over 4 hours on days 1 and 8 (dose levels 1-4) or 2, 9, and 16 (dose levels 5-8). Treatment repeats every 21 days (dose levels 1-4) or 28 days (dose levels 5-8) for up to 8 courses in the absence of disease progression or unacceptable toxicity.
Interventions:
  • Drug: Alisertib
  • Other: Laboratory Biomarker Analysis
  • Drug: Romidepsin
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 Completed
Actual Enrollment  ICMJE
 (submitted: January 25, 2019)
26
Original Estimated Enrollment  ICMJE
 (submitted: July 8, 2013)
30
Actual Study Completion Date  ICMJE November 30, 2018
Actual Primary Completion Date October 31, 2018   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

Inclusion Criteria:

  • Patients must have histologically or cytologically confirmed Hodgkin lymphoma, Burkitt's lymphoma, double-hit lymphoma, other c-Myc positive B-cell lymphoma, diffuse large-B cell lymphoma including those patients with history of transformed follicular lymphoma, mantle cell lymphoma, or peripheral T-cell lymphoma
  • Patients must have at least one 1.5 cm bidimensional measurable lesion
  • Relapsed or refractory after at least 1 front-line therapy
  • Eastern Cooperative Oncology Group (ECOG) performance status =< 2 (Karnofsky >= 60%)
  • Life expectancy of greater than 12 weeks
  • Absolute neutrophil count >= 1,500/mcL
  • Platelets >= 75,000/mcL
  • Direct bilirubin =< 1 mg/dL
  • Aspartate aminotransferase (AST) (serum glutamic oxaloacetic transaminase [SGOT])/alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT]) =< 2.5 x institutional upper limit of normal
  • Creatinine =< 2 x institutional upper limits of 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, for the duration of study participation, and 4 months after completion of MLN8237 plus romidepsin administration; 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 or enrolled 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 plus romidepsin administration
  • Ability to understand and the willingness to sign a written informed consent document
  • According to current guidelines, 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; these guidelines may change pending results from an ongoing food effects study

Exclusion Criteria:

  • Patients who have had chemotherapy, radiation therapy, or other investigational agents within 3 weeks prior to entering study, 6 weeks for nitrosoureas or mitomycin
  • 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, including but not limited to established allergic reaction to benzodiazepines, or romidepsin; agents that alter gastric pH may change MLN8237 absorption are not permitted; proton pump inhibitors need to be stopped 4 days prior to the first dose of MLN8237; histamine-2 (H2) receptor antagonists are not permitted from the day prior (day -1) through to the end of MLN8237 dosing; antacid preparations are not permitted for 2 hours before or 2 hours after administration of MLN8237
  • 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; bisphosphonate therapy may not be initiated after study entry
  • Any serious active disease or co-morbid condition, which in the opinion of the principal investigator, will interfere with the safety or compliance of the trial
  • Pregnant women are excluded from this study; breastfeeding should be discontinued if the mother is treated with MLN8237 and/or romidepsin
  • Ejection fraction (EF) < 40% or myocardial infarction (MI) within the past 3 months; 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
  • Requirement for constant administration of proton pump inhibitor, H2 antagonist, or pancreatic enzymes; intermittent uses of antacids or H2 antagonists are allowed
  • 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; treatment with clinically significant enzyme inducers, such as the enzyme-inducing antiepileptic drugs phenytoin, carbamazepine, oxcarbazepine, primidone or phenobarbital, or rifampin, rifabutin, rifapentine, or St. John's wort within 14 days prior to the first dose of MLN8237 and during the study; patients must be cautiously co-medicated with agents that cause corrected QT interval (QTc) prolongation and agents that are strong or moderate enzyme inhibitors during the study
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 NCT01897012
Other Study ID Numbers  ICMJE NCI-2013-01272
NCI-2013-01272 ( Registry Identifier: CTRP (Clinical Trial Reporting Program) )
TX035
2012-0602
9342 ( Other Identifier: M D Anderson Cancer Center )
9342 ( Other Identifier: CTEP )
P30CA016672 ( U.S. NIH Grant/Contract )
U01CA062461 ( U.S. NIH Grant/Contract )
UM1CA186688 ( U.S. NIH Grant/Contract )
Has Data Monitoring Committee No
U.S. FDA-regulated Product
Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
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: Hun Lee M.D. Anderson Cancer Center
PRS Account National Cancer Institute (NCI)
Verification Date January 2019

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