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

Recurrent Mantle Cell Lymphoma Clinical Trial

Official title:

A Phase 1 Trial of MLN8237 Plus Romidepsin for Relapsed/Refractory Aggressive B-Cell and T-Cell Lymphomas

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT01897012
• Other study ID #: NCI-2013-01272
• Secondary ID: NCI-2013-01272TX
• Status: Completed
• Phase: Phase 1
• Start date: July 17, 2013
• Est. completion date: November 30, 2018

Study information

• Verified date: January 2019
• Source: National Cancer Institute (NCI)
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 26
• Est. completion date: November 30, 2018
• Est. primary completion date: October 31, 2018
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

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

Related Conditions & MeSH terms

• Burkitt Lymphoma
• Hodgkin Disease
• Lymphoma
• Lymphoma, B-Cell
• Lymphoma, Follicular
• Lymphoma, Large B-Cell, Diffuse
• Lymphoma, Mantle-Cell
• Lymphoma, Non-Hodgkin
• Lymphoma, T-Cell
• Lymphoma, T-Cell, Peripheral
• 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

Drug:
• Alisertib
Given PO

Other:
• Laboratory Biomarker Analysis
Correlative studies

Drug:
• Romidepsin
Given IV

Locations

Country	Name	City	State
United States	M D Anderson Cancer Center	Houston	Texas

Sponsors (1)

Lead Sponsor	Collaborator
National Cancer Institute (NCI)

Country where clinical trial is conducted

United States, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Other	Aurora A kinase expression intensity, assessed by immunohistochemistry	Will be correlated with response.	Baseline
Other	Change in gene expression profiles	Will be correlated with response.	Baseline to up to 28 days (course 1)
Primary	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)		Up to 4 weeks post-treatment
Primary	Maximum tolerated dose graded according to NCI CTCAE version 5.0	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.	Up to 28 days
Secondary	Overall response rate	Point estimates along with 95% confidence intervals will be provided.	Up to 4 weeks post-treatment
Secondary	Complete response	Point estimates along with 95% confidence intervals will be provided.	Up to 4 weeks post-treatment