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.
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
