A Phase 1 Trial of MLN8237 Plus Romidepsin for Relapsed/Refractory Aggressive B-cell and T-cell Lymphomas
Michelle A. Fanale
You are being asked to take part in this study because you have relapsed (has come back after treatment) or refractory (has not responded to treatment) aggressive B or T-cell lymphoma including: Hodgkin lymphoma, Burkitt lymphoma (BL), double-hit lymphoma (DHL), another type of c-MYC positive B-cell lymphoma, diffuse large B cell lymphoma (DLBCL), mantle cell lymphoma (MCL), or T-cell lymphoma (TCL). The goal of this clinical research study is find the highest tolerable dose combination of romidepsin and MLN8237 that can be given to patients with relapsed/refractory aggressive B- or T-cell lymphoma including: Hodgkin lymphoma, Burkitt lymphoma (BL), double-hit lymphoma (DHL), another type of c-MYC positive B-cell lymphoma, diffuse large B cell lymphoma (DLBCL), mantle cell lymphoma (MCL), or T-cell lymphoma (TCL). Romidepsin is designed to stop the growth of cancer cells and block new blood vessels from forming around the cancer cells. This may cause the cancer cells to die. MLN8237 is designed to block a protein that is needed for cell division and cancer growth. By blocking this protein, the drug could cause cancer cells to die.
Disease Group: Lymphoma
Treatment Agent: MLN8237,Romidepsin
Treatment Location: Only at MDACC
Primary objectives: · To assess the safety profile of MLN8237 (Alisertib) plus romidepsin · To determine the maximum tolerated dose (MTD), if reached, of MLN8237 administered in combination with romidepsin. Secondary objectives: · To evaluate overall response rate (ORR) and complete remission (CR) of the combined regimen. · To assess whether higher levels of expression of Aurora kinase A correlate with outcomes. · To determine if this combination results in downregulation of targets of C-Myc in C-Myc positive patients, induces mitotic catastrophe, changes immune system or other host responses, or upregulates markers for apoptosis.
IRB Review and Approval Date: 07/17/2013
Recruitment Status: Open
Projected Accrual: N/A
1) 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.
2) Patients must have at least one 1.5 cm bidimensional measurable lesion.
3) Relapsed or refractory after at least 1 front-line therapy
4) Age >/= 18 years Because no dosing or adverse event data are currently available on the use of MLN8237 in combination with Romidepsin in patients <18 years of age, children are excluded from this study, but may be eligible for ongoing or future pediatric trials.
5) Eastern Cooperative Oncology Group (ECOG) performance status </= 2 (Karnofsky > 60%).
6) Life expectancy of greater than 12 weeks
7) Patients must have normal organ and marrow function as defined below: ? absolute neutrophil count >/= 1,500/mcL ? platelets >/= 75,000/mcL ? direct bilirubin </= 1 mg/dL ? AST(SGOT)/ALT(SGPT) </= 2.5 x institutional upper limit of normal ? creatinine </= 2 x institutional upper limits of normal
8) The effects of MLN8237 and romidepsin on the developing human fetus are unknown. For this reason and because aurora kinase A inhibitors as well as romidepsin are known to be teratogenic, 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
9) Ability to understand and the willingness to sign a written informed consent document.
10) 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.
1) Patients who have had chemotherapy, radiation therapy, or other
investigational agents within 3 weeks prior to entering study, 6 weeks
for nitrosoureas or mitomycin.
2) Patients with known brain metastases should be excluded from this clinical trial because of their poor prognosis and because they often develop progressive neurologic dysfunction that would confound the evaluation of neurologic and other adverse events.
3) 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.
4) 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.
5) Any serious active disease or co-morbid condition, which in the opinion of the principal investigator, will interefere with the safety or compliance of the trial.
6) Pregnant women are excluded from this study because MLN8237 is an aurora kinase A inhibitor and romidepsin is a histone deacetylase inhibitor with the potential for teratogenic or abortifacient effects. Because there is an unknown but potential risk for adverse events in nursing infants secondary to treatment of the mother with MLN8237 and romidepsin, breastfeeding should be discontinued if the mother is treated with MLN8237 and/or romidepsin.
7) 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.
8) cont. 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 QTc prolongation and agents that are strong or moderate enzyme inhibitors during the study
9) Both men and women of all races and ethnic groups are eligible for this trial.
Information and next steps
Michelle A. Fanale
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