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Phase I Study of the Aurora Kinase A Inhibitor MLN8237 in Combination With the Histone Deacetylase Inhibitor Vorinostat in Lymphoid Malignancies

Phase 1
18 Years
Open (Enrolling)
Extranodal Marginal Zone B-cell Lymphoma of Mucosa-associated Lymphoid Tissue, Nodal Marginal Zone B-cell Lymphoma, Peripheral T-cell Lymphoma, Recurrent Adult Burkitt Lymphoma, Recurrent Adult Diffuse Large Cell Lymphoma, Recurrent Adult Diffuse Mixed Cell Lymphoma, Recurrent Adult Diffuse Small Cleaved Cell Lymphoma, Recurrent Adult Grade III Lymphomatoid Granulomatosis, Recurrent Adult Hodgkin Lymphoma, Recurrent Adult Immunoblastic Large Cell Lymphoma, Recurrent Adult Lymphoblastic Lymphoma, Recurrent Adult T-cell Leukemia/Lymphoma, Recurrent Cutaneous T-cell Non-Hodgkin Lymphoma, Recurrent Grade 1 Follicular Lymphoma, Recurrent Grade 2 Follicular Lymphoma, Recurrent Grade 3 Follicular Lymphoma, Recurrent Mantle Cell Lymphoma, Recurrent Marginal Zone Lymphoma, Recurrent Mycosis Fungoides/Sezary Syndrome, Recurrent Small Lymphocytic Lymphoma, Refractory Hairy Cell Leukemia, Small Intestine Lymphoma, Splenic Marginal Zone Lymphoma, Testicular Lymphoma, Waldenström Macroglobulinemia

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Trial Information

Phase I Study of the Aurora Kinase A Inhibitor MLN8237 in Combination With the Histone Deacetylase Inhibitor Vorinostat in Lymphoid Malignancies


I. To determine the maximum-tolerated dose (MTD) of alisertib (MLN8237) when given in
combination with vorinostat and to select a dose and schedule for further testing
(recommended Phase 2 dose: RP2D) in patients with lymphoid malignancies.

II. To describe the toxicities of MLN8237 when given in combination with vorinostat on a
21-day schedule.

III. To determine any clinical responses with MLN8237 in combination with vorinostat.

IV. To compare the plasma pharmacokinetics of MLN8237 when given alone and in combination
with vorinostat.

V. To perform immunohistochemistry (IHC) and fluorescence in situ hybridization (FISH)
analysis to determine aurora kinase A (AURKA) expression in archival formalin-fixed
paraffin-embedded sections from the most recent available tumor specimens of patients.

VI. To perform correlative studies for apoptosis and proliferation on bone marrow and lymph
node specimens, where available, obtained from patients in the expanded cohort at RP2D.

OUTLINE: This is a dose-escalation study of alisertib.

Patients receive alisertib orally (PO) twice daily (BID) on days 1-7 and vorinostat PO BID
on days 1-14. Courses repeat every 21 days in the absence of disease progression or
unacceptable toxicity.

After completion of study treatment, patients are followed up for at least 30 days.

Inclusion Criteria:

- Patients must have a histologically or cytologically confirmed lymphoid malignancy
(like Hodgkin lymphoma or one of the mature B- or T-cell non-Hodgkin lymphomas as
classified by World Health Organization [WHO]) for which standard curative or
palliative measures do not exist or are no longer effective

- Patients must have measurable disease in two dimensions and >= 2 cm is acceptable (or
1.5 cm if 0.5 slices are used, as in spiral computed tomography [CT] scans); lesions
that are considered intrinsically non-measurable include the following:

- Bone lesions

- Leptomeningeal disease

- Ascites

- Pleural/pericardial effusion

- Inflammatory breast disease

- Lymphangitis cutis/pulmonis

- Abdominal masses that are not confirmed and followed by imaging techniques

- Cystic lesions

- Lesions that are situated in a previously irradiated area

- Patients must have had at least 1 prior systemic chemotherapy (not just steroids or
local radiation)

- Patients with known brain metastases should be excluded from this clinical trial

- Eastern Cooperative Oncology Group (ECOG) performance status ≤ 2 (Karnofsky ≥ 60%)

- Life expectancy of greater than 12 weeks

- Absolute neutrophil count ≥ 1,500/mcL

- Platelets ≥ 100,000/mcL

- Total bilirubin < 1.5 times institutional upper limit of normal (ULN); patients with
elevation of indirect (unconjugated) bilirubin alone, as in Gilbert's syndrome, are

- Aspartate aminotransferase (AST) (serum glutamic oxaloacetic transaminase
[SGOT])/alanine aminotransferase (ALT) (serum glutamic pyruvate transaminase [SGPT])
< 2.5 times institutional ULN

- Creatinine ≤ institutional upper limit of normal OR creatinine clearance ≥ 60
mL/min/1.73 m^2 for patients with creatinine levels above institutional 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

- No 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

- No 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

- Pregnant women are excluded from this study; breastfeeding should be discontinued if
the mother is treated with MLN8237

- No known history of uncontrolled sleep apnea syndrome or other conditions that could
result in excessive daytime sleepiness, such as severe chronic obstructive pulmonary

- No requirement for supplemental oxygen

- No conditions that could result in excessive toxicity associated with the
benzodiazepine-like effects of MLN8237

- No 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

- No patients with New York Heart Association (NYHA) Class II-IV heart failure

- See Disease Characteristics

- Last chemotherapy or radiation must be at least 4 weeks prior to enrollment on this

- Patients who decline other potentially curative therapy may be eligible

- Prior radiation therapy must not have been to more than 25% of the bone marrow

- Whole pelvic radiation is considered to be over 25%

- Prior allogeneic stem cell transplant patients will be allowed to enroll if they are
past day +100 of transplant, have no active graft-versus-host-disease, are not on any
immunosuppressants, and have been off immunosuppressants for at least 4 weeks

- Prior autologous stem cell transplant patients will be allowed to enter this study if
they are past their day +100 of transplant

- No patients who have had chemotherapy or radiotherapy within 4 weeks (6 weeks for
nitrosoureas or mitomycin C) prior to entering the study or those who have not
recovered from adverse events due to agents administered more than 4 weeks earlier

- No patients who are receiving any other investigational agents

- No treatment with valproic acid within 14 days prior to initiation of study and
during the study

- No prior use of valproic acid or any other histone deacetylase (HDAC) inhibitor
for lymphoma treatment

- Human immunodeficiency virus (HIV)-positive patients on combination antiretroviral
therapy are ineligible

- No requirement for constant administration of proton pump inhibitor, H2 antagonist,
or pancreatic enzymes

- Intermittent uses of antacids or H2 antagonists are allowed

- No treatment with clinically significant enzyme inducers, such as the enzyme-inducing
antiepileptic drugs phenytoin, carbamazepine, oxcarbazepine, primidone or
phenobarbital; rifampin, rifabutin, rifapentine; or St. John wort within 14 days
prior to the first dose of MLN8237 and during the study

Type of Study:


Study Design:

Endpoint Classification: Safety/Efficacy Study, Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Treatment

Outcome Measure:

MTD of alisertib defined as the highest dose tested in which less than 33% of patients experienced dose-limiting toxicity (DLT) graded according to the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) v4.0

Outcome Description:

The toxicities observed at each dose level will be summarized in terms of type (organ affected or laboratory determination such as absolute neutrophil count), severity (by NCI CTCAE version 4.0) and nadir or maximum values for the laboratory measures, time of onset (i.e. course number), duration, and reversibility or outcome. Tables will be created to summarize these toxicities and side effects by dose and by course.

Outcome Time Frame:

21 days

Safety Issue:


Principal Investigator

Tanya Siddiqi

Investigator Role:

Principal Investigator

Investigator Affiliation:

Beckman Research Institute


United States: Food and Drug Administration

Study ID:




Start Date:

April 2012

Completion Date:

Related Keywords:

  • Extranodal Marginal Zone B-cell Lymphoma of Mucosa-associated Lymphoid Tissue
  • Nodal Marginal Zone B-cell Lymphoma
  • Peripheral T-cell Lymphoma
  • Recurrent Adult Burkitt Lymphoma
  • Recurrent Adult Diffuse Large Cell Lymphoma
  • Recurrent Adult Diffuse Mixed Cell Lymphoma
  • Recurrent Adult Diffuse Small Cleaved Cell Lymphoma
  • Recurrent Adult Grade III Lymphomatoid Granulomatosis
  • Recurrent Adult Hodgkin Lymphoma
  • Recurrent Adult Immunoblastic Large Cell Lymphoma
  • Recurrent Adult Lymphoblastic Lymphoma
  • Recurrent Adult T-cell Leukemia/Lymphoma
  • Recurrent Cutaneous T-cell Non-Hodgkin Lymphoma
  • Recurrent Grade 1 Follicular Lymphoma
  • Recurrent Grade 2 Follicular Lymphoma
  • Recurrent Grade 3 Follicular Lymphoma
  • Recurrent Mantle Cell Lymphoma
  • Recurrent Marginal Zone Lymphoma
  • Recurrent Mycosis Fungoides/Sezary Syndrome
  • Recurrent Small Lymphocytic Lymphoma
  • Refractory Hairy Cell Leukemia
  • Small Intestine Lymphoma
  • Splenic Marginal Zone Lymphoma
  • Testicular Lymphoma
  • Waldenström Macroglobulinemia
  • Burkitt Lymphoma
  • Hodgkin Disease
  • Leukemia
  • Leukemia, Lymphocytic, Chronic, B-Cell
  • Leukemia, Hairy Cell
  • Leukemia, T-Cell
  • Leukemia-Lymphoma, Adult T-Cell
  • Lymphoma
  • Lymphoma, Follicular
  • Lymphoma, Large B-Cell, Diffuse
  • Lymphoma, Non-Hodgkin
  • Lymphomatoid Granulomatosis
  • Waldenstrom Macroglobulinemia
  • Mycoses
  • Mycosis Fungoides
  • Sezary Syndrome
  • Lymphoma, B-Cell
  • Lymphoma, Large-Cell, Immunoblastic
  • Precursor Cell Lymphoblastic Leukemia-Lymphoma
  • Lymphoma, T-Cell
  • Lymphoma, T-Cell, Cutaneous
  • Lymphoma, T-Cell, Peripheral
  • Lymphoma, B-Cell, Marginal Zone
  • Lymphoma, Extranodal NK-T-Cell
  • Lymphoma, Mantle-Cell



City of Hope Medical Center Duarte, California  91010
UC Davis Comprehensive Cancer Center Sacramento, California  95817
University of Southern California Los Angeles, California  90033
Penn State Milton S Hershey Medical Center Hershey, Pennsylvania  17033