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A Phase I Study of MLN8237 in Combination With Bortezomib and Rituximab in Relapsed and Refractory Mantle Cell and Low Grade Non-Hodgkin Lymphoma


Phase 1
18 Years
N/A
Open (Enrolling)
Both
Extranodal Marginal Zone B-cell Lymphoma of Mucosa-associated Lymphoid Tissue, Nodal Marginal Zone B-cell Lymphoma, Recurrent Adult Diffuse Small Cleaved Cell Lymphoma, Recurrent Grade 1 Follicular Lymphoma, Recurrent Grade 2 Follicular Lymphoma, Recurrent Mantle Cell Lymphoma, Recurrent Marginal Zone Lymphoma, Recurrent Small Lymphocytic Lymphoma, Refractory Hairy Cell Leukemia, Splenic Marginal Zone Lymphoma, Waldenström Macroglobulinemia

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Trial Information

A Phase I Study of MLN8237 in Combination With Bortezomib and Rituximab in Relapsed and Refractory Mantle Cell and Low Grade Non-Hodgkin Lymphoma


PRIMARY OBJECTIVES:

I. To determine the recommended phase II dose of MLN8237 (alisertib) and bortezomib when
combined with rituximab in patients with relapsed/refractory mantle cell and B-cell low
grade non-Hodgkin lymphoma.

SECONDARY OBJECTIVES:

I. To describe the rate of overall response (complete response and partial response) for
patients with relapsed/refractory mantle cell and B-cell low grade non-Hodgkin lymphoma
treated with the combination of MLN8237 plus bortezomib and rituximab.

TERTIARY OBJECTIVES:

I. To evaluate the clinical significance of Aurora A over-expression and the proliferative
index in initial tumor biopsy specimens from patients with relapsed/refractory mantle cell
and B-cell low grade non-Hodgkin lymphoma treated with the combination of MLN8237 plus
bortezomib and rituximab.

II. To evaluate and compare in paired biopsy specimens pre-treatment and on day 8: apoptosis
and G2M arrest and the expression level of cell cycle related proteins including: cyclin D1,
p53, BIM-1, p27, p21, noxa, puma and survivin.

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

Patients receive alisertib orally (PO) twice daily (BID) on days 1-7; bortezomib
subcutaneously (SC) on days 1, 4, 8, and 11; and rituximab intravenously (IV) on day 1.
Treatment repeats every 21 days* in the absence of disease progression or unacceptable
toxicity.

Note: *After 8 courses, treatment with rituximab repeats once every 3 courses (9 weeks) in
the absence of disease progression or unacceptable toxicity.

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


Inclusion Criteria:



- Patients must have histologically confirmed relapsed or refractory mantle cell
lymphoma or low grade B-cell non-Hodgkin lymphoma (NHL); patients with evidence of
transformation to a high grade histology will not be eligible

- Measurable or evaluable disease, as defined in 2008 Revised Response Criteria for
Malignant Lymphoma; baseline scans used for measurement should be obtained within 30
days of registration, and baseline bone marrow biopsy and/or aspiration should be
obtained with 90 days of registration

- Patients may have received one or more lines of prior chemotherapy with/without
rituximab (including high dose therapy plus stem cell transplant which is counted as
one regimen); prior bortezomib is allowed; patients must not have received bortezomib
in the past 6 months

- Patients with human immunodeficiency virus (HIV) who are not receiving cytochrome
p450 inhibitors, and who have a minimum of 300+ CD4+ cells/mm3, an undetectable viral
load, and no history of acquired immune deficiency syndrome (AIDS) indicator
conditions

- 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

- Eastern Cooperative Oncology Group (ECOG) performance status 0, 1, or 2 (Karnofsky >=
60%)

- Leukocytes >= 3,000/mcL

- Absolute neutrophil count >= 1,500/mcL

- Platelets >= 100,000/mcL

- Total bilirubin within normal institutional limits (may be elevated if direct
bilirubin normal)

- Aspartate aminotransferase (AST) (serum glutamic oxaloacetic transaminase
[SGOT])/alanine aminotransferase (ALT) (serum glutamic pyruvate transaminase [SGPT])
=< 3 X institutional upper limit of normal

- Creatinine within normal institutional limits 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 and
for the duration of study participation; 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 administration

- Ability to understand and the willingness to sign a written informed consent document

Exclusion Criteria:

- Patients who have had chemotherapy or radiotherapy within 4 weeks (6 weeks for
nitrosoureas or mitomycin C, 3 weeks for rituximab) prior to entering the study or
those who have not recovered from adverse events due to agents administered more than
4 weeks earlier

- Patients who are receiving any other investigational agents

- 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, bortezomib or rituximab

- 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

- 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

- 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

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

- HIV-positive patients on combination antiretroviral therapy which include cytochrome
p450 inhibitors are ineligible; patients with CD4 counts less than 300 CD4+ cells/mm3
and or a high viral load are at increased risk of lethal infections when treated with
marrow-suppressive therapy, and are ineligible

- Grade 2 or greater neuropathy

- The following agents are not permitted while patients are taking MLN8237, and should
be discontinued at prior to registration if patients are taking them:

- Patients must stop using the proton pump inhibitor (PPI) for at least 4 days
prior to the first dose of MLN8237; administration of PPI while on study is not
permitted

- Histamine-2 (H2) receptor antagonists are not permitted from the day prior
through to the end of MLN8237 dosing, except as required for premedication for
rituximab; constant dosing of H2 blockers is not permitted

- Antacid preparations are not permitted for 2 hours before or 2 hours after
administration of MLN8237

- Administration of pancreatic enzymes is not permitted at any time while on study

- 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; if bisphosphonate
therapy is initiated after study entry, bone lesions will not be considered
evaluable for disease response

- Patients must be willing not drive, operate dangerous tools or machinery, or
engage in any other potentially hazardous activity that requires full alertness
and coordination if they experience sedation; if a patient experiences excessive
sedation believed to be related to MLN8237, treatment with MLN8237 should be
interrupted

- Patients must be willing to limit alcohol consumption to no more than 1 standard
unit of alcohol (12 oz beer [350 mL], 1.5 oz [45 mL] of 80- proof alcohol, or
one 6-oz [175 mL] glass of wine per day during the study and for 30 days from
the last dose of MLN8237; minimize the use of agents with central nervous system
(CNS) effects

- Benzodiazepine use is discouraged but not prohibited

- Because of their structural and pharmacological similarity to MLN8237, benzodiazepine
use is discouraged but not prohibited

Type of Study:

Interventional

Study Design:

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

Outcome Measure:

Recommended phase II dose of alisertib and bortezomib when combined with rituximab, defined as the highest dose level at which < 33% of the dose cohort experience a dose limiting toxicity (DLT)

Outcome Description:

Adverse events will be graded using the National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) v4.0. Toxicities will be described by intensity at each dose level.

Outcome Time Frame:

21 days

Safety Issue:

Yes

Principal Investigator

Catherine Diefenbach

Investigator Role:

Principal Investigator

Investigator Affiliation:

Montefiore Medical Center

Authority:

United States: Food and Drug Administration

Study ID:

NCI-2012-01712

NCT ID:

NCT01695941

Start Date:

August 2012

Completion Date:

Related Keywords:

  • Extranodal Marginal Zone B-cell Lymphoma of Mucosa-associated Lymphoid Tissue
  • Nodal Marginal Zone B-cell Lymphoma
  • Recurrent Adult Diffuse Small Cleaved Cell Lymphoma
  • Recurrent Grade 1 Follicular Lymphoma
  • Recurrent Grade 2 Follicular Lymphoma
  • Recurrent Mantle Cell Lymphoma
  • Recurrent Marginal Zone Lymphoma
  • Recurrent Small Lymphocytic Lymphoma
  • Refractory Hairy Cell Leukemia
  • Splenic Marginal Zone Lymphoma
  • Waldenström Macroglobulinemia
  • Leukemia
  • Leukemia, Lymphocytic, Chronic, B-Cell
  • Leukemia, Hairy Cell
  • Lymphoma
  • Lymphoma, Follicular
  • Lymphoma, Non-Hodgkin
  • Waldenstrom Macroglobulinemia
  • Lymphoma, B-Cell
  • Lymphoma, B-Cell, Marginal Zone
  • Lymphoma, Mantle-Cell

Name

Location

Montefiore Medical CenterBronx, New York  10467-2490
New York University Langone Medical CenterNew York, New York  10016