Now Available for Public Comment: Notice of Proposed Rulemaking (NPRM) for FDAAA 801 and NIH Draft Reporting Policy for NIH-Funded Trials

Alisertib in Combination With Vorinostat in Treating Patients With Relapsed or Recurrent Hodgkin Lymphoma, B-Cell Non-Hodgkin Lymphoma, or Peripheral T-Cell Lymphoma

This study is currently recruiting participants. (see Contacts and Locations)
Verified November 2014 by National Cancer Institute (NCI)
Sponsor:
Information provided by (Responsible Party):
National Cancer Institute (NCI)
ClinicalTrials.gov Identifier:
NCT01567709
First received: March 29, 2012
Last updated: November 21, 2014
Last verified: November 2014
  Purpose

This phase I trial studies the side effects and the best dose of alisertib when given together with vorinostat in treating patients with relapsed or recurrent Hodgkin lymphoma, B-cell non-Hodgkin lymphoma, or peripheral T-cell lymphoma. Alisertib and vorinostat may stop the growth of cancer cells by blocking some of the enzymes needed for cell growth. Giving alisertib together with vorinostat may work as a treatment for Hodgkin and non-Hodgkin lymphoma.


Condition Intervention Phase
Adult B Acute Lymphoblastic Leukemia
Adult T Acute Lymphoblastic Leukemia
Anaplastic Large Cell Lymphoma
Angioimmunoblastic T-Cell Lymphoma
Chronic Lymphocytic Leukemia
Cutaneous B-Cell Non-Hodgkin Lymphoma
Extranodal Marginal Zone Lymphoma of Mucosa-Associated Lymphoid Tissue
Hepatosplenic T-Cell Lymphoma
Intraocular Lymphoma
Lymphomatous Involvement of Non-Cutaneous Extranodal Site
Mature T-Cell and NK-Cell Non-Hodgkin Lymphoma
Nodal Marginal Zone Lymphoma
Recurrent Adult Acute Lymphoblastic Leukemia
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 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 and Sezary Syndrome
Recurrent Small Lymphocytic Lymphoma
Refractory Chronic Lymphocytic Leukemia
Refractory Hairy Cell Leukemia
Small Intestinal Lymphoma
Splenic Marginal Zone Lymphoma
T-Cell Large Granular Lymphocyte Leukemia
Testicular Lymphoma
Waldenstrom Macroglobulinemia
Drug: Alisertib
Drug: Vorinostat
Other: Laboratory Biomarker Analysis
Other: Pharmacological Study
Phase 1

Study Type: Interventional
Study Design: Endpoint Classification: Safety/Efficacy Study
Intervention Model: Single Group Assignment
Masking: Open Label
Primary Purpose: Treatment
Official Title: Phase I Study of the Aurora Kinase a Inhibitor MLN8237 in Combination With the Histone Deacetylase Inhibitor Vorinostat in Lymphoid Malignancies

Resource links provided by NLM:


Further study details as provided by National Cancer Institute (NCI):

Primary Outcome Measures:
  • 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 (NCI) Common Terminology Criteria for Adverse Events (CTCAE) version (v.)4.0 [ Time Frame: 21 days ] [ Designated as safety issue: Yes ]
    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.


Secondary Outcome Measures:
  • Incidence of toxicities produced by alisertib in combination with vorinostat assessed by the NCI CTCAE version 4.0 [ Time Frame: Up to 2 years ] [ Designated as safety issue: Yes ]
    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.

  • Clinical response rate [ Time Frame: Up to 2 years ] [ Designated as safety issue: No ]
    Summarized by exact binomial confidence intervals.


Other Outcome Measures:
  • Degree of apoptosis, described using IHC and flow cytometry [ Time Frame: Baseline to up to 2 years ] [ Designated as safety issue: No ]
    All correlative study data summaries will be descriptive.

  • Degree of proliferation described using IHC and flow cytometry [ Time Frame: Baseline to up to 2 years ] [ Designated as safety issue: No ]
    All correlative study data summaries will be descriptive.

  • Change in AURKA expression in tissue samples by IHC and FISH [ Time Frame: Baseline to up to 2 years ] [ Designated as safety issue: No ]
    All correlative study data summaries will be descriptive.


Estimated Enrollment: 60
Study Start Date: April 2012
Estimated Primary Completion Date: April 2015 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: Treatment (alisertib, vorinostat)
Patients receive alisertib PO BID on days 1-7 or days 1-3 and 8-10, and vorinostat PO BID on days 1-14 or days 1-5 and 8-12. Courses repeat every 21 days in the absence of disease progression or unacceptable toxicity.
Drug: Alisertib
Given PO
Other Names:
  • Aurora A Kinase Inhibitor MLN8237
  • MLN-8237
  • MLN8237
Drug: Vorinostat
Given PO
Other Names:
  • L-001079038
  • SAHA
  • Suberanilohydroxamic Acid
  • Suberoylanilide Hydroxamic Acid
Other: Laboratory Biomarker Analysis
Correlative studies
Other: Pharmacological Study
Correlative studies
Other Name: pharmacological studies

Detailed Description:

PRIMARY OBJECTIVES:

I. To determine the maximum-tolerated dose (MTD) of MLN8237 (alisertib) 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 or days 1-3 and 8-10, and vorinostat PO BID on days 1-14 or days 1-5 and 8-12. 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.

  Eligibility

Ages Eligible for Study:   18 Years and older
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
Criteria

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); last chemotherapy or radiation must be at least 4 weeks prior to enrollment on this study; 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%
  • 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/direct bilirubin < 1.5 X institutional upper limit of normal; patients with elevation of indirect (unconjugated) bilirubin alone, as in Gilbert's syndrome, are eligible
  • 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 =< institutional upper limit of normal OR creatinine clearance >= 60 mL/min/1.73 m^2 for patients with creatinine levels above institutional normal
  • 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 also be allowed to enter this study if they are past their day +100 of transplant
  • 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 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 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 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
  • 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, including but not limited to established allergic reaction to benzodiazepines
  • Treatment with valproic acid within 14 days prior to initiation of study and during the study
  • Prior use of valproic acid or any other histone deacetylase (HDAC) inhibitor for lymphoma treatment
  • 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
  • Human Immunodeficiency virus (HIV)-positive patients on combination antiretroviral therapy are ineligible; appropriate studies will be undertaken in patients receiving combination antiretroviral therapy when indicated
  • 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, histamine (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 with New York Heart Association (NYHA) class II-IV heart failure
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT01567709

Locations
United States, California
City of Hope Recruiting
Duarte, California, United States, 91010
Contact: Tanya Siddiqi    626-256-4673    tanyasiddiqi@coh.org   
Principal Investigator: Tanya Siddiqi         
University of Southern California/Norris Cancer Center Recruiting
Los Angeles, California, United States, 90033
Contact: Kevin R. Kelly    323-224-7371    kellykev@usc.edu   
Principal Investigator: Kevin R. Kelly         
University of California at Davis Cancer Center Recruiting
Sacramento, California, United States, 95817
Contact: Joseph M. Tuscano    916-734-3771    joseph.tuscano@ucdmc.ucdavis.edu   
Principal Investigator: Joseph M. Tuscano         
United States, Pennsylvania
Penn State Milton S Hershey Medical Center Recruiting
Hershey, Pennsylvania, United States, 17033-0850
Contact: W. C. Ehmann    717-531-5059    cehmann@psu.edu   
Principal Investigator: W. C. Ehmann         
University of Pittsburgh Cancer Institute Recruiting
Pittsburgh, Pennsylvania, United States, 15232
Contact: Jan H. Beumer    412-623-3216    beumerjh@upmc.edu   
Principal Investigator: Jan H. Beumer         
Sponsors and Collaborators
Investigators
Principal Investigator: Tanya Siddiqi Beckman Research Institute
  More Information

No publications provided

Responsible Party: National Cancer Institute (NCI)
ClinicalTrials.gov Identifier: NCT01567709     History of Changes
Other Study ID Numbers: NCI-2012-00715, NCI-2012-00715, CDR0000729769, CHNMC-PHI-67, PHI-67, 9091, P30CA033572, U01CA062505
Study First Received: March 29, 2012
Last Updated: November 21, 2014
Health Authority: United States: Food and Drug Administration

Additional relevant MeSH terms:
Waldenstrom Macroglobulinemia
Burkitt Lymphoma
Hodgkin Disease
Immunoblastic Lymphadenopathy
Intraocular Lymphoma
Leukemia
Leukemia, Hairy Cell
Leukemia, Large Granular Lymphocytic
Leukemia, Lymphocytic, Chronic, B-Cell
Leukemia, Lymphoid
Leukemia, T-Cell
Leukemia-Lymphoma, Adult T-Cell
Lymphoma
Lymphoma, B-Cell
Lymphoma, B-Cell, Marginal Zone
Lymphoma, Extranodal NK-T-Cell
Lymphoma, Follicular
Lymphoma, Large B-Cell, Diffuse
Lymphoma, Large-Cell, Anaplastic
Lymphoma, Large-Cell, Immunoblastic
Lymphoma, Mantle-Cell
Lymphoma, Non-Hodgkin
Lymphoma, T-Cell
Lymphoma, T-Cell, Cutaneous
Lymphoma, T-Cell, Peripheral
Lymphomatoid Granulomatosis
Mycosis Fungoides
Precursor Cell Lymphoblastic Leukemia-Lymphoma
Precursor T-Cell Lymphoblastic Leukemia-Lymphoma
Sezary Syndrome

ClinicalTrials.gov processed this record on November 25, 2014