Aurora A Kinase Inhibitor MLN8237 and Bortezomib in Treating Patients With Relapsed or Refractory Multiple Myeloma

NCT ID: NCT01034553

Last Updated: 2016-05-25

Basic Information

• Recruitment Status: COMPLETED
• Clinical Phase: PHASE1/PHASE2
• Total Enrollment: 26 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2010-02-28
• Study Completion Date: 2014-11-30

Brief Summary

RATIONALE: Aurora A kinase inhibitor MLN8237 and bortezomib may stop the growth of cancer cells by blocking some of the enzymes needed for cell growth.

PURPOSE: This phase I/II trial is studying the side effects and best dose of giving aurora A kinase inhibitor MLN8237 together with bortezomib and to see how well they work in treating patients with relapsed or refractory multiple myeloma.

Detailed Description

PRIMARY OBJECTIVES:

I. To determine the maximum tolerated doses (MTD) with the combination of MLN8237 and bortezomib. (Phase I) II. To describe the toxicities associated with the combination of MLN8237 and bortezomib. (Phase I) III. To evaluate the overall response rate to the combination of MLN8237 and bortezomib in patients with relapsed or refractory multiple myeloma. (Phase II)

SECONDARY OBJECTIVE:

I. To assess progression-free survival in patients treated with this combination. (Phase II)

II. To assess overall survival in patients treated with this combination.(Phase II)

OUTLINE: This is a phase I dose escalation study followed by a phase II study. Patients receive oral aurora kinase inhibitor MLN8237 once daily on days 1-14 and bortezomib IV on days 1, 4, 8 and 11. Treatment repeats every 28 days for up to 10 courses in the absence of disease progression or unacceptable toxicity.

After completion of study treatment all patients are followed every 2 months for 1 year and then every 3 months for 1 year.

Conditions

Refractory Multiple Myeloma

Study Design

• Allocation Method: NA
• Intervention Model: SINGLE_GROUP
• Primary Study Purpose: TREATMENT
• Blinding Strategy: NONE

Study Groups

Arm I

Patients receive oral aurora A kinase inhibitor MLN8237 once daily on days 1-14 and bortezomib IV on days 1, 4, 8 and 11.

Group Type: EXPERIMENTAL

Aurora A kinase inhibitor MLN8237

Intervention Type: DRUG

Given orally

bortezomib

Intervention Type: DRUG

Given IV

Interventions

Aurora A kinase inhibitor MLN8237

Given orally

Intervention Type: DRUG

bortezomib

Given IV

Intervention Type: DRUG

Other Intervention Names

MLN8237; LDP 341; MLN341; PS-341; VELCADE

Eligibility Criteria

Inclusion Criteria

• ANC >= 1500/uL
• AST =< 2.5 x ULN
• Creatinine =< 1.5 x ULN
• Creatinine clearance as calculated by the method of Cockroft and Gault >= 30 mL/minute
• Patients with relapsed or refractory multiple myeloma requiring treatment
• Patients who have received prior bortezomib therapy will be allowed on trial as long as they did not progress during bortezomib or =< 60 days of therapy discontinuation
• Negative serum pregnancy test done =< 7 days prior to registration, for women of childbearing potential (WOCBP) only (a WOCBP is a sexually mature woman who: 1) has not undergone a hysterectomy or bilateral oophorectomy; or 2) has not been naturally postmenopausal for at least 24 consecutive months)
• Willingness to return to enrolling institution for follow-up
• Life expectancy >= 12 weeks
• Voluntary written informed consent before performance of any study-related procedure not part of normal medical care, with the understanding that consent may be withdrawn by the subject at any time without prejudice to future medical care
• Female subject is either post-menopausal or surgically sterilized or willing to use an acceptable method of birth control (i.e., a hormonal contraceptive, intra-uterine device, diaphragm with spermicide, condom with spermicide, or abstinence) for the duration of the study
• Male subject agrees to use an acceptable method for contraception for the duration of the study
• Patients have a baseline LVEF >= 45% at baseline
• Bisphosphonates are considered to be supportive care rather than therapy, and are thus allowed while on protocol treatment
• PLT >= 100,000/uL
• Total bilirubin =<1.5 x upper limit of normal (ULN) or if total bilirubin is > 1.5 x ULN, the direct bilirubin must be =< 2.0 mg/dL
• Measurable disease of multiple myeloma as defined by at least ONE of the following:
• Serum monoclonal protein >= 1.0 g/dL, >= 200 mg of monoclonal protein in the urine on 24 hour electrophoresis, serum immunoglobulin free light chain >= 10 mg/dL AND abnormal serum immunoglobulin kappa to lambda free light chain ratio, monoclonal bone marrow plasmacytosis >= 30% (evaluable disease), or measurable plasmacytoma
• ECOG Performance Status (PS) 0, 1, or 2
• Hgb >= 9 g/dl

Exclusion

• Major surgery, open biopsy (excluding bone marrow) or significant traumatic injury =< 4 weeks prior to registration
• Melphalan or other myelosuppressive agents including lenalidomide and non-myelosuppressive agents such as thalidomide or high dose corticosteroids =< 2 weeks prior to registration
• Concurrent use of corticosteroids, but patients may be on chronic steroids (maximum dose 20 mg/day prednisone equivalent) if they are being given for disorders other than myeloma, i.e., adrenal insufficiency, rheumatoid arthritis, etc
• Uncontrolled infection
• Pregnant women or women of reproductive ability who are unwilling to use effective contraception
• Nursing women
• Men who are unwilling to use a condom (even if they have undergone a prior vasectomy) while having intercourse with any woman, while taking the drug and for 4 weeks after stopping treatment
• Other co-morbidity or psychiatric illness which would interfere with patient's ability to participate in this trial
• Recent history of myocardial infarction in the six months prior to registration
• Uncontrolled angina or electrocardiographic evidence of acute ischemia
• Severe uncontrolled ventricular arrhythmias or electrocardiographic evidence of active conduction system abnormalities
• Cardiac amyloidosis with hypotension (systolic BP less than 100mmHg)
• MGUS or smoldering myeloma
• Serious non-healing wound, or ulcer
• Known hypersensitivity to Bortezomib, boron or mannitol
• Patient has >=Grade 2 peripheral neuropathy within 14 days before enrollment
• Patient has received other investigational drugs with 14 days before enrollment
• Diagnosed or treated for another malignancy within 2 years of enrollment, with the exception of complete resection of basal cell carcinoma or squamous cell carcinoma of the skin, an in situ malignancy, or low-risk prostate cancer after curative therapy
• Infection requiring systemic antibiotic therapy within 14 days preceding the first dose of study drug, or other severe infection
• Inability to swallow orally administered medication
• Prior allogeneic bone marrow or organ transplantation
• Patients who are currently receiving digoxin, cyclosporine, tacrolimus or sirolimus
• Severe cardiac comorbidity
• Known positive for HIV or active infectious hepatitis, type A, B or C

• Minimum Eligible Age: 18 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

Mayo Clinic

OTHER

Sponsor Role: lead

Responsible Party

Responsibility Role: SPONSOR

Principal Investigators

Alexander K. Stewart, M.D.

Role: STUDY_CHAIR

Mayo Clinic

Shaji K. Kumar, M.D.

Role: PRINCIPAL_INVESTIGATOR

Mayo Clinic

Locations

Mayo Clinic in Arizona

Scottsdale, Arizona, United States

University of California, San Francisco

San Francisco, California, United States

Dana-Farber Cancer Institute

Boston, Massachusetts, United States

Mayo Clinic

Rochester, Minnesota, United States

Washington University School of Medicine

St Louis, Missouri, United States

Ohio State University

Columbus, Ohio, United States

Countries

United States

Other Identifiers

NCI-2009-01475

Identifier Type: REGISTRY

Identifier Source: secondary_id

08-006317

Identifier Type: OTHER

Identifier Source: secondary_id

X14003

Identifier Type: OTHER

Identifier Source: secondary_id

MC088A

Identifier Type: OTHER

Identifier Source: secondary_id

MC088A

Identifier Type: -

Identifier Source: org_study_id