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

Study Overview
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Brief Summary
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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
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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.

Official Title
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Phase I/II Study of Combination of Aurora Kinase Inhibitor MLN8237 and Bortezomib in Relapsed or Refractory Multiple Myeloma

Conditions
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Refractory Multiple Myeloma

Intervention / Treatment
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* Drug: Aurora A kinase inhibitor MLN8237
* Drug: bortezomib


Participation Criteria
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Eligibility Criteria
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Inclusion 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

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Arm I<br>Patients receive oral aurora A kinase inhibitor MLN8237 once daily on days 1-14 and bortezomib IV on days 1, 4, 8 and 11. | Drug: Aurora A kinase inhibitor MLN8237<br>* Given orally<br>* Other names: MLN8237;Drug: bortezomib<br>* Given IV<br>* Other names: VELCADE;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Dose-limiting Toxicity (DLT) (Phase I) | Patients were evaluated over the first cycle of treatment for Dose Limiting Toxicities. For this trail DLTs are as follows: An AE attributed (definitely, probably, or possibly) to study treatment during cycle 1 and the following criteria: Grade 4 Neutropenia Grade 4 Thrombocytopenia, or grade 3 with bleeding Febrile neutropenia Creatinine serum great than 2 times baseline or upper limit of normal Grade 3 or higher Fatigue Grade 3 or higher nausea, vomiting, or diarrhea Any grade 3 or higher Non-hematologic toxicity per NCI CTCAE V4.0 Inability to initiate the scheduled cycle 2, day 1 due to toxicity The maximum tolerated dose level (MTD) will be defined as the highest safely tolerated dose. | 28 days | 
| Overall Response Rate to the Combination of MLN8237 and Bortezomib in Patients With Relapsed or Refractory Multiple Myeloma. | sCR: Normal serum FLC ratio, and absence of clonal cells in bone marrow by immunohistochemistry or immunofluorescence, negative immunofixation of the serum and urine, <5% plasma cells in bone marrow, disappearance of any soft tissue plasmacytomas, and normalization of FLC ratio. VGPR:PR and serum and urine M-component detectable by immunofixation but not on electrophoresis, or if serum measurable,≥90% or greater reduction in serum M-component plus urine M-component <100 mg per 24h and if only measurable non-bone marrow parameter was FLC,≥90% or greater reduction in difference from involved and uninvolved FLC levels. PR:≥50% reduction of serum M-protein or reduction in 24-h urinary M-protein by ≥90% or to <200 mg per 24h or if FLC, ≥50% decrease in the difference between involved and uninvolved FLC levels or ≥50% reduction in bone marrow plasma cells is required in place of M-protein, provided baseline percentage was ≥30%, and ≥50% reduction in the size of soft tissue plasmacytomas | Every 28 day cycle(up to 10 cycles) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Progression-free Survival |  | Every 28 day cycle(up to 10 cycles) then follow-up for up to 2 years | 
| Overall Survival |  | Every 28 day cycle(up to 10 cycles) then follow-up for up to 2 years |