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

Mayo Clinic

Status and phase

Completed

Phase 2

Phase 1

Conditions

Refractory Multiple Myeloma

Treatments

Drug: Aurora A kinase inhibitor MLN8237

Drug: bortezomib

Study type

Interventional

Funder types

Other

Identifiers

NCT01034553

NCI-2009-01475 (Registry Identifier)

MC088A (Other Identifier)

08-006317 (Other Identifier)

X14003 (Other Identifier)

Details and patient eligibility

About

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.

Full 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.

Enrollment

26 patients

Sex

All

Ages

18+ years old

Volunteers

No Healthy Volunteers

Inclusion and exclusion criteria

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