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

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 and 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.

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not part of normal medical care, with the understanding that consent may be withdrawn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