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

Refractory Multiple Myeloma Clinical Trial

Official title:

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

Clinical Trial Details — Status: Active, not recruiting

Administrative data

• NCT number: NCT01034553
• Other study ID #: MC088A
• Secondary ID: NCI-2009-0147508
• Status: Active, not recruiting
• Phase: Phase 1/Phase 2
• First received: December 16, 2009
• Last updated: March 23, 2015
• Start date: February 2010

Study information

• Verified date: March 2015
• Source: Mayo Clinic
• Contact: n/a
• Is FDA regulated: No
• Health authority: United States: Food and Drug Administration
• Study type: Interventional

Clinical Trial 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.

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 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.

Recruitment information / eligibility

• Status: Active, not recruiting
• Enrollment: 69
• Est. primary completion date: August 2015
• Accepts healthy volunteers: No
• Gender: Both
• Age group: 18 Years and older

Eligibility

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

Study Design

Endpoint Classification: Safety/Efficacy Study, Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Treatment

Related Conditions & MeSH terms

• Multiple Myeloma
• Neoplasms, Plasma Cell
• Refractory Multiple Myeloma

Intervention

Drug:
• Aurora A kinase inhibitor MLN8237
Given orally
• bortezomib
Given IV

Locations

Country	Name	City	State
United States	Dana-Farber Cancer Institute	Boston	Massachusetts
United States	Ohio State University	Columbus	Ohio
United States	Mayo Clinic	Rochester	Minnesota
United States	Washington University School of Medicine	Saint Louis	Missouri
United States	University of California, San Francisco	San Fransisco	California
United States	Mayo Clinic in Arizona	Scottsdale	Arizona

Sponsors (1)

Lead Sponsor	Collaborator
Mayo Clinic

Country where clinical trial is conducted

United States, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Adverse events profile (Phase I)			Yes
Primary	Toxicity profile as per NCI CTCAE v3.0 (Phase I)			Yes
Primary	MTD (Phase I)			Yes
Primary	Confirmed response (PR or better) (Phase II)			No
Secondary	Survival time (Phase II)			No
Secondary	Progression-free survival time (Phase II)			No
Secondary	Time to treatment failure (Phase II)			No
Secondary	Duration of response (Phase II)			No
Secondary	Adverse events (Phase II)			Yes