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

This study has been completed.
Sponsor:
Information provided by (Responsible Party):
Mayo Clinic
ClinicalTrials.gov Identifier:
NCT01034553
First received: December 16, 2009
Last updated: April 18, 2016
Last verified: February 2016

December 16, 2009
April 18, 2016
February 2010
September 2014   (final data collection date for primary outcome measure)
  • Dose-limiting Toxicity (DLT) (Phase I) [ Time Frame: 28 days ] [ Designated as safety issue: Yes ]

    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.

  • Overall Response Rate to the Combination of MLN8237 and Bortezomib in Patients With Relapsed or Refractory Multiple Myeloma. [ Time Frame: Every 28 day cycle(up to 10 cycles) ] [ Designated as safety issue: Yes ]
    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
  • Adverse events profile (Phase I) [ Designated as safety issue: Yes ]
  • Toxicity profile as per NCI CTCAE v3.0 (Phase I) [ Designated as safety issue: Yes ]
  • MTD (Phase I) [ Designated as safety issue: Yes ]
  • Confirmed response (PR or better) (Phase II) [ Designated as safety issue: No ]
Complete list of historical versions of study NCT01034553 on ClinicalTrials.gov Archive Site
  • Progression-free Survival [ Time Frame: Every 28 day cycle(up to 10 cycles) then follow-up for up to 2 years ] [ Designated as safety issue: No ]
  • Overall Survival [ Time Frame: Every 28 day cycle(up to 10 cycles) then follow-up for up to 2 years ] [ Designated as safety issue: No ]
  • Survival time (Phase II) [ Designated as safety issue: No ]
  • Progression-free survival time (Phase II) [ Designated as safety issue: No ]
  • Time to treatment failure (Phase II) [ Designated as safety issue: No ]
  • Duration of response (Phase II) [ Designated as safety issue: No ]
  • Adverse events (Phase II) [ Designated as safety issue: Yes ]
Not Provided
Not Provided
 
Aurora A Kinase Inhibitor MLN8237 and Bortezomib in Treating Patients With Relapsed or Refractory Multiple Myeloma
Phase I/II Study of Combination of Aurora Kinase Inhibitor MLN8237 and Bortezomib in Relapsed or Refractory Multiple Myeloma

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.

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.

Interventional
Phase 1
Phase 2
Endpoint Classification: Safety/Efficacy Study
Intervention Model: Single Group Assignment
Masking: Open Label
Primary Purpose: Treatment
Refractory Multiple Myeloma
  • Drug: Aurora A kinase inhibitor MLN8237
    Given orally
    Other Name: MLN8237
  • Drug: bortezomib
    Given IV
    Other Names:
    • LDP 341
    • MLN341
    • PS-341
    • VELCADE
Experimental: 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.
Interventions:
  • Drug: Aurora A kinase inhibitor MLN8237
  • Drug: bortezomib
Not Provided

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Completed
26
November 2014
September 2014   (final data collection date for primary outcome measure)

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
Both
18 Years and older   (Adult, Senior)
No
Contact information is only displayed when the study is recruiting subjects
United States
 
NCT01034553
MC088A, NCI-2009-01475, 08-006317, X14003, MC088A
Yes
Not Provided
Not Provided
Mayo Clinic
Mayo Clinic
Not Provided
Study Chair: Alexander K. Stewart, M.D. Mayo Clinic
Principal Investigator: Shaji K. Kumar, M.D. Mayo Clinic
Mayo Clinic
February 2016

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP