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

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ClinicalTrials.gov Identifier: NCT01034553
Recruitment Status : Completed
First Posted : December 17, 2009
Results First Posted : May 25, 2016
Last Update Posted : May 25, 2016
Sponsor:
Information provided by (Responsible Party):
Mayo Clinic

Study Type Interventional
Study Design Intervention Model: Single Group Assignment;   Masking: None (Open Label);   Primary Purpose: Treatment
Condition Refractory Multiple Myeloma
Interventions Drug: Aurora A kinase inhibitor MLN8237
Drug: bortezomib
Enrollment 26
Recruitment Details  
Pre-assignment Details  
Arm/Group Title Phase I, Dose 0** Phase I, Dose 0 Phase I, Dose 1 Phase I, Dose 2 Phase I, Dose 3 Phase II, Dose 3
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Patients receive 25mg aurora A kinase inhibitor MLN8237 once daily on days 1-14 and 1.3mg Bortezomib on days 1, 4,8, and 11.

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

Patients receive 20mg aurora A kinase inhibitor MLN8237 twice daily on days 1-7 and 1.5mg Bortezomib on days 1, 8,15, and 22.

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

Patients receive 30mg aurora A kinase inhibitor MLN8237 twice daily on days 1-7 and 1.5mg Bortezomib on days 1, 8,15, and 22.

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

Patients receive 40mg aurora A kinase inhibitor MLN8237 twice daily on days 1-7 and 1.5mg Bortezomib on days 1, 8,15, and 22.

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

Patients receive 50mg aurora A kinase inhibitor MLN8237 twice daily on days 1-7 and 1.5mg Bortezomib on days 1, 8,15, and 22.

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

Patients receive 50mg aurora A kinase inhibitor MLN8237 twice daily on days 1-7 and 1.5mg Bortezomib on days 1, 8,15, and 22.

>

> Aurora A kinase inhibitor MLN8237: Given orally

>

> bortezomib: Given IV

Period Title: Overall Study
Started 3 4 3 3 6 7
Completed 3 4 3 3 6 7
Not Completed 0 0 0 0 0 0
Arm/Group Title All Patients
Hide Arm/Group Description

All Patients that received oral aurora A kinase inhibitor MLN8237 and bortezomib IV are summarized in this section.

Aurora A kinase inhibitor MLN8237: Given orally

Overall Number of Baseline Participants 26
Hide Baseline Analysis Population Description
[Not Specified]
Age, Continuous  
Median (Full Range)
Unit of measure:  Years
Number Analyzed 26 participants
64.5
(46 to 79)
Sex: Female, Male  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 26 participants
Female
10
  38.5%
Male
16
  61.5%
Region of Enrollment  
Measure Type: Number
Unit of measure:  Participants
United States Number Analyzed 26 participants
26
Previous treatment   [1] 
Measure Type: Number
Unit of measure:  Participants
Number Analyzed 26 participants
26
[1]
Measure Description: Previous treatment for this study is defined as any prior therapy given to the patient for treatment of Myeloma.
1.Primary Outcome
Title Dose-limiting Toxicity (DLT) (Phase I)
Hide Description

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.

Time Frame 28 days
Hide Outcome Measure Data
Hide Analysis Population Description
[Not Specified]
Arm/Group Title Dose 0** Dose 0 Dose 1 Dose 2 Dose 3
Hide Arm/Group Description:

Patients receive 25mg aurora A kinase inhibitor MLN8237 once daily on days 1-14 and 1.3mg Bortezomib on days 1, 4,8, and 11.

>

> Aurora A kinase inhibitor MLN8237: Given orally

>

> bortezomib: Given IV

Patients receive 20mg aurora A kinase inhibitor MLN8237 twice daily on days 1-7 and 1.5mg Bortezomib on days 1, 8,15, and 22.

>

> Aurora A kinase inhibitor MLN8237: Given orally

>

> bortezomib: Given IV

Patients receive 30mg aurora A kinase inhibitor MLN8237 twice daily on days 1-7 and 1.5mg Bortezomib on days 1, 8,15, and 22.

>

> Aurora A kinase inhibitor MLN8237: Given orally

>

> bortezomib: Given IV

Patients receive 40mg aurora A kinase inhibitor MLN8237 twice daily on days 1-7 and 1.5mg Bortezomib on days 1, 8,15, and 22.

>

> Aurora A kinase inhibitor MLN8237: Given orally

>

> bortezomib: Given IV

Patients receive 50mg aurora A kinase inhibitor MLN8237 twice daily on days 1-7 and 1.5mg Bortezomib on days 1, 8,15, and 22.

>

> Aurora A kinase inhibitor MLN8237: Given orally

>

> bortezomib: Given IV

Overall Number of Participants Analyzed 3 4 3 3 6
Measure Type: Number
Unit of Measure: participants
0 0 0 0 0
2.Primary Outcome
Title Overall Response Rate to the Combination of MLN8237 and Bortezomib in Patients With Relapsed or Refractory Multiple Myeloma.
Hide Description 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
Time Frame Every 28 day cycle(up to 10 cycles)
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Hide Analysis Population Description
All patients that received treatment were evaluated.
Arm/Group Title Dose Level 0 Dose Level 1 Dose Level 2 Dose Level 3
Hide Arm/Group Description:
This includes patients who received 25mg aurora A kinase inhibitor MLN8237 once daily on days 1-14 and 1.3mg Bortezomib on days 1, 4,8, and 11. As well as, patients who received 20mg aurora A kinase inhibitor MLN8237 twice daily on days 1-7 and 1.5mg Bortezomib on days 1, 8,15, and 22.
Patients received 30mg aurora A kinase inhibitor MLN8237 twice daily on days 1-7 and 1.5mg Bortezomib on days 1, 8,15, and 22.
Patients received 40mg aurora A kinase inhibitor MLN8237 twice daily on days 1-7 and 1.5mg Bortezomib on days 1, 8,15, and 22.
Patients received 50mg aurora A kinase inhibitor MLN8237 twice daily on days 1-7 and 1.5mg Bortezomib on days 1, 8,15, and 22.
Overall Number of Participants Analyzed 7 3 3 13
Measure Type: Number
Unit of Measure: percentage of patients per dose level
Strong Complete Response 14.3 0 0 0
Very Good Partial Response 0 33.3 0 7.7
Partial Response 14.3 0 0 23.1
3.Secondary Outcome
Title Progression-free Survival
Hide Description [Not Specified]
Time Frame Every 28 day cycle(up to 10 cycles) then follow-up for up to 2 years
Hide Outcome Measure Data
Hide Analysis Population Description
All patients that received treatment were evaluated.
Arm/Group Title All Patients
Hide Arm/Group Description:

Patients receive oral aurora A kinase inhibitor MLN8237 once daily on days 1-14 and bortezomib IV on days 1, 4, 8 and 11.

>

> Aurora A kinase inhibitor MLN8237: Given orally

>

> bortezomib: Given IV

Overall Number of Participants Analyzed 26
Median (95% Confidence Interval)
Unit of Measure: Months
5.9
(4.1 to 15.8)
4.Secondary Outcome
Title Overall Survival
Hide Description [Not Specified]
Time Frame Every 28 day cycle(up to 10 cycles) then follow-up for up to 2 years
Hide Outcome Measure Data
Hide Analysis Population Description
All patients that received treatment were evaluated.
Arm/Group Title All Patients
Hide Arm/Group Description:

Patients receive oral aurora A kinase inhibitor MLN8237 and bortezomib IV. >

> Aurora A kinase inhibitor MLN8237: Given orally

>

> bortezomib: Given IV

Overall Number of Participants Analyzed 26
Median (95% Confidence Interval)
Unit of Measure: Months
23.6 [1] 
(17.4 to NA)
[1]
Insufficient number of participants with events
Time Frame [Not Specified]
Adverse Event Reporting Description [Not Specified]
 
Arm/Group Title All Patients
Hide Arm/Group Description bortezomib: Given IV
All-Cause Mortality
All Patients
Affected / at Risk (%)
Total   --/--    
Show Serious Adverse Events Hide Serious Adverse Events
All Patients
Affected / at Risk (%) # Events
Total   11/26 (42.31%)    
Blood and lymphatic system disorders   
Anemia  1  2/26 (7.69%)  2
Febrile neutropenia  1  1/26 (3.85%)  1
Cardiac disorders   
Heart failure  1  1/26 (3.85%)  1
Gastrointestinal disorders   
Diarrhea  1  2/26 (7.69%)  2
Ileus  1  1/26 (3.85%)  1
Nausea  1  1/26 (3.85%)  2
Small intestinal obstruction  1  1/26 (3.85%)  1
Vomiting  1  1/26 (3.85%)  1
General disorders   
Fatigue  1  1/26 (3.85%)  1
Pain  1  1/26 (3.85%)  1
Infections and infestations   
Infections and infestations - Other, specify  1  3/26 (11.54%)  5
Urinary tract infection  1  1/26 (3.85%)  1
Investigations   
Lymphocyte count decreased  1  3/26 (11.54%)  4
Neutrophil count decreased  1  5/26 (19.23%)  11
Platelet count decreased  1  2/26 (7.69%)  7
White blood cell decreased  1  3/26 (11.54%)  6
Musculoskeletal and connective tissue disorders   
Generalized muscle weakness  1  3/26 (11.54%)  3
Pain in extremity  1  1/26 (3.85%)  1
Nervous system disorders   
Peripheral motor neuropathy  1  2/26 (7.69%)  2
Somnolence  1  1/26 (3.85%)  1
Psychiatric disorders   
Psychiatric disorders - Other, specify  1  1/26 (3.85%)  1
Indicates events were collected by systematic assessment
1
Term from vocabulary, MedDRA 10
Show Other (Not Including Serious) Adverse Events Hide Other (Not Including Serious) Adverse Events
Frequency Threshold for Reporting Other Adverse Events 0%
All Patients
Affected / at Risk (%) # Events
Total   26/26 (100.00%)    
Blood and lymphatic system disorders   
Anemia  1  10/26 (38.46%)  24
Gastrointestinal disorders   
Abdominal pain  1  1/26 (3.85%)  2
Bloating  1  1/26 (3.85%)  1
Constipation  1  2/26 (7.69%)  2
Diarrhea  1  16/26 (61.54%)  52
Dysphagia  1  1/26 (3.85%)  1
Mucositis oral  1  5/26 (19.23%)  7
Nausea  1  18/26 (69.23%)  79
Vomiting  1  9/26 (34.62%)  14
General disorders   
Edema limbs  1  1/26 (3.85%)  9
Fatigue  1  21/26 (80.77%)  93
Fever  1  1/26 (3.85%)  1
Gait disturbance  1  1/26 (3.85%)  1
Infections and infestations   
Device related infection  1  1/26 (3.85%)  1
Infections and infestations - Other, specify  1  11/26 (42.31%)  29
Lung infection  1  2/26 (7.69%)  2
Sepsis  1  1/26 (3.85%)  1
Urinary tract infection  1  1/26 (3.85%)  1
Injury, poisoning and procedural complications   
Bruising  1  1/26 (3.85%)  1
Fracture  1  1/26 (3.85%)  1
Investigations   
Alkaline phosphatase increased  1  1/26 (3.85%)  1
Aspartate aminotransferase increased  1  5/26 (19.23%)  36
Creatinine increased  1  7/26 (26.92%)  15
Electrocardiogram QT corrected interval prolonged  1  1/26 (3.85%)  1
INR increased  1  1/26 (3.85%)  5
Lymphocyte count decreased  1  8/26 (30.77%)  33
Neutrophil count decreased  1  12/26 (46.15%)  61
Platelet count decreased  1  22/26 (84.62%)  128
Weight loss  1  3/26 (11.54%)  3
White blood cell decreased  1  7/26 (26.92%)  35
Metabolism and nutrition disorders   
Anorexia  1  2/26 (7.69%)  3
Dehydration  1  1/26 (3.85%)  1
Hypocalcemia  1  1/26 (3.85%)  2
Hypokalemia  1  1/26 (3.85%)  2
Hyponatremia  1  1/26 (3.85%)  1
Hypophosphatemia  1  2/26 (7.69%)  2
Musculoskeletal and connective tissue disorders   
Back pain  1  1/26 (3.85%)  1
Bone pain  1  2/26 (7.69%)  3
Muscle weakness lower limb  1  1/26 (3.85%)  1
Pain in extremity  1  1/26 (3.85%)  3
Nervous system disorders   
Depressed level of consciousness  1  1/26 (3.85%)  1
Dizziness  1  3/26 (11.54%)  3
Peripheral motor neuropathy  1  7/26 (26.92%)  46
Peripheral sensory neuropathy  1  17/26 (65.38%)  111
Somnolence  1  1/26 (3.85%)  1
Renal and urinary disorders   
Urinary retention  1  1/26 (3.85%)  1
Respiratory, thoracic and mediastinal disorders   
Allergic rhinitis  1  1/26 (3.85%)  2
Bronchospasm  1  1/26 (3.85%)  1
Cough  1  2/26 (7.69%)  3
Hypoxia  1  1/26 (3.85%)  1
Sore throat  1  1/26 (3.85%)  1
Skin and subcutaneous tissue disorders   
Alopecia  1  7/26 (26.92%)  24
Hyperhidrosis  1  1/26 (3.85%)  1
Palmar-plantar erythrodysesthesia syndrome  1  1/26 (3.85%)  1
Rash maculo-papular  1  5/26 (19.23%)  7
Vascular disorders   
Hypertension  1  1/26 (3.85%)  1
Phlebitis  1  1/26 (3.85%)  1
Thromboembolic event  1  1/26 (3.85%)  1
Vasculitis  1  1/26 (3.85%)  1
Indicates events were collected by systematic assessment
1
Term from vocabulary, MedDRA 10
Certain Agreements
All Principal Investigators ARE employed by the organization sponsoring the study.
Results Point of Contact
Name/Title: Alexander Keith Stewart, M.B.CH.B
Organization: Mayo Clinic
Phone: (480)301-4411
Responsible Party: Mayo Clinic
ClinicalTrials.gov Identifier: NCT01034553     History of Changes
Other Study ID Numbers: MC088A
NCI-2009-01475 ( Registry Identifier: NCI-CTRP )
08-006317 ( Other Identifier: Mayo Clinic IRB )
X14003 ( Other Identifier: MPI Protocol )
MC088A ( Other Identifier: Mayo Clinic Cancer Center )
First Submitted: December 16, 2009
First Posted: December 17, 2009
Results First Submitted: October 16, 2015
Results First Posted: May 25, 2016
Last Update Posted: May 25, 2016