Phase 1/2 study of oral MLN9708, a novel,
investigational proteasome inhibitor, in
combination with lenalidomide and
dexamethasone in patients with previously
untreated multiple myeloma
Jesus G. Berdeja,1 Paul G. Richardson,2 Sagar Lonial,3 Ruben Niesvizky,4
Ai-Min Hui,5 Deborah Berg,5 Neeraj Gupta,5 Guohui Liu,5
Alessandra Di Bacco,5 Shaji K. Kumar6
1Sarah Cannon Research Institute, Nashville, TN, USA;
2Dana-Farber Cancer Institute, Boston, MA, USA;
3Winship Cancer Institute of Emory University, Atlanta, GA, USA;
4Center of Excellence for Lymphoma and Myeloma, Weill Medical College of
Cornell University, New York, NY, USA; 5Millennium Pharmaceuticals, Inc.,
Cambridge, MA, USA; 6Mayo Clinic, Rochester, MN, USA
Background
MLN9708 is an oral, potent, reversible, and specific 20S
proteasome inhibitor1
Immediately hydrolyzes to MLN2238, the biologically active
dipeptidyl leucine boronic acid
In preclinical studies, MLN2238 has shown faster proteasome
dissociation and greater tissue penetration than bortezomib
Both twice-weekly and weekly schedules of oral MLN9708 are being
investigated in patients with relapsed and/or refractory MM2,3
Single agent is active and well tolerated
No grade 3 peripheral neuropathy (PN) observed
Updated results presented at ASH 2011
· Paul Richardson, Abstract 301, Session 653, Ballroom 20D, 7.00am
· Shaji Kumar, Abstract 816, Session 653, Ballroom 20D, 5.45pm
1. Kupperman E, et al. Cancer Res 2010;70:197080.
2. Richardson PG, et al. Haematologica 2011;96(s1):S104 (abstract P-246).
3. Niesvizky R, et al. Haematologica 2011;96(s2):125 (abstract 0301).
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Rationale
The combination of a proteasome inhibitor, an IMiD, and steroids is
feasible and active in patients with previously untreated MM
Ph 1/2 with RVD in a 21-day cycle1
· PR rate after 4 cycles: 74%
· PR rate overall: 100%
Ph 1/2 with VDR in a 21-day cycle2
· PR rate after 4 cycles: 71%
· PR rate overall: 83%
In an in-vitro model, MLN2238 combined with lenalidomide
or dexamethasone was associated with synergistic anti-MM activity3
Weekly schedule of MLN9708 selected based on established
28-day cycle length of lenalidomide
Here we present the Ph 1 dose escalation portion of the study
1. Richardson PG, et al. Blood 2010;116(5):67986.
2. Kumar S, et al. Blood (ASH Annual Meeting Abstracts) 2010;116(21): abstract 621.
3. Chauhan D, et al. Blood (ASH Annual Meeting Abstracts) 2010;116(21): abstract 2992.
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Study objectives (NCT01217957)
Primary objectives:
Safety profile/tolerability
Maximum tolerated dose (MTD)
Recommended phase 2 dose (RP2D)
Secondary objectives:
Plasma pharmacokinetics (PK) of MLN2238 to assess
PK interaction
Response rates
Exploratory objectives:
Detection of minimal residual disease in patients achieving CR
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2
Patients
Inclusion criteria:
Age 18 years
ECOG performance status of 02
Adequate hepatic, renal, and hematologic function
Measurable disease (serum M-protein 1 g/dL,
urine M-protein 200 mg/24 hours, involved FLC 10 mg/dL)
Transplant eligible and ineligible allowed
Exclusion criteria:
Grade 2 PN
Prior/concurrent deep vein thrombosis (DVT)/
pulmonary embolism
Prior systemic MM therapy
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Study design
Dose escalation of oral MLN9708:
3+3 schema, based on cycle 1 DLTs
Starting dose based on dose-escalation portion of twice-weekly
dosing study (C16003),1 33% dose increments
1.68 2.23 2.97 3.95 mg/m2
Up to 12 months of induction (28-day cycles)
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15
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Maintenance
9708
9708
9708
· Responders and SD
· Oral MLN9708 on days
1, 8, 15 of 28-day cycles
Dex
Dex
Dex
Dex 40 mg/day PO
· Until progression or
unacceptable toxicity
Lenalidomide 25 mg/day PO
· Transplant-eligible patients could undergo SCT after 6 cycles
· Mandatory thromboprophylaxis with aspirin or low molecular weight heparin
1. Richardson PG, et al. Haematologica 2011;96(s1):S104 (abstract P-246).
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Assessments
Adverse events (AEs) graded using NCI-CTCAE v4.02
DLTs defined as:
Grade 4 thrombocytopenia or neutropenia lasting >7 days,
or platelets <10,000 mm3 at any time
Grade 3 neutropenia with fever and/or infection, or grade 3
thrombocytopenia with clinically significant bleeding
Grade 3 non-hematologic toxicity
Grade 2 PN with pain
Blood samples collected pre-dose and at multiple time points on days
1 and 15 of cycle 1 and pre-dose on day 1 of cycle 2, for PK analyses
Response assessed using IMWG uniform response criteria
With addition of minor response and near CR
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Patient enrollment
As of October 15, 2011, 15 patients have been enrolled
3 at 1.68 mg/m2
3 at 2.23 mg/m2
6 at 2.97 mg/m2
3 at 3.95 mg/m2
All patients
DLT-evaluable (received all MLN9708 doses in cycle 1 or had
a DLT in cycle 1)
Safety and response evaluable
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Treatment exposure
Patients have received a median of 5 cycles (range 19)
Seven patients received 58 cycles
One patient received 9 cycles
At data cut-off (October 12, 2011), 11 patients remain on treatment
No patient has progressed to date
Two patients discontinued to proceed to SCT
Two patients discontinued due to AEs (one unrelated)
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DLTs / MTD / RP2D
No DLTs seen at doses up to 2.23 mg/m2
DLT of grade 3 rash seen in 1 patient treated at 2.97 mg/m2
DLTs seen in 3 patients treated at 3.95 mg/m2:
Grade 3 nausea and vomiting despite adequate anti-emetic therapy,
grade 2 syncope
<80% of lenalidomide taken due to grade 3 nausea and vomiting
related to MLN9708
Grade 3 nausea and vomiting despite adequate anti-emetic therapy
MTD determined to be 2.97 mg/m2
MLN9708 RP2D in combination with lenalidomide and dexamethasone
decided to be 2.23 mg/m2 weekly
Based on efficacy and toxicity analyses across multiple treatment cycles, the
2.23 mg/m2 dose was at least as active as the 2.97 mg/m2 dose with improved
tolerability; furthermore, it did not compromise dosing of the background therapy
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MLN9708 safety profile
Patients
Total
(N=15)
Any AE, n
15
Any drug-related AE, n
13
Any grade 3 AE, n
11
Any grade 3 drug-related AE, n
9
Any serious AE (SAE), n
7
Any serious drug-related AE, n
4
Dose reduction due to AEs*, n
4
Discontinuation due to AEs, n
1
On-study death, n
0
*Study drug requiring dose reduction dependent on the toxicity,
its onset, and time course
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All-cause adverse events in 4 patients
All Grades
AE, n
Grade 3/ 4
Total
(N=15)
Fatigue
9 (60%)
0/0
Rash*
9 (60%)
2/0
Vomiting
8 (53%)
2/0
Anemia
6 (40%)
2/0
Diarrhea
5 (33%)
2/0
Nausea
5 (33%)
1/0
Insomnia
4 (27%)
0/0
Peripheral edema
4 (27%)
0/0
Thrombocytopenia
4 (27%)
0/1
*Erythematous, maculo-papular, papular
AEs transient and manageable with standard supportive care or dose reduction/ discontinuation of
the most likely offending agent
Grade 1 drug-related PN in 3 patients (2 at 1.68 mg/m2 and 1 at 2.97 mg/m2)
No grade >1 PN
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Preliminary responses
15 patients evaluable for response
15 achieved PR
· PR rate through 4 cycles: 100%
Best response includes 4 CR, 5 VGPR, and 6 PR
Time to response was rapid
14/15 responders achieved 50% decrease in M-protein in cycle 1
· 1 patient had a 48% reduction in M-protein after 1 cycle;
PR achieved after cycle 2
Two patients discontinued after cycle 6 to undergo SCT: 1 patient in VGPR
and 1 in CR
Molecular CR was achieved in the 1 CR patient assessable to date for
minimal residual disease
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Response and duration of treatment
3.95 mg/m2
VGPR
CR
sCR
MLN9708
3.95 mg/m2
3.95 mg/m2
PR
PR
PR
2.97 mg/m2
3.95 mg/m2
PR
2.23 mg/m2
2.97 mg/m2
1.68 mg/m2
PR
PR
PR
PR
PR
2.97 mg/m2
MR
PR
PR
PR
2.97 mg/m2
PR
PR
VGPR
2.97 mg/m2
VGPR
VGPR
2.97 mg/m2
PR
PR
PR
PR
VGPR
2.97 mg/m2
PR
VGPR
2.23 mg/m2
PR
VGPR
VGPR
CR
CR
2.23 mg/m2
PR
PR
PR
PR
PR
2.23 mg/m2
PR
VGPR
VGPR
CR
CR
CR
CR
1.68 mg/m2
PR
PR
VGPR
VGPR
VGPR
CR
1.68 mg/m2
PR
1.68 mg/m2
PR
PR
PR
VGPR
VGPR
VGPR
Cycle 1
Cycle 2
Cycle 3
Cycle 4
Cycle 5
Cycle 6
Cycle 7
Cycle 8
Cycle 9
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Conclusions
This is the first combination study of oral MLN9708 administered weekly
with standard-dose lenalidomide and dexamethasone in previously
untreated MM patients
The combination appears to be generally well tolerated
Low rate of PN and no grade >1 PN
Rash was manageable with standard supportive care, dose reduction,
or discontinuation
Preliminary evidence of antitumor activity with rapid responses
Recommended phase 2 dose of MLN9708 in combination with a
28-day cycle of lenalidomide and dexamethasone is 2.23 mg/m2 weekly
In phase 2, the RP2D will be converted to a fixed dose of 4 mg weekly,
as supported by population PK analyses1
1. Gupta N, et al. ASH 2011, abstr 1433. Fixed-dosing versus BSA-based dosing for MLN9708, an investigational
proteasome inhibitor: population pharmacokinetic analysis of pooled data from four phase 1 studies.
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Acknowledgments
We thank all patients and their families who participated in this study
We also thank the physicians, research nurses, study coordinators, and
research staff involved in the study
We acknowledge Dennis Noe of Millennium Pharmaceuticals, Inc. for PK
analysis and Natalie Beavan of FireKite for writing assistance during the
development of this presentation, which was funded by Millennium
Pharmaceuticals, Inc.
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