A Phase 1/2 Multi-center, Randomized, Open-label Dose Escalation Study to Determine the Maximum Tolerated Dose, Safety, and Efficacy of CC-4047 Alone Or in Combination With Low-dose Dexamethasone in Patients With Relapsed and Refractory Multiple Myeloma Who Have Received Prior Treatment That Includes Lenalidomide and Bortezomib
The Phase 1 segment of the study was designed to determine the maximum tolerated dose (MTD)
of single-agent pomalidomide, which was to be determined in the first cycle of treatment.
Following completion of the first cycle, participants were allowed to continue the study at
their assigned dose of pomalidomide. Participants who developed progressive disease (PD) at
any time, or who had not achieved at least a 25% reduction of serum myeloma (M)-protein
levels (if measurable) and a 50% reduction of urine M-protein (if measurable) compared with
baseline after completion of 4 cycles of pomalidomide, had the option to receive oral
dexamethasone 40 mg on days 1, 8, 15, and 22 of each 28-day treatment cycle in addition to
their current dose of pomalidomide. Participants with PD who chose not to add dexamethasone
to pomalidomide therapy were to be discontinued from the study. Participants who chose to
add dexamethasone were allowed to continue study treatment until PD developed again, at
which time they were to be discontinued.
Based on results from the phase 1 portion, the Data Monitoring Committee confirmed 4 mg/day
as MTD of pomalidomide. Therefore, the recommended starting dose of pomalidomide for Phase
2 was 4 mg/day on Days 1-21 of each 28-day cycle. In the combination treatment arm, the
starting dose of dexamethasone was 40 mg once per day on Days 1, 8, 15 and 22 of each 28-day
cycle for subjects who were ≤ 75 years of age. For subjects who were > 75 years of age, the
starting dose of dexamethasone was 20 mg once per day on Days 1, 8, 15 and 22 of each 28-day
cycle. As prophylactic anti-thrombotic treatment, all participants were to be given aspirin
81-100 mg daily (commercial supply) unless contraindicated. If aspirin was contraindicated,
participants were to receive another form of anti-thrombotic therapy according to hospital
guidelines or physician preference.
Participants in the combination treatment arm could continue study treatment until PD
developed, at which time they were to be discontinued. Participants in the single agent
pomalidomide treatment arm who developed confirmed PD at any time had the option to receive
oral dexamethasone in addition to their current dose of pomalidomide at the starting dose
described above. Participants with PD who chose not to add dexamethasone to pomalidomide
therapy were discontinued from study treatment. Participants who chose to add dexamethasone
to pomalidomide therapy could continue study treatment until PD developed again, at which
point they were discontinued.
Upon discontinuation from study treatment for PD or any other reason, participants were to
be assessed three times per year (April, August and December), up to five years, for
survival and subsequent anti-myeloma therapies.
Two analyses were planned during the course of the Phase 2 segment: one interim analysis (at
50% information of progression-free survival (PFS) events) and one final analysis. Data
cut-off for the interim analysis was 29 October 2010. For the interim analysis, results
using aggregated data were provided by Celgene, and analyses by treatment arm were performed
by an independent statistician for the Data Monitoring Committee (DMC). The DMC recommended
that Celgene personnel be unblinded based on the strength of the data. Limited Celgene
personnel were unblinded and shared that unblinded data during a meeting with the FDA.
Subsequently, Celgene decided to file an application based on more current study data; the
data cut-off for the application was 1 April 2011. The product was approved by the FDA in
February 2013 based on data from the 01 April 2011 data cut-off. Results from the 01 April
2011 data cut-off are reported.
The study continues. A final analysis will be performed when the study is completed and
results reported as available.
Allocation: Randomized, Endpoint Classification: Safety/Efficacy Study, Intervention Model: Parallel Assignment, Masking: Open Label, Primary Purpose: Treatment
Phase 1: Participants With Dose-Limiting Toxicities (DLT) in Cycle 1
The maximum tolerated dose was defined as the highest dose level at which no more than 1 of 6 participants experiences a DLT within the first 28-day cycle. DLTs were defined as: Grade 4 neutropenia or thrombocytopenia Febrile neutropenia Grade 3 or 4 nausea, vomiting or diarrhea despite optimal symptomatic treatment Serum transaminase > 20 * upper limit of normal (ULN) Serum transaminase > 5 * ULN for >= 7 days Delay of the start of cycle 2 by >7 days due to pomalidomide-related adverse event
Up to Day 28 (Cycle 1)
Christian J Jacques, MD
United States: Food and Drug Administration
|University of Michigan Comprehensive Cancer Center||Ann Arbor, Michigan 48109-0752|
|University of Pittsburgh Cancer Institute||Pittsburgh, Pennsylvania 15213|
|Dana-Farber Cancer Institute||Boston, Massachusetts 02115|
|Massachusetts General Hospital||Boston, Massachusetts 02114-2617|
|Emory University||Atlanta, Georgia 30322|
|Mayo Clinic Arizona||Scottsdale, Arizona 85259|
|Mt. Sinai Hospital||New York, New York 10029|
|The Cancer Center Hackensack University Medical Center||Hackensack, New Jersey 07601|
|Colorado Blood Cancer Institute HCA-HealthONE/Rocky Mountain Blood and Marrow Transplant Program||Denver, Colorado 80218|
|H. Lee Moffitt Cancer and Research Institute||Tampa, Florida 33612|
|Mayo Clinic Minnesota||Rochester, Minnesota 55905|
|Washington University - Siteman Cancer Center||St. Louis, Missouri 63110|
|The Ohio State University - James Cancer Hospital||Columbus, Ohio 43210|