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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


Phase 1/Phase 2
18 Years
N/A
Open (Enrolling)
Both
Multiple Myeloma

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Trial Information

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.


Inclusion Criteria:



- Must be greater than or equal to 18 years at the time of signing the informed consent
form

- Must be able to adhere to the study visit schedule and other protocol requirements

- Have a documented diagnosis of multiple myeloma and have relapsed and refractory
disease. Patients must have received at least 2 prior therapies. Patients must have
relapsed after having achieved at least stable disease for at least one cycle of
treatment to at least one prior regimen and then developed PD. Patients must also
have documented evidence of PD during or within 60 days (measured from the end of the
last cycle) of completing treatment with the last anti-myeloma drug regimen used just
prior to study entry (refractory disease)

- Patients must have also undergone prior treatment with at least 2 cycles of
lenalidomide and at least 2 cycles of bortezomib (either in separate regimens or
within the same regimen)

- Measurable levels of myeloma paraprotein in serum (greater than or equal to 0.5 g/dL)
or urine (greater than or equal 0.2 g/dL excreted in a 24 hour collection sample)

- Eastern Cooperative Oncology Group (ECOG) performance status score of 0, 1, or 2

- Females of childbearing potential (FCBP) [An FCBP 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 (i.e., who has had menses
at any time in the preceding 24 consecutive months)] must agree to refrain from
becoming pregnant for 28 days prior to initiation of study drug, while on study drug
and for 28 days after discontinuation of study drug and must agree to regular
pregnancy testing during this timeframe.

- All patients must also agree to refrain from donating blood while on study drug and
for 28 days after discontinuation from this study

- Males must agree to use a latex condom during any sexual contact with FCBP while
participating in the study and for 28 days following discontinuation from this study
even if he has undergone a successful vasectomy. Males must also agree to refrain
from donating blood, semen or sperm during the above referenced timeframe.

- All patients must agree not to share medication with another person.

Exclusion Criteria:

- Any serious medical condition, laboratory abnormality, or psychiatric illness that
would prevent the patient from signing the informed consent form.

- Any serious concurrent medical conditions that may make the patient non-evaluable or
put the patient's safety at risk.

- Pregnant or lactating females

- Any of the following laboratory abnormalities:

- Absolute neutrophil count (ANC) < 1,000 cells/mm3

- Platelet count < 75,000/mm3 for patients in whom < 50% of bone marrow nucleated
cells are plasma cells; or a platelet count < 30,000/mm3 for patients in whom ≥
50% of bone marrow nucleated cells are plasma cells

- Serum creatinine > 3.0 mg/dL

- Serum glutamic oxaloacetic transaminase/Aspartate transaminase (SGOT/AST) or
Serum Glutamic Pyruvate Transaminase/Alanine transaminase (SGPT/ALT) > 3.0 X
upper limit of normal (ULN)

- Serum total bilirubin > 2.0 mg/dL

- Prior history of malignancies, other than multiple myeloma, unless the patient has
been free of the disease for ≥ 3 years. Exceptions include the following:

- Basal or squamous cell carcinoma of the skin

- Carcinoma in situ of the cervix or breast

- Incidental histologic finding of prostate cancer (TNM stage of T1a or T1b)

- Known Human Immunodeficiency Virus (HIV), Hepatitis B Virus (HBV) and/or Hepatitis C
Virus (HCV) infection

- Hypersensitivity to thalidomide, lenalidomide, or dexamethasone

- Peripheral neuropathy ≥ Grade 2

- Use of any anti-myeloma drug therapy within 14 days of the initiation of study drug
treatment or use of any experimental non-drug therapy within 28 days of the
initiation of study drug treatment

- Radiation therapy within 14 days of initiation of study drug treatment Inability or
unwillingness to comply with birth control requirements

Type of Study:

Interventional

Study Design:

Allocation: Randomized, Endpoint Classification: Safety/Efficacy Study, Intervention Model: Parallel Assignment, Masking: Open Label, Primary Purpose: Treatment

Outcome Measure:

Phase 1: Participants With Dose-Limiting Toxicities (DLT) in Cycle 1

Outcome Description:

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

Outcome Time Frame:

Up to Day 28 (Cycle 1)

Safety Issue:

Yes

Principal Investigator

Christian J Jacques, MD

Investigator Role:

Study Director

Investigator Affiliation:

Celgene Corporation

Authority:

United States: Food and Drug Administration

Study ID:

CC-4047-MM-002

NCT ID:

NCT00833833

Start Date:

June 2008

Completion Date:

September 2015

Related Keywords:

  • Multiple Myeloma
  • Multiple Myeloma
  • Neoplasms, Plasma Cell

Name

Location

University of Michigan Comprehensive Cancer CenterAnn Arbor, Michigan  48109-0752
University of Pittsburgh Cancer InstitutePittsburgh, Pennsylvania  15213
Dana-Farber Cancer InstituteBoston, Massachusetts  02115
Massachusetts General HospitalBoston, Massachusetts  02114-2617
Emory UniversityAtlanta, Georgia  30322
Mayo Clinic ArizonaScottsdale, Arizona  85259
Mt. Sinai HospitalNew York, New York  10029
The Cancer Center Hackensack University Medical CenterHackensack, New Jersey  07601
Colorado Blood Cancer Institute HCA-HealthONE/Rocky Mountain Blood and Marrow Transplant ProgramDenver, Colorado  80218
H. Lee Moffitt Cancer and Research InstituteTampa, Florida  33612
Mayo Clinic MinnesotaRochester, Minnesota  55905
Washington University - Siteman Cancer CenterSt. Louis, Missouri  63110
The Ohio State University - James Cancer HospitalColumbus, Ohio  43210