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A Phase III, Multicentre, Randomised, Double-Blind, Placebo-Controlled, 3 Arm Parallel-Group Study to Determine the Efficacy and Safety of Lenalidomide (Revlimid) in Combination With Melphalan and Prednisone Versus Placebo Plus Melphalan and Prednisone in Subjects With Newly Diagnosed Multiple Myeloma Who Are 65 Years of Age or Older


Phase 3
65 Years
N/A
Open (Enrolling)
Both
Newly Diagnosed Multiple Myeloma

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Trial Information

A Phase III, Multicentre, Randomised, Double-Blind, Placebo-Controlled, 3 Arm Parallel-Group Study to Determine the Efficacy and Safety of Lenalidomide (Revlimid) in Combination With Melphalan and Prednisone Versus Placebo Plus Melphalan and Prednisone in Subjects With Newly Diagnosed Multiple Myeloma Who Are 65 Years of Age or Older


The three phases for the study as originally defined and as represented in the results of 11
May 2010 are:

Double-blind Treatment Phase: Induction Melphalan/prednisone and lenalidomide 10 mg (MPR)
(2 treatment arms), or melphalan/prednisone and placebo (MPp) (1 treatment arm) for up to 9
cycles. If disease progression, subjects have the option to enter into the Open-Label
Extension Phase. There is also an option to enter into the Follow-Up Phase. If the disease
has not progressed, subject can continue blinded therapy into Maintenance.

Double-blind Treatment Phase: Maintenance One MPR treatment arm (MPR+R) will continue
taking lenalidomide 10 mg in Maintenance. The other MPR treatment arm (MPR+p) will take
placebo in Maintenance. The MPp treatment arm will take placebo in Maintenance (MPp+p). If
disease progression, subjects have the option to enter the Open-Label Extension Phase to
obtain treatment with lenalidomide, or to enter into the Follow-up Phase.

Open-label Extension Phase:

Treatment consists of oral lenalidomide (up to 25 mg) with or without dexamethasone until
disease progression or treatment is discontinued for any reason until all study subjects are
followed for at least 5 years from the date of randomization or have died. Subjects who
discontinue from the Open-Label Extension Phase prior to completing a total of 5 years in
the study will enter the Follow-up Phase.

Follow-up Phase:

Subjects are followed for overall survival and subsequent anti-myeloma treatment regimens
until all subjects in this study are followed for at least 5 years from randomization or
have died.

The pre-planned interim analysis for the Independent Data Monitoring Committee (IDMC) showed
that the difference in progression-free survival (PFS) between treatment arms MPR+R and
MPp+p (the defined primary comparative analysis for this study) surpassed the pre-specified
O'Brien-Fleming boundary for superiority. The IDMC recommended the release of this
information to the sponsor and also recommended that all patient and physician study
participants receive information concerning the full findings of the MM-015 interim
analysis. Therefore, due to these recommendations from the IDMC, treatment-arm codes were
sent to the clinical trial centers to unblind the treatment arms of their study subjects
once the amended protocol was reviewed and approved by the respective country Health
Authorities and Ethics Committees. Subject participation in the MM-015 study continued
after unblinding to obtain long-term data for all study endpoints, including overall
survival.

When the study was unblinded, subjects still on protocol therapy had completed the
Double-Blind Induction, and were on monotherapy in Double-Blind Maintenance. Subjects in
arm MPR+R continued their monotherapy on lenalidomide. Subjects in arms MPR+p and MPp+p
discontinued their placebo monotherapy and went into an observation period in which no
antimyeloma therapy was taken. If disease progressed for any subject, the investigator had
the option of entering the subject in Open Label Extension Phase to receive lenalidomide
therapy (up to 25 mg daily) or the Follow-up Phase. All subjects were to be followed for at
least 5 years from the start of the study.

Inclusion Criteria


Inclusion Criteria

1. Must understand and voluntarily sign an informed consent form

2. Age greater than or equal to 65 years at the time of signing the informed consent

3. Newly diagnosed with symptomatic multiple myeloma as defined by the 3 criteria below:

MM diagnostic criteria (all of next 3 required)

1. Monoclonal plasma cells in the bone marrow greater than or equal to 10% and/or
presence of a biopsy-proven plasmacytoma

2. Monoclonal protein present in the serum and/or urine

3. Myeloma-related organ dysfunction (at least one of the following) [C] Calcium
elevation in the blood (serum calcium >10.5mg/dl or upper limit of normal) [R] Renal
insufficiency (serum creatinine >2mg/dl) [A] Anemia (hemoglobin <10g/dl or 2g <
normal) [B] Lytic bone lesions or osteoporosis AND have measurable disease as defined
by the following; IgG multiple myeloma: Serum monoclonal paraprotein (M-protein)
level greater than or equal to 1.0 g/dL or urine M-protein level greater than or
equal to 200 mg/24 hours IgA multiple myeloma: Serum M-protein level greater than or
equal to 0.5 g/dL or urine M-protein level greater than or equal to 200 mg/24 hours
IgD multiple myeloma: Serum M-protein level greater than or equal to 0.05 g/dL or
urine M-protein level greater than or equal to 200 mg/24 hours Light chain multiple
myeloma: Serum M-protein level greater than or equal to 1.0 g/dL or urine M-protein
level greater than or equal to 200 mg/24 hours IgM multiple myeloma (IgM M-protein
plus lytic bone disease documented by skeletal survey plain films): Serum M-protein
level greater than or equal to 1.0g/dL or urine M-protein level greater than or equal
to 200mg/24hours

4. Karnofsky performance status greater than or equal to 60%.

5. Able to adhere to the study visit schedule and other protocol requirements.

6. Women of Childbearing potential (WCBP) must:

a. Have a negative medically supervised pregnancy test prior to the start of study
therapy. She must agree to ongoing pregnancy testing during the course of the study,
and after end of study therapy. This applies even if the subject practices and
continues sexual abstinence.

b Either commit to continued abstinence from heterosexual intercourse (which must be
reviewed on a monthly basis) or agree to use, and be able to comply with, effective
contraception without interruption, 28 days prior to starting study drug, during the
study therapy (including dose interruptions), and for 28 days after discontinuation
of study therapy.

7. Males Subjects must:

1. Agree to use a condom during sexual contact with a WCBP, even if they have had a
vasectomy, throughout study drug therapy, during any dose interruption and after
the cessation of study therapy.

2. Agree to not donate semen during study drug therapy and for a period after end
of study drug therapy.

8. All subjects must

1. Have an understanding that the study drug could have potential teratogenic risk.

2. Agree to abstain from donating blood while taking study drug therapy and
following discontinuation of study drug therapy.

3. Agree not to share study medication with another person.

4. All patients must be counseled about pregnancy precautions and risks of fetal
exposure.

Female Subjects:

Females of childbearing potential (FCBP) with regular cycles must agree to have pregnancy
tests weekly for the first 28 days of study participation and then every 28 days while on
study, at study discontinuation, and at day 28 following discontinuation from the study.
If menstrual cycles are irregular, the pregnancy testing must occur weekly for the first
28 days and then every 14 days while on study, at study discontinuation, and at days 14
and 28 following discontinuation from the study.

In addition to the required pregnancy testing, the Investigator must confirm with FCBP
that she is continuing to use two reliable methods of birth control at each visit.
Counseling about pregnancy precautions and the potential risks of fetal exposure must be
conducted at a minimum of every 28 days. During counseling, subjects must be reminded to
not share study drug and to not donate blood.

Pregnancy testing and counseling must be performed if a subject misses her period or if
her pregnancy test or her menstrual bleeding is abnormal. Study drug treatment must be
discontinued during this evaluation.

Females must agree to abstain from breastfeeding during study participation and for at
least 28 days after the discontinuation from the study.

Male Subjects:

Counseling about the requirement for latex condom use during sexual contact with females
of childbearing potential and the potential risks of fetal exposure must be conducted at a
minimum of every 28 days. During counseling, subjects must be reminded to not share study
drug and to not donate blood, sperm, or semen.

If pregnancy or a positive pregnancy test does occur in a study subject or the partner of
a study subject during study participation, study drug must be immediately discontinued.

Exclusion Criteria

1. Previous treatment with antimyeloma therapy (does not include radiotherapy,
bisphosphonates, or a single short course of steroid [i.e., less than or equal to the
equivalent of dexamethasone 40 mg/day for 4 days; such a short course of steroid
treatment must not have been given within 28 days [4 weeks] of randomization]).

2. Any serious medical condition, including the presence of laboratory abnormalities,
which places the subject at an unacceptable risk if he or she participates in this
study or confounds experimental the ability to interpret data from the study.

3. Pregnant or lactating females.

4. Radiotherapy within 14 days (2 weeks) of randomization.

5. Plasmapheresis within 28 days (4 weeks) of randomization.

6. Any of the following laboratory abnormalities:

Absolute neutrophil count (ANC) < 1,500 cells/mL (1.5*10^9/L) Platelet count <
75,000 cells/uL (75*10^9/L) for subjects in whom < 50% of bone marrow nucleated
cells are plasma cells; but platelet count <30,000/uL for subjects in whom >= 50% of
bone marrow nucleated cells are plasma cells Haemoglobin < 8.0 g/dL (80 g/L) Serum
creatinine > 2.5 mg/dL (221 ┬Ámol/L) Serum aspartate aminotransferase (SGOT/AST) or
alanine aminotransferase (SGPT/ALT) > 3.0 times upper limit of normal (ULN)

7. Prior history of malignancies, other than multiple myeloma, unless the subject has
been free of the disease for greater than or equal to 3 years.

Exceptions include the following:

Basal cell carcinoma of the skin Squamous cell carcinoma of the skin Carcinoma in
situ of the cervix Carcinoma in situ of the breast Incidental histologic finding of
prostate cancer (TNM Classification of Malignant Tumours (TNM) stage of T1a or T1b)

8. Neuropathy of >= grade 2 severity.

9. Known human immunodeficiency virus (HIV) positivity or active infectious hepatitis,
type A, B or C.

Type of Study:

Interventional

Study Design:

Allocation: Randomized, Endpoint Classification: Safety/Efficacy Study, Intervention Model: Parallel Assignment, Masking: Double Blind (Subject, Caregiver, Investigator, Outcomes Assessor), Primary Purpose: Treatment

Outcome Measure:

Kaplan Meier Estimates of Progression-free Survival (PFS) Based on the Response Assessment by the Central Adjudication Committee (CAC)

Outcome Description:

Data as of 11 May 2010 cutoff. PFS was calculated as the time from randomization to the earlier of the first documentation of progressive disease (PD) as determined by the CAC, or death on study due to any cause. PD was based on the European Group for Blood and Marrow Transplantation/International Bone Marrow Transplant Registry/Autologous Bone Marrow Transplant Registry [EBMT/IBMTR/ABMTR] criteria. PD criteria includes increasing monoclonal paraprotein levels, bone marrow findings, worsening lytic bone disease, progressively enlarging extramedullary plasmacytomas, or hypercalcemia.

Outcome Time Frame:

up to 165 weeks

Safety Issue:

No

Principal Investigator

Antonio Palumbo, M.D.

Investigator Role:

Principal Investigator

Investigator Affiliation:

Azienda Sanitaria Ospedaliera Molinette S. Giovanni Battista

Authority:

Australia: Department of Health and Ageing Therapeutic Goods Administration

Study ID:

CC-5013-MM-015

NCT ID:

NCT00405756

Start Date:

February 2007

Completion Date:

September 2013

Related Keywords:

  • Newly Diagnosed Multiple Myeloma
  • Newly Diagnosed Multiple Myeloma
  • Celgene
  • CC-5013
  • Revlimid
  • Lenalidomide
  • Melphalan
  • Prednisone
  • Elderly
  • Multiple Myeloma
  • Neoplasms, Plasma Cell

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