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Multiple Myeloma

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Dexamethasone

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Arm A: Oral CC-5013 is initiated on Day 1 of Cycle 1 at a dose of 25 mg daily for 21 days every 28 days. Therefore, the subject will take a placebo identical in appearance to the CC-5013 capsule for week 4 of every 28 days. Oral pulse dexamethasone is administered at a dose of 40mg daily on Days 1-4, 9-12, and 17-20 of each 28 day cycle for Cycles 1 through 4. Beginning with Cycle 5, the oral dexamethasone dosing schedule will be reduced to 40mg daily for Days 1-4 every 28 days. In addition, oral CC-5013 placebo capsules will be administered for 28 days of every cycle.

Arm B: Oral pulse dexamethasone is administered at a dose of 40mg daily on Days 1-4, 9-12, and 17-20 of each 28 day cycle for Cycles 1 through 4. Beginning with Cycle 5, the oral dexamethasone dosing schedule will be reduced to 40mg daily for Days 1-4 every 28 days. In addition, oral placebo capsules will be administered for 28 days of every cycle.

CC-5013 plus dexamethasone

Oral pulse dexamethasone is administered at a dose of 40mg daily on Days 1-4, 9-12, and 17-20 of each 28 day cycle for Cycles 1 through 4. Beginning with Cycle 5, the oral dexamethasone dosing schedule will be reduced to 40mg daily for Days 1-4 every 28 days. In addition, oral placebo capsules will be administered for 28 days of every cycle.

Dexamethasone plus Placebo

Robert Knight, MD

To compare the efficacy of oral CC-5013 in combination with oral pulse high-dose dexamethasone to that of placebo and oral high-dose pulse dexamethasone as treatment for subjects with relapsed or refractory multiple myeloma."

A Study of CC-5013 Plus Dexamethasone Versus Dexamethasone Alone in Previously Treated Subjects With Multiple Myeloma

The Official Title is A Multi-center, Randomized, Parallel-group, Double-blind, Placebo Controlled Study of CC-5013 Plus Dexamethasone Versus Dexamethasone Alone in Previously Treated Subjects With Multiple Myeloma.

Time to progression was calculated as the time from randomization to the first occurrence of disease progression, as determined by a detailed review of all the myeloma response assessment data using the Bladé criteria (Bladé, 1998). Disease progression was also based on bone marrow findings, worsening lytic bone disease, progressively enlarging extramedullary plasmacytomas, or hypercalcemia.

OS was calculated as the time from randomization to death from any cause. OS was censored at the last date that the participant was known to be alive for participants who were alive at the time of analysis and for participants who were lost to follow-up before death was documented.

Complete Response (CR): Disappearance of monoclonal paraprotein and maintained for ≥ 6 weeks . Remission Response (RR):75-99% reduction in the level of the serum monoclonal paraprotein compared to baseline; 90-99% reduction in 24-hr urinary light chain excretion. Partial Response (PR): 50-74% reduction in the level of monoclonal paraprotein compared to baseline; 50-89% reduction in 24-hr urinary light chain excretion. Stable Disease (SD): Criteria for PR or PD have not been met. Plateau Phase: If PR, stable monoclonal paraprotein values (within 25% above or below nadir)/stable soft tissue plasmacytomas maintained for at least 3 months. Progressive Disease (PD): Reappearance of serum or urinary monoclonal paraprotein on immunofixation or electrophoresis on two consecutive occasions at least one week apart. Increase of percentage of plasma cells in bone marrow aspirate or biopsy to ≥ 5%. Development of at least one new lytic bone lesion or soft tissue plasmacytoma.

An AE is any sign, symptom, illness, or diagnosis that appears or worsens during the course of the study. Treatment-emergent AEs (TEAEs) are any AE occurring or worsening on or after the first treatment of the study drug and within 30 days after the last cycle end date of study drug. A serious AE = any AE which results in death; is life-threatening; requires or prolongs existing inpatient hospitalization; results in persistent or significant disability is a congenital anomaly/birth defect; constitutes an important medical event.

The severity of AEs were graded according to the National Cancer Institute (NCI) Common Terminology Criteria for AEs (CTCAE, Version 2.0): Grade 1 = Mild (no limitation in activity or intervention required); Grade 2 = Moderate (some limitation in activity; no/minimal medical intervention required); Grade 3 = Severe (marked limitation in activity; medical intervention required, hospitalization possible); Grade 4 = Life-threatening; Grade 5 = Death.

Time from randomization to the date of the first occurrence of a symptomatic SRE (clinical need for radiotherapy or surgery to bone).

The time to first worsening of the ECOG performance status was calculated as the time from randomization to the date of the first worsening compared with the last ECOG evaluation obtained prior to randomization. Data were censored at the last date that the participant was known to be unchanged or improved from before randomization for the participants who had not had worsened at the time of the analysis and for the patients who were lost to follow-up before worsening in the ECOG performance status was documented.

Celgene

Includes adverse events for those who received Lenalidomide after unblinding.

Lenalidomide 25 mg by mouth (PO) daily (QD) on Days 1 to 21 and a matching placebo capsule QD on Days 22 to 28 of each 28-day cycle.

Dexamethasone 40mg PO QD on Days 1-4, 9-12, and 17-20 of each 28 day cycle for cycles 1 through 4. Beginning with Cycle 5, dexamethasone dosing schedule was reduced to 40mg PO QD on Days 1 to 4 every 28 days for the remaining cycles.

Lenalidomide Plus Dexamethasone

Placebo PO daily on Days 1 to 28 of each 28 day cycle.

Dexamethasone 40mg PO QD on Days 1-4, 9-12, and 17-20 of each 28-day cycle for Cycles 1 through 4. Beginning with Cycle 5, dexamethasone dosing schedule was reduced to 40mg PO QD for Days 1-4 every 28 days.

Placebo Plus Dexamethasone

Total

Age, Continuous

Sex: Female, Male

0 = (Fully Active)

1 = (Restrictive but Ambulatory)

2 = Ambulatory unable to Work)

3 = (Limited Self-Care)

4 = (Completely Disabled)

Missing

Eastern Cooperative Oncology Group (ECOG) Performance Status is used by doctors and researchers to assess how a participants' disease is progressing, assess how the disease affects the daily living activities of the participant and determine appropriate treatment and prognosis.

Eastern Cooperative Oncology Group Performance Status

1 Prior anti-myeloma therapy

2 or more prior anti-myeloma therapies

Number of Prior Anti-Myeloma Therapies

Time from First Pathological Diagnosis

Stage I

Stage II

Stage III

The International Staging System divides myeloma into 3 stages based only on the serum beta-2 microglobulin and serum albumin levels.

Stage I: Serum beta-2 microglobulin is less than 3.5 (mg/L) and the albumin level is above 3.5 (g/L);

Stage II: Neither stage I or III, meaning that either:

* The beta-2 microglobulin level is between 3.5 and 5.5 (with any albumin level), OR
* The albumin is below 3.5 while the beta-2 microglobulin is less than 3.5

Stage III: Serum beta-2 microglobulin is greater than 5.5.

Baseline multiple myeloma stage

Intent to treat population included all participants who were randomized

Anne McClain, Senior Manager

Lenalidomide 25 mg by mouth (PO) daily (QD) on Days 1 to 21 and a matching placebo capsule QD on Days 22 to 28 of each 28-day cycle.

Pulse dexamethasone 40mg PO QD on Days 1-4, 9-12, and 17-20 of each 28 day cycle for cycles 1 through 4. Beginning with Cycle 5, dexamethasone dosing schedule was reduced to 40mg PO QD on Days 1 to 4 every 28 days for the remaining cycles.

Placebo PO daily on Days 1 to 28 of each 28 day cycle.

Pulse dexamethasone 40mg PO QD on Days 1-4, 9-12, and 17-20 of each 28-day cycle for Cycles 1 through 4. Beginning with Cycle 5, dexamethasone dosing schedule was reduced to 40mg PO QD for Days 1-4 every 28 days.

Intent to treat included all participants who were randomized.

Kaplan-Meier Estimate of Time to Tumor Progression (TTP)

Intent to Treat population includes all participants who were randomized.

Kaplan-Meier Estimate of Overall Survival (OS)

Placebo PO daily on Days 1 to 28 of each 28 day cycle. Pulse dexamethasone 40 mg PO QD on Days 1-4, 9-12, and 17-20 of each 28-day cycle for Cycles 1 through 4. Beginning with Cycle 5, dexamethasone dosing schedule was reduced to 40 mg PO QD for Days 1-4 every 28 days.

Participants with documented progressive disease were permitted to crossover to receive lenalidomide at the same doses mentioned.

After the study was unblinded in August 2005 participants were given the option to add lenalidomide to their dexamethasone treatment regimen immediately or to add lenalidomide to their dexamethasone therapy at the time of disease progression.

Kaplan-Meier Estimate of Overall Survival (OS) (Later Cut-off Date of 02 March 2008)

Complete Response (CR)

Partial Response (PR)

Stable Disease (SD)

Progressive Disease (PD)

Not Evaluable (NE) those without response data

Intent to Treat Population includes all participants who were randomized

Summary of Myeloma Response Rates Based on Best Response Assessment

Myeloma Response Rates Based on the Reviewers Best Response Assessment (Later Cut-off Date of 02 March 2008)

≥ 1 Adverse Event

≥ 1 Serious Adverse Event

≥ 1 AE leading to study drug discontinuation

≥ 1 AE leading to dose reduction or interruption

≥ 1 Drug-Related Adverse Event

≥ 1 Drug-Related Serious Adverse Event

≥Death within ≤ 30 days of last dose of study drug

≥ 1 Grade 1 or Higher Adverse Event

≥ 1 Grade 2 or Higher Adverse Event

≥ 1 Grade 3 or Higher Adverse Event

≥ 1 Grade 4 or Higher Adverse Event

Placebo PO daily on Days 1 to 28 of each 28 day cycle. Pulse dexamethasone 40 mg PO QD on Days 1-4, 9-12, and 17-20 of each 28-day cycle for Cycles 1 through 4. Beginning with Cycle 5, dexamethasone dosing schedule was reduced to 40 mg PO QD for Days 1-4 every 28 days. Participants with documented progressive disease were permitted to crossover to receive lenalidomide at the same doses mentioned.

After the study was unblinded in August 2005 participants were given the option to add lenalidomide to their dexamethasone treatment regimen immediately or to add lenalidomide to their dexamethasone therapy at the time of disease progression.

The safety population includes all participants who received at least one dose of study drug regimen

Number of Participants With Adverse Events (AE)

Analysis not performed due to an insufficient number of participants with SRE

Time to First Symptomatic Skeletal-related Event (SRE) (Clinical Need for Radiation or Surgery to Bone)

Duration of response was calculated for responders and defined as the time from the first observation of a response (e.g., the first time that the appropriate decrease in M-protein level was observed for confirmed responders) to the first documented progression or relapse. Response duration was censored at the last adequate assessment showing evidence of no progression.

Intent to Treat population includes all participants who were randomized to study drug.

Kaplan-Meier Estimate of Duration of Response

Placebo PO daily on Days 1 to 28 of each 28 day cycle. Pulse dexamethasone 40 mg PO QD on Days 1-4, 9-12, and 17-20 of each 28-day cycle for Cycles 1 through 4. Beginning with Cycle 5, dexamethasone dosing schedule was reduced to 40 mg PO QD for Days 1-4 every 28 days.

Participants with documented progressive disease were permitted to crossover to receive lenalidomide at the same doses mentioned. After the study was unblinded in August 2005 participants were given the option to add lenalidomide to their dexamethasone treatment regimen immediately or to add lenalidomide to their dexamethasone therapy at the time of disease progression.

Kaplan-Meier Estimate of Time to Tumor Progression (TTP) (Later Cut-off Date of 02 Mar 2008)

Intent to Treat includes all participants who were randomized to study drug; a total of six ECOG scores were missing at the time of the Aug 2005 cut-off.

Time to First Worsening on the Eastern Cooperative Oncology Group (ECOG) Performance Scale

Intent to Treat includes all participants who were randomized to study drug; six ECOG scores were missing at the March 2008 cut-off.

Time to First Worsening on the Eastern Cooperative Oncology Group (ECOG) Performance Scale (Later Cut-off Date of 02 March 2008)

Kaplan-Meier Estimate of Duration of Response (Cut-off at a Later Date of 03 March 2008)

Lenalidomide 25 mg by mouth (PO) daily (QD) on Days 1 to 21 and a matching placebo capsule QD on Days 22 to 28 of each 28-day cycle.

Pulse dexamethasone 40mg PO QD on Days 1-4, 9-12, and 17-20 of each 28-day cycle for cycles 1 through 4. Beginning with Cycle 5, dexamethasone dosing schedule was reduced to 40mg PO QD on Days 1 to 4 every 28 days for the remaining cycles.

Lenalidomide Plus Dexamethasone (Len/Dex)

Placebo PO daily on Days 1 to 28 of each 28 day cycle.

Pulse dexamethasone 40mg PO QD on Days 1-4, 9-12, and 17-20 of each 28-day cycle for Cycles 1 through 4. Beginning with Cycle 5, dexamethasone dosing schedule was reduced to 40mg PO QD for Days 1-4 every 28 days.

Participants with documented progressive disease were permitted to crossover to receive lenalidomide at the same doses mentioned.

After the study was unblinded in August 2005 participants were given the option to add lenalidomide to their dexamethasone treatment regimen immediately or to add lenalidomide to their dexamethasone therapy at the time of disease progression.

Spots Global Cancer Trial Database for dexamethasone plus placebo