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Revlimid (Lenalidomide) - Description and Clinical Pharmacology

 
 



DESCRIPTION

REVLIMID, a thalidomide analogue, is an immunomodulatory agent with antiangiogenic and antineoplastic properties. The chemical name is 3-(4-amino-1-oxo 1,3-dihydro-2H-isoindol-2-yl) piperidine-2,6-dione and it has the following chemical structure:


3-(4-amino-1-oxo 1,3-dihydro-2H-isoindol-2-yl) piperidine-2,6-dione

The empirical formula for lenalidomide is C13H13N3O3, and the gram molecular weight is 259.3.

Lenalidomide is an off-white to pale-yellow solid powder. It is soluble in organic solvent/water mixtures, and buffered aqueous solvents. Lenalidomide is more soluble in organic solvents and low pH solutions. Solubility was significantly lower in less acidic buffers, ranging from about 0.4 to 0.5 mg/ml. Lenalidomide has an asymmetric carbon atom and can exist as the optically active forms S(-) and R(+), and is produced as a racemic mixture with a net optical rotation of zero.

REVLIMID is available in 2.5 mg, 5 mg, 10 mg, 15 mg, 20 mg and 25 mg capsules for oral administration. Each capsule contains lenalidomide as the active ingredient and the following inactive ingredients: lactose anhydrous, microcrystalline cellulose, croscarmellose sodium, and magnesium stearate. The 5 mg and 25 mg capsule shell contains gelatin, titanium dioxide and black ink. The 2.5 mg and 10 mg capsule shell contains gelatin, FD&C blue #2, yellow iron oxide, titanium dioxide and black ink. The 15 mg capsule shell contains gelatin, FD&C blue #2, titanium dioxide and black ink. The 20 mg capsule shell contains gelatin, FD&C blue #2, yellow iron oxide, titanium dioxide and black ink.

CLINICAL PHARMACOLOGY

Mechanism of action

Lenalidomide is an analogue of thalidomide with immunomodulatory, antiangiogenic, and antineoplastic properties. Lenalidomide inhibits proliferation and induces apoptosis of certain hematopoietic tumor cells including multiple myeloma, mantle cell lymphoma, and del (5q) myelodysplastic syndromes in vitro. Lenalidomide causes a delay in tumor growth in some in vivo nonclinical hematopoietic tumor models including multiple myeloma. Immunomodulatory properties of lenalidomide include activation of T cells and natural killer (NK) cells, increased numbers of NKT cells, and inhibition of pro-inflammatory cytokines (e.g., TNF-α and IL-6) by monocytes. In multiple myeloma cells, the combination of lenalidomide and dexamethasone synergizes the inhibition of cell proliferation and the induction of apoptosis.

Pharmacodynamics

The effect of lenalidomide on the QTc interval was evaluated in 60 healthy male subjects in a randomized, thorough QT study with placebo and positive controls. At a dose two times the maximum recommended dose, lenalidomide does not prolong the QTc interval to any clinically relevant extent. The largest upper bound of the 2-sided 90% CI for the mean differences between lenalidomide and placebo was below 10 ms.

Pharmacokinetics

Absorption

Lenalidomide is rapidly absorbed following oral administration. Following single and multiple doses of REVLIMID in patients with MM or MDS the maximum plasma concentrations occurred between 0.5 and 6 hours post-dose. The single and multiple dose pharmacokinetic disposition of lenalidomide is linear with AUC and Cmax values increasing proportionally with dose. Multiple dosing at the recommended dose-regimen does not result in drug accumulation.

Systemic exposure (AUC) of lenalidomide in MM and MDS patients with normal or mild renal function (CLcr ≥ 60 mL/min) is approximately 60% higher as compared to young healthy male subjects.

Administration of a single 25 mg dose of REVLIMID with a high-fat meal in healthy subjects reduces the extent of absorption, with an approximate 20% decrease in AUC and 50% decrease in Cmax. In the trials where the efficacy and safety were established for REVLIMID, the drug was administered without regard to food intake. REVLIMID can be administered with or without food.

Population pharmacokinetic analyses show that the oral absorption rate of lenalidomide in patients with MCL is similar to that observed in patients with MM or MDS.

Distribution

In vitro (14C)-lenalidomide binding to plasma proteins is approximately 30%.

Metabolism

Lenalidomide -undergoes limited metabolism. Unchanged lenalidomide is the predominant circulating component in humans. Two identified metabolites are hydroxy-lenalidomide and N-acetyl-lenalidomide; each constitutes less than 5% of parent levels in circulation.

Elimination

Elimination is primarily renal. Following a single oral administration of [14C]-lenalidomide (25 mg) to healthy subjects, approximately 90% and 4% of the radioactive dose is eliminated within ten days in urine and feces, respectively. Approximately 82% of the radioactive dose is excreted as lenalidomide in the urine within 24 hours. Hydroxy-lenalidomide and N-acetyl-lenalidomide represent 4.59% and 1.83% of the excreted dose, respectively. The renal clearance of lenalidomide exceeds the glomerular filtration rate.

The mean half-life of lenalidomide is 3 hours in healthy subjects and 3 to 5 hours in patients with MM, MDS or MCL.

Effect of Dexamethasone

Co-administration of single or multiple doses of dexamethasone (40 mg) has no clinically relevant effect on the multiple dose pharmacokinetics of REVLIMID (25 mg).

Specific Populations

Patients with Renal Impairment: The pharmacokinetics of lenalidomide were studied in patients with renal impairment due to nonmalignant conditions. In this study, 5 patients with mild renal impairment (creatinine clearance 57-74 mL/min), 6 patients with moderate renal impairment (creatinine clearance 33-46 mL/min), 6 patients with severe renal impairment (creatinine clearance 17-29 mL/min), and 6 patients with end stage renal disease requiring dialysis were administered a single oral 25-mg dose of REVLIMID. As a control group comparator, 7 healthy subjects of similar age with normal renal function (creatinine clearance 83-145 mL/min) were also administered a single oral 25-mg dose of REVLIMID. As creatinine clearance decreased from mild to severe impairment, half-life increased and drug clearance decreased linearly. Patients with moderate and severe renal impairment had a 3-fold increase in half-life and a 66% to 75% decrease in drug clearance compared to healthy subjects. Patients on hemodialysis (n=6) given a single, 25-mg dose of lenalidomide has an approximate 4.5-fold increase in half-life and an 80% decrease in drug clearance compared to healthy subjects. Approximately 40% of the administered dose was removed from the body during a single dialysis session.

In MM patients, those patients with mild renal impairment had an AUC 56% greater than those with normal renal function.

Adjustment of the starting dose of REVLIMID is recommended in patients with moderate or severe (CLcr < 60 mL/min) renal impairment and in patients on dialysis [see Dosage and Administration (2.4)].

Elderly Patients: No dedicated clinical studies have been conducted to evaluate pharmacokinetics of lenalidomide in the elderly. Population pharmacokinetic analyses included patients with ages ranging from 39 to 85 years old and show that age does not influence the disposition of lenalidomide.

Patients with Hepatic Disease: Population pharmacokinetic analyses included patients with mild hepatic impairment (N = 16, total bilirubin >1 to ≤ 1.5 x ULN or AST > ULN) and show that mild hepatic impairment does not influence the disposition of lenalidomide. There are no data available for patients with moderate to severe hepatic impairment.

Pediatric: No pharmacokinetic data are available in patients below the age of 18 years.

Other Intrinsic Factors: Population pharmacokinetic analyses show that body weight (33-135 kg), gender, race, and type of hematological malignancies (MM, MDS or MCL) do not have a clinically relevant effect on lenalidomide clearance in adult patients.

NONCLINICAL TOXICOLOGY

Carcinogenesis, mutagenesis, impairment of fertility

Carcinogenicity studies with lenalidomide have not been conducted.

Lenalidomide was not mutagenic in the bacterial reverse mutation assay (Ames test) and did not induce chromosome aberrations in cultured human peripheral blood lymphocytes, or mutations at the thymidine kinase (tk) locus of mouse lymphoma L5178Y cells. Lenalidomide did not increase morphological transformation in Syrian Hamster Embryo assay or induce micronuclei in the polychromatic erythrocytes of the bone marrow of male rats.

A fertility and early embryonic development study in rats, with administration of lenalidomide up to 500 mg/kg (approximately 200 times the human dose of 25 mg, based on body surface area) produced no parental toxicity and no adverse effects on fertility.

CLINICAL STUDIES

Multiple Myeloma

Two randomized studies (Studies 1 and 2) were conducted to evaluate the efficacy and safety of REVLIMID. These multicenter, multinational, double-blind, placebo-controlled studies compared REVLIMID plus oral pulse high-dose dexamethasone therapy to dexamethasone therapy alone in patients with multiple myeloma who had received at least one prior treatment. These studies enrolled patients with absolute neutrophil counts (ANC) ≥ 1000/mm3, platelet counts ≥ 75,000/mm3, serum creatinine ≤ 2.5 mg/dL, serum SGOT/AST or SGPT/ALT ≤ 3 x upper limit of normal (ULN), and serum direct bilirubin ≤ 2 mg/dL

In both studies, patients in the REVLIMID/dexamethasone group took 25 mg of REVLIMID orally once daily on Days 1 to 21 and a matching placebo capsule once daily on Days 22 to 28 of each 28-day cycle. Patients in the placebo/dexamethasone group took 1 placebo capsule on Days 1 to 28 of each 28-day cycle. Patients in both treatment groups took 40 mg of dexamethasone orally once daily on Days 1 to 4, 9 to 12, and 17 to 20 of each 28-day cycle for the first 4 cycles of therapy.

The dose of dexamethasone was reduced to 40 mg orally once daily on Days 1 to 4 of each 28-day cycle after the first 4 cycles of therapy. In both studies, treatment was to continue until disease progression.

In both studies, dose adjustments were allowed based on clinical and laboratory findings. Sequential dose reductions to 15 mg daily, 10 mg daily and 5 mg daily were allowed for toxicity [see Dosage and Administration (2.1)].

Table 8 summarizes the baseline patient and disease characteristics in the two studies. In both studies, baseline demographic and disease-related characteristics were comparable between the REVLIMID/dexamethasone and placebo/dexamethasone groups.

Table 8: Baseline Demographic and Disease-Related Characteristics – Studies 1 and 2
Study 1 Study 2

REVLIMID/Dex
N=177
Placebo/Dex
N=176
REVLIMID/Dex
N=176
Placebo/Dex
N=175
Patient Characteristics
Age (years)
    Median
    Min, Max
64
36, 86
62
37, 85
63
33, 84
64
40, 82
Sex
    Male
    Female
106 (60%)
71 (40%)
104 (59%)
72 (41%)
104 (59%)
72 (41%)
103 (59%)
72 (41%)
Race/Ethnicity
    White
    Other
141(80%)
36 (20%)
148 (84%)
28 (16%)
172 (98%)
4 (2%)
175(100%)
0 (0%)
ECOG Performance
Status 0-1
157 (89%) 168 (95%) 150 (85%) 144 (82%)
Disease Characteristics
Multiple Myeloma Stage (Durie-
Salmon)
                          I
                          II
                          III
3%
32%
64%
3%
31%
66%
6%
28%
65%
5%
33%
63%
B2-microglobulin
                          (mg/L)
    ≤ 2.5 mg/L
     >2.5 mg/L
52 (29%)
125 (71%)
51 (29%)
125 (71%)
51 (29%)
125 (71%)
48 (27%)
127 (73%)
Number of Prior Therapies
    1
    ≥ 2
38%
62%
38%
62%
32%
68%
33%
67%
Types of Prior Therapies
Stem Cell Transplantation 62% 61% 55% 54%
Thalidomide 42% 46% 30% 38%
Dexamethasone 81% 71% 66% 69%
Bortezomib 11% 11% 5% 4%
Melphalan 33% 31% 56% 52%
Doxorubicin 55% 51% 56% 57%

The primary efficacy endpoint in both studies was time to progression (TTP). TTP was defined as the time from randomization to the first occurrence of progressive disease.

Preplanned interim analyses of both studies showed that the combination of REVLIMID/dexamethasone was significantly superior to dexamethasone alone for TTP. The studies were unblinded to allow patients in the placebo/dexamethasone group to receive treatment with the REVLIMID/dexamethasone combination. For both studies, the extended follow-up survival data with crossovers were analyzed. In study 1, the median survival time was 39.4 months (95%CI: 32.9, 47.4) in REVLIMID/dexamethasone group and 31.6 months (95%CI: 24.1, 40.9) in placebo/dexamethasone group, with a hazard ratio of 0.79 (95% CI: 0.61-1.03). In study 2, the median survival time was 37.5 months (95%CI: 29.9, 46.6) in REVLIMID/dexamethasone group and 30.8 months (95%CI: 23.5, 40.3) in placebo/dexamethasone group, with a hazard ratio of 0.86 (95% CI: 0.65-1.14).

Table 9: TTP Results in Study 1 and Study 2
Study 1 Study 2
REVLIMID/Dex
N=177
Placebo/Dex
N=176
REVLIMID/Dex
N=176
Placebo/Dex N=175
TTP
Events n (%) 73 (41) 120 (68) 68 (39) 130 (74)
Median TTP in months [95% CI] 13.9
[9.5, 18.5]
4.7
[3.7, 4.9]
12.1
[9.5, NE]
4.7
[3.8, 4.8]
Hazard Ratio
[95% CI]
0.285
[0.210, 0.386]
0.324
[0.240, 0.438]
Log-rank Test p-value 3 <0.001 <0.001
Response
Complete Response (CR) n (%) 23 (13) 1 (1) 27 (15) 7 (4)
Partial Response (RR/PR) n (%) 84 (48) 33 (19) 77 (44) 34 (19)
Overall Response n (%) 107 (61) 34 (19) 104 (59) 41 (23)
p-value <0.001 <0.001
Odds Ratio [95% CI] 6.38
[3.95, 10.32]
4.72
[2.98, 7.49]

Figure 1: Kaplan-Meier Estimate of Time to Progression — Study 1

Figure 2: Kaplan-Meier Estimate of Time to Progression — Study 2

Myelodysplastic Syndromes (MDS) with a Deletion 5q Cytogenetic Abnormality

The efficacy and safety of REVLIMID were evaluated in patients with transfusion-dependent anemia in low- or intermediate-1- risk MDS with a 5q (q31-33) cytogenetic abnormality in isolation or with additional cytogenetic abnormalities, at a dose of 10 mg once daily or 10 mg once daily for 21 days every 28 days in an open-label, single-arm, multi-center study. The major study was not designed nor powered to prospectively compare the efficacy of the 2 dosing regimens. Sequential dose reductions to 5 mg daily and 5 mg every other day, as well as dose delays, were allowed for toxicity [Dosage and Administration (2.2)].

This major study enrolled 148 patients who had RBC transfusion dependent anemia. RBC transfusion dependence was defined as having received ≥ 2 units of RBCs within 8 weeks prior to study treatment. The study enrolled patients with absolute neutrophil counts (ANC) ≥ 500/mm3, platelet counts ≥ 50,000/mm3, serum creatinine ≤ 2.5 mg/dL, serum SGOT/AST or SGPT/ALT ≤ 3 x upper limit of normal (ULN), and serum direct bilirubin ≤ 2 mg/dL. Granulocyte colony-stimulating factor was permitted for patients who developed neutropenia or fever in association with neutropenia. Baseline patient and disease-related characteristics are summarized in Table 10.

Table 10: Baseline Demographic and Disease-Related Characteristics in the MDS Study

[a] IPSS Risk Category: Low (combined score = 0), Intermediate-1 (combined score = 0.5 to 1.0), Intermediate-2 (combined score = 1.5 to 2.0), High (combined score ≥ 2.5); Combined score = (Marrow blast score + Karyotype score + Cytopenia score)

[b] French-American-British (FAB) classification of MDS.

Overall
(N=148)
Age (years)
  Median 71.0
  Min, Max 37.0, 95.0
Gender n (%)
  Male 51 (34.5)
  Female 97 (65.5)
Race n (%)
  White 143 (96.6)
  Other 5 (3.4)
Duration of MDS (years)
  Median 2.5
  Min, Max 0.1, 20.7
Del 5 (q31-33) Cytogenetic Abnormality n (%)
  Yes 148 (100.0)
  Other cytogenetic abnormalities 37 (25.2)
IPSS Score [a] n (%)
  Low (0) 55 (37.2)
  Intermediate-1 (0.5-1.0) 65 (43.9)
  Intermediate-2 (1.5-2.0) 6 (4.1)
  High (≥2.5) 2 (1.4)
  Missing 20 (13.5)
FAB Classification [b] from central review n (%)
  RA 77 (52.0)
  RARS 16 (10.8)
  RAEB 30 (20.3)
  CMML 3 (2.0)

The frequency of RBC transfusion independence was assessed using criteria modified from the International Working Group (IWG) response criteria for MDS. RBC transfusion independence was defined as the absence of any RBC transfusion during any consecutive “rolling” 56 days (8 weeks) during the treatment period.

Transfusion independence was seen in 99/148 (67%) patients (95% CI [59, 74]). The median duration from the date when RBC transfusion independence was first declared (i.e., the last day of the 56-day RBC transfusion-free period) to the date when an additional transfusion was received after the 56-day transfusion-free period among the 99 responders was 44 weeks (range of 0 to >67 weeks). Ninety percent of patients who achieved a transfusion benefit did so by completion of three months in the study.

RBC transfusion independence rates were unaffected by age or gender.

The dose of REVLIMID was reduced or interrupted at least once due to an adverse event in 118 (79.7%) of the 148 patients; the median time to the first dose reduction or interruption was 21 days (mean, 35.1 days; range, 2-253 days), and the median duration of the first dose interruption was 22 days (mean, 28.5 days; range, 2-265 days). A second dose reduction or interruption due to adverse events was required in 50 (33.8%) of the 148 patients. The median interval between the first and second dose reduction or interruption was 51 days (mean, 59.7 days; range, 15-205 days) and the median duration of the second dose interruption was 21 days (mean, 26 days; range, 2-148 days).

Mantle Cell Lymphoma

A multicenter, single-arm, open-label trial of single-agent lenalidomide was conducted to evaluate the safety and efficacy of lenalidomide in patients with mantle cell lymphoma who have relapsed after or were refractory to bortezomib or a bortezomib-containing regimen. Patients with a creatinine clearance >60 mL/min were given lenalidomide at a dose of 25 mg once daily for 21 days every 28 days. Patients with a creatinine clearance ≥30 mL/min and <60 mL/min were given lenalidomide at a dose of 10 mg once daily for 21 days every 28 days. Treatment was continued until disease progression, unacceptable toxicity, or withdrawal of consent.

The trial included patients who were at least 18 years of age with biopsy-proven MCL with measurable disease by CT scan. Patients were required to have received prior treatment with an anthracycline or mitoxantrone, cyclophosphamide, rituximab, and bortezomib, alone or in combination. Patients were required to have documented refractory disease (defined as without any response of PR or better during treatment with bortezomib or a bortezomib-containing regimen), or relapsed disease (defined as progression within one year after treatment with bortezomib or a bortezomib-containing regimen). At enrollment patients were to have an absolute neutrophil counts (ANC) ≥1500/ mm3, platelet counts ≥ 60,000/mm3, serum SGOT/AST or SGPT/ALT ≤3x upper limit of normal (ULN) unless there was documented evidence of liver involvement by lymphoma, serum total bilirubin ≤1.5 x ULN except in cases of Gilbert’s syndrome or documented liver involvement by lymphoma, and calculated creatinine clearance (Cockcroft-Gault formula) ≥30 mL/min.

The median age was 67 years (43-83), 81% were male and 96% were Caucasian. The table below summarizes the baseline disease-related characteristics and prior anti-lymphoma therapy in the Mantle Cell Lymphoma trial.

Table 11: Baseline Disease-related Characteristics and Prior Anti –Lymphoma Therapy in Mantle Cell Lymphoma Trial

a)ECOG = Eastern Cooperative Oncology Group

b)MIPI = MCL International Prognostic Index

c) High tumor burden is defined as at least one lesion that is ≥5 cm in diameter or 3 lesions that are ≥3 cm in diameter

d) Bulky disease is defined as at least one lesion that is ≥7cm in the longest diameter

Baseline Disease Characteristics and Prior Anti -
Lymphoma Treatment
Total Patients
(N=134)
ECOG Performance Statusa n (%)
     0
     1
     2
     3
43 (32)
73 (54)
17 (13)
1 (<1)
Advanced MCL Stage, n (%)
     III
     IV
27 (20)
97 (72)
High or Intermediate MIPI Score b, n (%) 90 (67)
High Tumor Burdenc, n (%) 77 (57)
Bulky Diseased, n (%) 44 (33)
Extranodal Disease 101 (75)
Number of Prior Systemic Anti-Lymphoma
Therapies, n (%)

     Median (range)
     1
     2
     3
     ≥ 4
4 (2, 10)
0 (0)
29 (22)
34 (25)
71 (53)
Number of Subjects Who Received Prior Regimen
Containing, n (%):

     Anthracycline/mitoxantrone
     Cyclophosphamide
     Rituximab
     Bortezomib
133 (99)
133 (99)
134 (100)
134 (100)
Refractory to Prior Bortezomib 81 (60)
Refractory to Last Prior Therapy 74 (55)
Prior Autologous Bone Marrow or Stem Cell
Transplant, n (%)
39 (29)

The efficacy endpoints in the MCL trial were overall response rate (ORR) and duration of response (DOR). Response was determined based on review of radiographic scans by an independent review committee according to a modified version of the International Workshop Lymphoma Response Criteria (Cheson, 1999). The DOR is defined as the time from the initial response (at least PR) to documented disease progression. The efficacy results for the MCL population were based on all evaluable patients who received at least one dose of study drug and are presented in Table 12. The median time to response was 2.2 months (range 1.8 to 13 months).

Table 12: Response Outcomes in the Pivotal Mantle Cell Lymphoma Trial
Response Analyses (N = 133) N (%) 95% CI
Overall Response Rate (IWRC) (CR + CRu +PR)
     Complete Response (CR + CRu)
          CR
          CRu
     Partial Response (PR)
34 (26)
9 (7)
1 (1)
8 (6)
25 (19)
(18.4, 33.9)
(3.1, 12.5)
Duration of Response (months) Median 95% CI
Duration of Overall Response (CR + CRu + PR)     (N = 34) 16.6 (7.7, 26.7)

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