September 5, 2015
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Pomalyst

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Pomalyst

CLINICAL PHARMACOLOGY

Mechanism Of Action

Pomalidomide, an analogue of thalidomide, is an immunomodulatory agent with antineoplastic activity. In in vitro cellular assays, pomalidomide inhibited proliferation and induced apoptosis of hematopoietic tumor cells. Additionally, pomalidomide inhibited the proliferation of lenalidomide-resistant multiple myeloma cell lines and synergized with dexamethasone in both lenalidomide-sensitive and lenalidomide-resistant cell lines to induce tumor cell apoptosis. Pomalidomide enhanced T cell- and natural killer (NK) cell-mediated immunity and inhibited production of pro-inflammatory cytokines (e.g., TNF-α and IL-6) by monocytes. Pomalidomide demonstrated anti-angiogenic activity in a mouse tumor model and in the in vitro umbilical cord model.

Pharmacodynamics

The QTc prolongation potential of pomalidomide was evaluated in a single center, randomized, double-blind crossover study (N=72) using 4 mg pomalidomide, 20 mg pomalidomide, placebo, and 400 mg moxifloxacin (positive control). No significant QTc prolongation effect of pomalidomide was observed following pomalidomide doses of 4 and 20 mg.

Pharmacokinetics

Absorption

Following administration of single oral doses of POMALYST, the maximum plasma concentration (Cmax) for pomalidomide occurs at 2 and 3 hours postdose. The systemic exposure (AUC) of pomalidomide increases in an approximately dose proportional manner.

In patients with multiple myeloma who received POMALYST 4 mg daily alone or in combination with dexamethasone, pomalidomide steady-state drug exposure was characterized by AUC(T) of 400 ng•h/mL and Cmax of 75 ng/mL. Following multiple doses, pomalidomide has an accumulation ratio of 27% to 31%.

Distribution

Pomalidomide has a mean apparent volume of distribution (Vd/F) between 62 and 138 L at steady state. Pomalidomide is distributed in semen of healthy subjects at a concentration of approximately 67% of plasma level at 4 hours postdose (~Tmax) after 4 days of once-daily dosing at 2 mg. Human plasma protein binding ranges from 12% to 44% and is not concentration dependent. Pomalidomide is a substrate for P-glycoprotein (P-gp).

Metabolism

Pomalidomide is primarily metabolized in the liver by CYP1A2 and CYP3A4. In vitro, CYP1A2 and CYP3A4 were identified as the primary enzymes involved in the CYP-mediated hydroxylation of pomalidomide, with additional minor contributions from CYP2C19 and CYP2D6.

Elimination

Pomalidomide is eliminated with a median plasma half-life of approximately 9.5 hours in healthy subjects and approximately 7.5 hours in patients with multiple myeloma. Pomalidomide has a mean total body clearance (CL/F) of 7-10 L/h.

Following a single oral administration of [14C]-pomalidomide (2 mg) to healthy subjects, approximately 73% and 15% of the radioactive dose was eliminated in urine and feces, respectively, with approximately 2% and 8% of the radiolabeled dose eliminated unchanged as pomalidomide in urine and feces.

Drug Interactions

Drugs that Inhibit Pomalidomide Metabolism

CYP1A2 Inhibitors: The effect of CYP1A2 inhibitors, in the absence of a co-administered CYP3A4 and P-gp inhibitor, is unknown. However, co-administration of fluvoxamine (a strong CYP1A2 inhibitor) in the presence of ketoconazole (a strong CYP3A4 and P-gp inhibitor) to 12 healthy male subjects increased exposure (geometric mean AUCINF) to pomalidomide by 146% compared to pomalidomide administered alone [see DOSAGE AND ADMINISTRATION and DRUG INTERACTIONS].

Strong CYP3A4 and P-glycoprotein (P-gp) Inhibitors: Co-administration of ketoconazole (a strong CYP3A4 and P-gp inhibitor) in 16 healthy male subjects resulted in an increased exposure (geometric mean AUCINF) to pomalidomide of 19% compared to pomalidomide administered alone.

Drugs that Induce Pomalidomide Metabolism

Strong CYP1A2 Inducers: Co-administration of POMALYST with drugs that are CYP1A2 inducers has not been studied and may reduce pomalidomide exposure.

Strong CYP3A4 Inducers: Co-administration of carbamazepine to 16 healthy male subjects decreased exposure (geometric mean AUCINF) to pomalidomide by 21% compared to pomalidomide administered alone.

Dexamethasone: Co-administration of multiple doses of 4 mg POMALYST with 20 mg to 40 mg dexamethasone (a weak to moderate inducer of CYP3A4) to patients with multiple myeloma had no effect on the pharmacokinetics of pomalidomide compared with pomalidomide administered alone.

In Vitro Inhibition of Drug Metabolizing Enzymes and Transporters by Pomalidomide

Pomalidomide does not inhibit or induce CYP450 enzymes or transporters in vitro.

Clinical Studies

Multiple Myeloma

Trial 1 was a phase 2, multicenter, randomized open-label study in patients with relapsed multiple myeloma who were refractory to their last myeloma therapy and had received lenalidomide and bortezomib. Patients were considered relapsed if they had achieved at least stable disease for at least 1 cycle of treatment to at least 1 prior regimen and then developed progressive disease. Patients were considered refractory if they experienced disease progression on or within 60 days of their last therapy. A total of 221 patients were randomized to receive POMALYST alone or POMALYST with Low-dose Dex. In Trial 1, the safety and efficacy of POMALYST 4 mg, once daily for 21 of 28 days, until disease progression, were evaluated alone and in combination with Low-dose Dex (40 mg/day given only on Days 1, 8, 15, and 22 of each 28-day cycle for patients aged 75 years or younger, or 20 mg/day given only on Days 1, 8, 15, and 22 of each 28-day cycle for patients aged greater than 75 years). Patients in the POMALYST alone arm were allowed to add Low-dose Dex upon disease progression.

Table 4 summarizes the baseline patient and disease characteristics in Trial 1. The baseline demographics and disease characteristics were balanced and comparable between the study arms.

Table 4: Baseline Demographic and Disease-Related Characteristics – Trial 1

  POMALYST
(n=108)
POMALYST + Low-dose Dex
(n=113)
Patient Characteristics
Median age, years (range) 61 (37-88) 64 (34-88)
Age distribution, n (%)
   < 65 years 65 (60.2) 60 (53.1)
   ≥ 65 years 43 (39.8) 53 (46.9)
Sex, n (%)
  Male 57 (52.8) 62 (54.9)
  Female 51 (47.2) 51 (45.1)
Race/ethnicity, n (%)
  White 86 (79.6) 92 (81.4)
  Black or African American 16 (14.8) 17 (15)
  All other race 6 (5.6) 4 (3.6)
ECOG Performance, n (%)
  Status 0-1 95 (87.9) 100 (88.5)
Disease Characteristics
Number of prior therapies
  Median (min, max) 5 (2, 12) 5 (2, 13)
Prior transplant, n (%) 82 (75.9) 84 (74.3)
Refractory to bortezomib and lenalidomide, n (%) 64 (59.3) 69 (61.1)
Data cutoff: 01 April 2011

Table 5 summarizes the analysis results of overall response rate (ORR) and duration of response (DOR), based on assessments by the Independent Review Adjudication Committee for the treatment arms in Trial 1. ORR did not differ based on type of prior antimyeloma therapy.

Table 5: Trial 1 Results

  POMALYSTa
(n=108)
POMALYST + Low-dose Dex
(n=113)
Response
Overall Response Rate (ORR),b n (%) 8 (7.4) 33 (29.2)
95% CI for ORR (%) (3.3, 14.1) (21.0, 38.5)
Complete Response (CR), n (%) 0 (0.0) 1 (0.9)
Partial Response (PR), n (%) 8 (7.4) 32 (28.3)
Duration of Response (DOR)
Median, months NE 7.4
95% CI for DOR (months) NE (5.1, 9.2)
a Results are prior to the addition of dexamethasone.
b ORR = PR + CR per EBMT criteria.
CI, confidence interval; NE, not established (the median has not yet been reached).
Data cutoff: 01 April 2011

Trial 2 was a Phase 3 multi-center, randomized, open-label study, where POMALYST + Lowdose Dex therapy was compared to High-dose Dex in adult patients with relapsed and refractory multiple myeloma, who had received at least two prior treatment regimens, including lenalidomide and bortezomib, and demonstrated disease progression on or within 60 days of the last therapy. Patients with creatinine clearance ≥ 45mL/min qualified for the trial. A total of 455 patients were enrolled in the trial: 302 in the POMALYST + Low-dose Dex arm and 153 in the High-dose Dex arm. Patients in the POMALYST + Low-dose Dex arm were administered 4 mg POMALYST orally on Days 1 to 21 of each 28-day cycle. Dexamethasone (40 mg) was administered once per day on Days 1, 8, 15 and 22 of a 28-day cycle. Patients > 75 years of age started treatment with 20 mg dexamethasone using the same schedule. For the High-dose Dex arm, dexamethasone (40 mg) was administered once per day on Days 1 through 4, 9 through 12, and 17 through 20 of a 28-day cycle. Patients > 75 years of age started treatment with 20 mg dexamethasone using the same schedule. Treatment continued until patients had disease progression.

Baseline patient and disease characteristics were balanced and comparable between the study arms, as summarized in Table 6. Overall, 94% of patients had disease refractory to lenalidomide, 79% had disease refractory to bortezomib and 74% had disease refractory to both lenalidomide and bortezomib.

Table 6: Baseline Demographic and Disease-Related Characteristics – Trial 2

  POMALYST + Low-dose Dex
(N=302)
High-dose Dex
(N=153)
Patient Characteristics
Median Age, years (range) 64 (35, 84) 65 (35, 87)
Age Distribution n (%)
< 65 years 158 (52) 74 (48)
≥ 65 years 144 (48) 79 (52)
Sex n (%)
Male 181 (60) 87 (57)
Female 121 (40) 66 (43)
Race/Ethnicity n (%)
White 244 (81) 113 (74)
Black or African American 4 (1) 3 (2)
Asian 4 (1) 0 (0)
Other Race 2 (1) 2 (1)
Not Collected 48 (16) 35 (23)
ECOG Performance n (%)
Status 0 110 (36) 36 (24)
Status 1 138 (46) 86 (56)
Status 2 52 (17) 25 (16)
Status 3 0 (0) 3 (2)
Missing 2 (1) 3 (2)
Disease Characteristics
Number of Prior Therapies
Median, (Min, Max) 5 (2, 14) 5 (2, 17)
Prior stem cell transplant n (%) 214 (71) 105 (69)
Refractory to bortezomib and lenalidomide n (%) 225 (75) 113 (74)
Data cutoff: 01March 2013

Table 7 summarizes the progression free survival (PFS) and overall response rate (ORR) based on the assessment by the Independent Review Adjudication Committee (IRAC) review at the final PFS analysis and overall survival (OS) at the OS analysis. PFS was significantly longer with POMALYST + Low-dose Dex than High-dose Dex: HR 0.45 (95% CI: 0.35-0.59 p < 0.001). OS was also significantly longer with POMALYST + Low-dose Dex than High-dose Dex: HR 0.70 (95% CI: 0.54-0.92 p = 0.009).The Kaplan-Meier curves for PFS and OS for the ITT population are provided in Figures 1 and 2, respectively.

Table 7: Trial 2 Results

  POMALYST + Low-dose Dex
(N=302)
High-dose Dex
(N=153)
Progression Free Survival Time
Number (%) of events 164 (54.3) 103 (67.3)
Mediana (2-sided 95% CI) (months) 3.6 [3.0, 4.6] 1.8 [1.6, 2.1]
Hazard Ratio (Pom+LD-Dex:HD-Dex) 2-Sided 95% CIb 0.45 [0.35, 0.59]
Log-Rank Test 2-sided P-Valuec < 0.001
Overall Survival Timed
Number (%) of deaths 147 (48.7) 86 (56.2)
Mediana (2-sided 95% CI) (months) 12.4 [10.4, 15.3] 8.0[6.9, 9.0]
Hazard Ratio (Pom+LD-Dex:HD-Dex) 2-Sided 95% CIe 0.70 [0.54, 0.92]
Log-Rank Test 2-sided P-Value f g 0.009
Overall Response Rate, n (%) 71 (23.5) 6 (3.9)
  Complete Response 1 (0.3) 0
  Very Good Partial Response 8 (2.6) 1 (0.7)
  Partial Response 62 (20.5) 5 (3.3)
Note: CI=Confidence interval; HD-Dex=High dose dexamethasone; IRAC=Independent Review Adjudication Committee; LD-Dex=Low dose dexamethasone.
a The median is based on Kaplan-Meier estimate.
b Based on Cox proportional hazards model comparing the hazard functions associated with treatment groups, stratified by age ( ≤ 75 vs > 75), diseases population (refractory to both Lenalidomide and Bortezomib vs not refractory to both drugs), and prior number of antimyeloma therapy (=2 vs > 2), stratification factors for the trial.
c The p-value is based on a stratified log-rank test with the same stratification factors as the above Cox model.
d 53% of patients in the High-dose Dex arm subsequently received POMALYST.
e Based on Cox proportional hazards model (unstratified) comparing the hazard functions associated with treatment groups.
f The p-value is based on an unstratified log-rank test.
gAlpha control for PFS and OS.
Data cutoff: 07 Sep 2012 for PFS
Data cutoff: 01 Mar 2013 for OS and ORR

Figure 1: Progression Free Survival Based on IRAC Review of Response by IMWG Criteria (Stratified Log Rank Test) (ITT Population)

Progression Free Survival Based on IRAC Review of Response by IMWG Criteria - Illustration

Figure 2: Kaplan-Meier Curve of Overall Survival (ITT Population)

Kaplan-Meier Curve of Overall Survival - Illustration

Last reviewed on RxList: 5/12/2015
This monograph has been modified to include the generic and brand name in many instances.

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