Sutent (Sunitinib Malate) - Description and Clinical Pharmacology

Indications and Usage (1.2)	7/2006
Warnings and Precautions, Left Ventricular Function (5.2)	7/2006
Warnings and Precautions, QT Interval Prolongation (5.3)	7/2006
Warnings and Precautions, Hemorrhagic Events (5.4)	7/2006
Warnings and Precautions, Hypertension (5.5)	7/2006

11 DESCRIPTION

SUTENT, an oral multi-kinase inhibitor targeting several receptor tyrosine kinases (RTK), is the malate salt of sunitinib. Sunitinib malate is described chemically as Butanedioic acid, hydroxy-, (2S)-, compound with N -[2-(diethylamino)ethyl]-5-[(Z)-(5-fluoro-1,2-dihydro-2-oxo- 3H -indol-3-ylidine)methyl]-2,4-dimethyl- 1H -pyrrole-3-carboxamide (1:1). The molecular formula is C₂₂H₂₇FN₄O₂• C₄H₆O₅ and the molecular weight is 532.6 Daltons. The chemical structure of sunitinib malate is:

Sunitinib malate is a yellow to orange powder with a pKa of 8.95. The solubility of sunitinib malate in aqueous media over the range pH 1.2 to pH 6.8 is in excess of 25 mg/mL. The log of the distribution coefficient (octanol/water) at pH 7 is 5.2.

SUTENT ^{(sunitinib malate) capsules are supplied as printed hard shell capsules containing sunitinib malate equivalent to 12.5 mg, 25 mg or 50 mg of sunitinib together with mannitol, croscarmellose sodium, povidone (K-25) and magnesium stearate as inactive ingredients.}

The orange gelatin capsule shells contain titanium dioxide, and red iron oxide. The caramel gelatin capsule shells also contain yellow iron oxide and black iron oxide. The printing ink contains shellac, propylene glycol, sodium hydroxide, povidone and titanium dioxide.

12 CLINICAL PHARMACOLOGY

12.1 Mechanism Of Action

Sunitinib malate is a small molecule that inhibits multiple RTKs, some of which are implicated in tumor growth, pathologic angiogenesis, and metastatic progression of cancer. Sunitinib was evaluated for its inhibitory activity against a variety of kinases (>80 kinases) and was identified as an inhibitor of platelet-derived growth factor receptors (PDGFRα and PDGFRβ), vascular endothelial growth factor receptors (VEGFR1, VEGFR2 and VEGFR3), stem cell factor receptor (KIT), Fms-like tyrosine kinase-3 (FLT3), colony stimulating factor receptor Type 1 (CSF-1R), and the glial cell-line derived neurotrophic factor receptor (RET). Sunitinib inhibition of the activity of these RTKs has been demonstrated in biochemical and cellular assays, and inhibition of function has been demonstrated in cell proliferation assays. The primary metabolite exhibits similar potency compared to sunitinib in biochemical and cellular assays.

Sunitinib inhibited the phosphorylation of multiple RTKs (PDGFRβ, VEGFR2, KIT) in tumor xenografts expressing RTK targets in vivo and demonstrated inhibition of tumor growth or tumor regression and/or inhibited metastases in some experimental models of cancer. Sunitinib demonstrated the ability to inhibit growth of tumor cells expressing dysregulated target RTKs (PDGFR, RET, or KIT) in vitro and to inhibit PDGFRβ- and VEGFR2-dependent tumor angiogenesis in vivo.

12.3 Pharmacokinetics

The pharmacokinetics of sunitinib and sunitinib malate have been evaluated in 135 healthy volunteers and in 266 patients with solid tumors.

Maximum plasma concentrations (C_max) of sunitinib are generally observed between 6 and 12 hours (T_max) following oral administration. Food has no effect on the bioavailability of sunitinib. Sunitinib may be taken with or without food.

Binding of sunitinib and its primary active metabolite to human plasma protein in vitro was 95% and 90%, respectively, with no concentration dependence in the range of 100 – 4000 ng/mL. The apparent volume of distribution (Vd/F) for sunitinib was 2230 L. In the dosing range of 25 – 100 mg, the area under the plasma concentration-time curve (AUC) and C_max increase proportionately with dose.

Sunitinib is metabolized primarily by the cytochrome P450 enzyme, CYP3A4, to produce its primary active metabolite, which is further metabolized by CYP3A4. The primary active metabolite comprises 23 to 37% of the total exposure. Elimination is primarily via feces. In a human mass balance study of [¹⁴C] sunitinib, 61% of the dose was eliminated in feces, with renal elimination accounting for 16% of the administered dose. Sunitinib and its primary active metabolite were the major drug-related compounds identified in plasma, urine, and feces, representing 91.5%, 86.4% and 73.8% of radioactivity in pooled samples, respectively. Minor metabolites were identified in urine and feces but generally not found in plasma. Total oral clearance (CL/F) ranged from 34 to 62 L/hr with an inter-patient variability of 40%.

Following administration of a single oral dose in healthy volunteers, the terminal half-lives of sunitinib and its primary active metabolite are approximately 40 to 60 hours and 80 to 110 hours, respectively. With repeated daily administration, sunitinib accumulates 3- to 4-fold while the primary metabolite accumulates 7- to 10-fold. Steady-state concentrations of sunitinib and its primary active metabolite are achieved within 10 to 14 days. By Day 14, combined plasma concentrations of sunitinib and its active metabolite ranged from 62.9 – 101 ng/mL. No significant changes in the pharmacokinetics of sunitinib or the primary active metabolite were observed with repeated daily administration or with repeated cycles in the dosing regimens tested.

The pharmacokinetics were similar in healthy volunteers and in the solid tumor patient populations tested, including patients with GIST and MRCC.

Pharmacokinetics in Special Populations

Population pharmacokinetic analyses of demographic data indicate that there are no clinically relevant effects of age, body weight, creatinine clearance, race, gender, or ECOG score on the pharmacokinetics of SUTENT or the primary active metabolite.

Pediatric Use: The pharmacokinetics of sunitinib have not been evaluated in pediatric patients.

Renal Insufficiency: No clinical studies were conducted in patients with impaired renal function. Studies that were conducted excluded patients with serum creatinine > 2.0 × ULN. Population pharmacokinetic analyses have shown that sunitinib pharmacokinetics were unaltered in patients with calculated creatinine clearances in the range of 42 –347 mL/min.

Hepatic Insufficiency: Systemic exposures after a single dose of SUTENT were similar in subjects with mild (Child-Pugh Class A) or moderate (Child-Pugh Class B) hepatic impairment compared to subjects with normal hepatic function.

12.4 Cardiac Electrophysiology

QT interval prolongation was investigated in a trial with 24 evaluable patients, aged 20–87 years, with advanced malignancies. At therapeutic plasma concentrations, the maximum QTcF (Fridericia's Correction) mean change from baseline was 9.6 msec (90% CI 15.1 msec). At approximately twice therapeutic concentrations, the maximum QTcF mean change from baseline was 15.4 msec (90% CI 22.4 msec). Moxifloxacin (400 mg) used as a positive control showed a 5.6 msec maximum mean QTcF change from baseline. No subjects experienced an effect on the QTc interval greater than Grade 2 (CTCAE v.3.0). No patient on this study presented with a cardiac arrhythmia (see 5 WARNINGS AND PRECAUTIONS).

13 NONCLINICAL TOXICOLOGY

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

Carcinogenicity studies with sunitinib have not been performed.

Sunitinib did not cause genetic damage when tested in in vitro assays (bacterial mutation [AMES Assay], human lymphocyte chromosome aberration) and an in vivo rat bone marrow micronucleus test.

Effects on the female reproductive system were identified in a 3-month repeat dose monkey study (2, 6, 12 mg/kg/day), where ovarian changes (decreased follicular development) were noted at 12 mg/kg/day (approximately 5.1 times the AUC in patients administered the RDD), while uterine changes (endometrial atrophy) were noted at ≥2 mg/kg/day (approximately 0.4 times the AUC in patients administered the RDD). With the addition of vaginal atrophy, the uterine and ovarian effects were reproduced at 6 mg/kg/day in the 9-month monkey study (0.3, 1.5 and 6 mg/kg/day administered daily for 28 days followed by a 14 day respite; the 6 mg/kg dose produced a mean AUC that was approximately 0.8 times the AUC in patients administered the RDD). A no effect level was not identified in the 3 month study; 1.5 mg/kg/day represents a no effect level in monkeys administered sunitinib for 9 months.

Although fertility was not affected in rats, SUTENT may impair fertility in humans. In female rats, no fertility effects were observed at doses of ≤5.0 mg/kg/day [(0.5, 1.5, 5.0 mg/kg/day) administered for 21 days up to gestational day 7; the 5.0 mg/kg dose produced an AUC that was approximately 5 times the AUC in patients administered the RDD], however significant embryolethality was observed at the 5.0 mg/kg dose. No reproductive effects were observed in male rats dosed (1, 3 or 10 mg/kg/day) for 58 days prior to mating with untreated females. Fertility, copulation, conception indices, and sperm evaluation (morphology, concentration, and motility) were unaffected by sunitinib at doses ≤10 mg/kg/day (the 10-mg/kg/day dose produced a mean AUC that was approximately 25.8 times the AUC in patients administered the RDD).

14 CLINICAL STUDIES

The clinical safety and efficacy of SUTENT have been studied in patients with gastrointestinal stromal tumor (GIST) after progression on or intolerance to imatinib mesylate, and in patients with metastatic renal cell carcinoma (MRCC).

14.1 Gastrointestinal Stromal Tumor

Study A

Study A was a two-arm, international, randomized, double-blind, placebo-controlled trial of SUTENT in patients with GIST who had disease progression during prior imatinib mesylate (imatinib) treatment or who were intolerant of imatinib. The primary objective was to compare time-to-tumor progression (TTP) in patients receiving SUTENT plus best supportive care versus patients receiving placebo plus best supportive care. Secondary objectives included progression-free survival (PFS), objective response rate (ORR), and overall survival (OS). Patients were randomized (2:1) to receive either 50 mg SUTENT or placebo orally, once daily, on a schedule of 4 weeks on treatment followed by 2 weeks off (Schedule 4/2) until disease progression or withdrawal from the study for another reason. Treatment was unblinded at the time of disease progression. Patients randomized to placebo were then offered crossover to open-label SUTENT, and patients randomized to SUTENT were permitted to continue treatment per investigator judgment.

The intent-to-treat (ITT) population included 312 patients. Two-hundred seven patients were randomized to the SUTENT arm, and 105 patients were randomized to the placebo arm. Baseline age, gender, race and ECOG performance status were comparable between the placebo and SUTENT groups. Prior exposure to imatinib was similar between the two study arms. Demographics and patient characteristics are shown in Table 4.

Table 4. Baseline Demographics in Study A

	GIST
	SUTENT (n=207)	Placebo (n=105)
Gender [N (%)]
Male	132 (64)	64 (61)
Female	75 (36)	41 (39)
Self-identified Race [N (%)]
White	183 (88)	92 (88)
Asian	10 (5)	5 (5)
Black	8 (4)	4 (4)
Not reported	6 (3)	4 (4)
Age Group [N (%)]
< 65 years	143 (69)	76 (72)
≥ 65 years	64 (31)	29 (28)
Performance Status [N (%)]
0	92 (44)	48 (46)
1	113 (55)	55 (52)
2	2 (1)	2 (2)
Prior Treatment [N (%)]
Surgery (other than biopsy)	194 (94)	98 (93)
Radiotherapy	16 (8)	16 (15)
Imatinib outcome [N (%)]
Intolerance	9 (4)	4 (4)
Progression within 6 months	36 (17)	17 (16)
Progression beyond 6 months	162 (78)	84 (80)

A planned interim efficacy and safety analysis was performed after 149 TTP events had occurred. There was a statistically significant advantage for SUTENT over placebo in the primary endpoint of TTP, as well as in the secondary endpoint of progression-free survival. Data were not mature enough to determine the overall survival benefit. Efficacy results are summarized in Table 5 and the Kaplan-Meyer curve for TTP is in Figure 1.

Table 5. GIST Efficacy Results from Study A (interim analysis)

Efficacy Parameter	SUTENT (N = 207)	Placebo (N = 105)	P-value (log-rank test)	HR (95% CI)
	CI=Confidence interval, HR=Hazard ratio, PR=Partial response
Time to Tumor ProgressionTime from randomization to progression; deaths prior to documented progression were censored at time of last radiographic evaluation [median, weeks (95% CI)]	27.3 (16.0, 32.1)	6.4 (4.4, 10.0)	<0.0001A comparison is considered statistically significant if the p-value is < 0.0042 (O'Brien Fleming stopping boundary)	0.33 (0.23, 0.47)
Progression-free SurvivalTime from randomization to progression or death due to any cause [median, weeks (95% CI)]	24.1 (11.1, 28.3)	6.0 (4.4, 9.9)	<0.0001	0.33 (0.24, 0.47)
Objective Response Rate (PR) [%, (95% CI)]	6.8 (3.7, 11.1)	0	0.006Pearson chi-square test

Figure 1. Kaplan-Meier Curve of TTP in Study A (Intent-to-Treat Population)

Study B

Study B was an open-label, multi-center, single-arm, dose-escalation study conducted in patients with GIST following progression on or intolerance to imatinib. Following identification of the recommended Phase 2 regimen (50 mg once daily on Schedule 4/2), 55 patients in this study received the 50 mg dose of SUTENT on treatment Schedule 4/2. Partial responses were observed in 5 of 55 patients [9.1% PR rate, 95% CI (3.0, 20.0)].

14.2 Renal Cell Carcinoma

Treatment-Naïve MRCC

A Phase 3 randomized study comparing single-agent SUTENT with IFN-α was conducted in patients with treatment-naïve MRCC. The primary objective was to compare PFS in patients receiving SUTENT versus patients receiving IFN-α. Secondary objectives included TTP, ORR, OS safety and patient reported outcomes (PRO). Seven hundred fifty (750) patients were randomized (1:1) to receive either 50 mg SUTENT once daily on Schedule 4/2 or to receive IFN-α administered subcutaneously at 9 MIU three times a week. Patients are treated until disease progression or withdrawal from the study for another reason.

The ITT population for this interim analysis included 750 patients, 375 randomized to SUTENT and 375 randomized to IFN-α. Baseline age, gender, race and ECOG performance status were comparable and balanced between the SUTENT and IFN-α groups. Demographics and patient characteristics are shown in Table 6. The most common site of metastases present at screening was the lung (78% versus 80%, respectively), followed by the lymph nodes (58% versus 53%, respectively) and bone (30% each arm); the majority of the patients had multiple (2 or more) metastatic sites at baseline (80% versus 77%, respectively).

Table 6. Baseline Demographics in Treatment-Naïve MRCC Study

	Treatment-Naïve MRCC
	SUTENT (n=375)	IFN-α (n=375)
Gender [n (%)]
Male	267 (71)	269 (72)
Female	108 (29)	106 (28)
Self-identified Race [n (%)]
White	354 (94)	340 (91)
Asian	7 (2)	12 (3)
Black	4 (1)	9 (2)
Not reported	10 (3)	14 (4)
Age Group [n (%)]
< 65 years	223 (59)	252 (67)
≥ 65 years	152 (41)	123 (33)
Performance Status [n (%)]
0	231 (62)	229 (61)
1	144 (38)	142 (38)
2	0 (0)	4 (1)Patients had ECOG performance status of 1 at screening which changed to 2 at baseline
Prior Treatment [n (%)]
Nephrectomy	340 (91)	335 (89)
Radiotherapy	53 (14)	54 (14)

A planned interim analysis showed a statistically significant advantage for SUTENT over IFN-α in the primary endpoint of PFS, with PFS for SUTENT more than double that of IFN-α (47.3 and 22.0 weeks, respectively). The secondary endpoint of ORR was more than four times higher for SUTENT than IFN-α (27.5% and 5.3%, respectively). Data were not mature enough to determine the overall survival benefit; at the time of this analysis, 374 of 750 patients enrolled (50%) continued on study, 248/375 (66%) on the SUTENT arm and 126/375 (34%) on the IFN-α arm. Efficacy results are summarized in Table 7 and the Kaplan-Meier curve for PFS is in Figure 2. The results were similar in the supportive analyses and they were robust when controlling for demographic (age, gender, race and performance status) and known risk factors. For 264 of 750 patients (35%) with no MSKCC risk factors,¹ median PFS was not yet reached in the SUTENT arm and was 34.3 weeks on the IFN-α arm (HR 0.371, 95% CI [0.214 – 0.643]); for the 421 patients (56%) with 1 or 2 risk factors, median PFS was 47.3 weeks on the SUTENT arm and 16.0 weeks on the IFN-α arm (HR 0.388, 95% CI [0.281 – 0.537]); and for the 48 patients (6%) with ≥3 risk factors, median PFS was 18.0 weeks on the SUTENT arm and 5.7 weeks on the IFN-α arm (HR 0.534 95% CI [0.231 – 1.234]).

Table 7. MRCC Efficacy Results

CI=Confidence interval, NA=Not applicable
	Treatment-Naive MRCC
Efficacy Parameter	SUTENT (n=375)	IFN-α (n=375)	P-value (log-rank test)	HR (95% CI)
Progression-Free SurvivalAssessed by blinded core radiology laboratory; 90 patients' scans had not been read at time of analysis [median, weeks (95% CI)]	47.3 (42.6, 50.7)	22.0 (16.4, 24.0)	<0.000001	0.415 (0.320, 0.539)
Time to Tumor Progression [median, weeks (95% CI)]	47.9 (45.9, 50.7)	22.3 (17.3, 31.3)	<0.0001	0.416 (0.318, 0.545)
Objective Response Rate [%, (95% CI)]	27.5 (23.0, 32.3)	5.3 (3.3, 8.1)	<0.0001	NA
Efficacy Parameter	Cytokine-Refractory MRCC
	Study 1 (N = 106)		Study 2 (N = 63)
Objective Response Rate [%, (95% CI)]	34.0 (25.0, 43.8)		36.5Assessed by investigators (24.7, 49.6)
Duration of Response [median, weeks (95% CI)]	Median DR has not yet been reached (42.0, Data not mature enough to determine upper confidence limit)		54 (34.3, 70.1)

Figure 2. Kaplan-Meier Curve of PFS in Treatment-Naïve MRCC Study (Intent-to-Treat Population)

The FKSI-DRS (Disease Related Symptom Scale of the Functional Assessment of Cancer Therapy - Advanced Kidney Cancer Symptom Index) was used to assess patient-reported kidney cancer related symptoms (lack of energy/fatigue, pain/bone pain, weight loss, shortness of breath, cough, fever, and hematuria) in 719 patients. Patients treated with SUTENT reported statistically significant (p<0.0001) better FKSI-DRS index scores than patients treated with IFN-α in all post-baseline assessment time points up to nine cycles of treatment.

Cytokine-Refractory MRCC

The use of single agent SUTENT in the treatment of cytokine-refractory MRCC was investigated in two single-arm, multi-center studies. All patients enrolled into these studies experienced failure of prior cytokine-based therapy. In Study 1, failure of prior cytokine therapy was based on radiographic evidence of disease progression defined by RECIST or World Health Organization (WHO) criteria during or within 9 months of completion of 1 cytokine therapy treatment (IFN-α, interleukin-2, or IFN-α plus interleukin-2; patients who were treated with IFN-α alone must have received treatment for at least 28 days). In Study 2, failure of prior cytokine therapy was defined as disease progression or unacceptable treatment-related toxicity. The primary endpoint for both studies was ORR. DR was also evaluated.

One hundred six patients were enrolled into Study 1, and 63 patients were enrolled into Study 2. Patients received 50 mg SUTENT on Schedule 4/2. Therapy was continued until the patients met withdrawal criteria or had progressive disease. The baseline age, gender, race and ECOG performance statuses of the patients were comparable between Studies 1 and 2. Approximately 86–94% of patients in the two studies were white. Men comprised 65% of the pooled population. The median age was 57 years and ranged from 24 to 87 years in the studies. All patients had an ECOG performance status <2 at the screening visit.

The baseline malignancy and prior treatment history of the patients were comparable between Studies 1 and 2. Across the two studies, 95% of the pooled population of patients had at least some component of clear-cell histology. All patients in Study 1 were required to have a histological clear-cell component. Most patients enrolled in the studies (97% of the pooled population) had undergone nephrectomy; prior nephrectomy was required for patients enrolled in Study 1. All patients had received one previous cytokine regimen. Metastatic disease present at the time of study entry included lung metastases in 81% of patients. Liver metastases were more common in Study 1 (27% vs. 16% in Study 2) and bone metastases were more common in Study 2 (51% vs. 25% in Study 1); 52% of patients in the pooled population had at least 3 metastatic sites. Patients with known brain metastases or leptomeningeal disease were excluded from both studies.

The ORR and DR data from Studies 1 and 2 are provided in Table 7. There were 36 PRs in Study 1 as assessed by a core radiology laboratory for an ORR of 34.0% (95% CI 25.0, 43.8). There were 23 PRs in Study 2 as assessed by the investigators for an ORR of 36.5% (95% CI 24.7, 49.6). The majority (>90%) of objective disease responses were observed during the first four cycles; the latest reported response was observed in cycle 10. DR data from Study 1 is premature as only 9 of 36 patients (25%) responding to treatment had experienced disease progression or died at the time of the data cutoff.