Antineoplastic Agent (Protein Kinase Inhibitor).
Sunitinib inhibits multiple receptor tyrosine kinases (RTKs) that are implicated in tumor growth, pathologic angiogenesis, and metastatic progression of cancer. Sunitinib was identified as an inhibitor of platelet-derived growth factor receptors (PDGFRα and PDGFRβ), VEGF 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 in 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
The clinical safety and efficacy of sunitinib has been studied in subjects with malignant GIST who were resistant to imatinib (i.e., those who experienced disease progression during or following treatment with imatinib); or intolerant to imatinib (i.e., those who experienced significant toxicity during treatment with imatinib that precluded further treatment); in subjects with metastatic renal cell carcinoma (MRCC); and in subjects with unresectable pNET.
Efficacy is based on time to tumor progression and an increase in survival in GIST.
Efficacy is based on progression-free survival (PFS) and objective response rates (ORR) for treatment-naïve and cytokine-refractory MRCC, respectively and on PFS for pNET.
Gastrointestinal Stromal Tumors (GIST): An initial open-label, dose-escalation study was conducted in subjects with GIST after failure of imatinib (median maximum daily dose 800 mg) due to resistance or intolerance. Ninety-seven subjects were enrolled at various doses and schedules; 55 subjects received 50 mg at the recommended treatment schedule of 4 weeks on/2 weeks off (Schedule 4/2). In this study, the median TTP and PFS were 34.0 weeks (95% confidence interval [CI]: 22.0, 46.0).
A Phase 3, randomized, double-blind, placebo-controlled study of sunitinib was conducted in subjects with GIST who were intolerant to, or had experienced disease progression during or following treatment with imatinib (median maximum daily dose 800 mg). In this study, 312 subjects were randomized (2:1) to receive either 50 mg sunitinib or placebo, orally once daily on Schedule 4/2 until disease progression or withdrawal from the study for another reason (207 subjects received sunitinib and 105 subjects received placebo). The primary efficacy endpoint of the study was TTP (as assessed by the Independent Review), defined as the time from randomization to first documentation of objective tumor progression. Secondary objectives included PFS, ORR, and overall survival (OS).
At the time of the pre-specified interim analysis, the median TTP on sunitinib was 28.9 weeks (95% CI: 21.3, 34.1) as assessed by the Investigator and 27.3 weeks (95% CI: 16.0, 32.1) as assessed by the Independent Review and was statistically significantly longer than the TTP of 5.1 weeks (95% CI: 4.4, 10.1) as assessed by the Investigator and 6.4 weeks (95% CI: 4.4, 10.0) as assessed by the Independent Review. The difference in OS was statistically in favor of sunitinib (hazard ratio [HR]: 0.491 [95% CI 0.290, 0.831]); the risk of death was 2 times higher in subjects in the placebo arm compared to the sunitinib arm.
After the positive interim analysis of efficacy and safety, at the recommendation of the independent Data and Safety Monitoring Board (DSMB), the study was unblinded and subjects on the placebo arm were offered open-label sunitinib treatment.
A total of 255 subjects received sunitinib in the open-label treatment phase of the study, including 99 subjects who were initially treated with placebo. In this final analysis, the placebo arm included those subjects randomized to placebo who subsequently received open-label sunitinib treatment.
The final analyses of primary and secondary endpoints of the study reaffirmed the results obtained at the time of the interim analysis, as shown in Table 1 as follows: See Table 1.
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Of those subjects randomized to the sunitinib arm, 62.7% survived longer than 1 year, 35.5% survived longer than 2 years, and 22.3% survived longer than 3 years.
Overall the study demonstrated a statistically significant and clinically meaningful improvement in TTP, the primary endpoint, for sunitinib plus best supportive care compared with placebo plus best supportive care.
Pancreatic Neuroendocrine Tumors (pNET): A Phase 2, open-label, multi-center study evaluated the efficacy and safety of single-agent Sunitinib malate (Sutent) 50 mg daily on Schedule 4/2 in subjects with advanced unresectable pNET. In a pancreatic islet cell tumor cohort of 66 subjects, a 17% ORR was observed.
A pivotal Phase 3, multi-center, international, randomized, double-blind placebo-controlled study of single-agent sunitinib was conducted in subjects with unresectable pNET.
Subjects were required to have documented progression, based on Response Evaluation Criteria in Solid Tumors (RECIST), within the prior 12 months and were randomized (1:1) to receive either 37.5 mg sunitinib once daily without a scheduled off-treatment period (n=86), or placebo (n=85).
The primary objective was to compare PFS in subjects receiving sunitinib versus subjects receiving placebo. Other endpoints included OS, ORR, patient-reported outcomes (PRO), and safety. Demographics were comparable between the sunitinib and placebo groups. Additionally, 49% of sunitinib subjects had non-functioning tumors versus 52% of placebo subjects and 92% of subjects in both arms had liver metastases. Use of somatostatin analogs was allowed in the study. A total of 66% of sunitinib subjects received prior systemic therapy compared with 72% of placebo subjects. In addition, 24% of sunitinib subjects had received somatostatin analogs compared with 22% of placebo subjects.
A clinically significant advantage in investigator-assessed PFS for sunitinib over placebo was observed. The median PFS was 11.4 months for the sunitinib arm compared to 5.5 months for the placebo arm [HR: 0.418 (95% CI: 0.263, 0.662), p-value=0.0001]. Similar results were observed when derived tumor response assessments based upon application of RECIST to investigator tumor measurements were used to determine disease progression, as shown in Table 2. A hazard ratio favoring sunitinib was observed in all subgroups of baseline characteristics evaluated, including an analysis by number of prior systemic therapies. A total of 29 subjects in the sunitinib arm and 24 in the placebo arm had received no prior systemic treatment; among these subjects, the hazard ratio for PFS was 0.365 (95% CI: 0.156, 0.857), p=0.0156. Similarly, among 57 subjects in the sunitinib arm (including 28 with 1 prior systemic therapy and 29 with 2 or more prior systemic therapies), and 61 subjects in the placebo arm (including 25 with 1 prior systemic therapy and 36 with 2 or more prior systemic therapies), the hazard ratio for PFS was 0.456 (95% CI: 0.264, 0.787), p=0.0036.
A sensitivity analysis of PFS was conducted in which progression was based upon investigator-reported tumor measurements and in which all subjects censored for reasons other than study termination were treated as having PFS events. This analysis provided a conservative estimate of the treatment effect of sunitinib and supported the primary analysis, demonstrating a hazard ratio of 0.507 (95% CI: 0.350, 0.733), p=0.000193. The pivotal study in pNET was terminated prematurely at the recommendation of an independent Drug Monitoring Committee, and the primary endpoint was based upon investigator assessment, both of which may have affected the estimates of the treatment effect.
In order to rule out bias in the investigator-based assessment of PFS, a blinded independent central review (BICR) of scans was performed; this review supported the investigator assessment, as shown in Table 2. The Kaplan-Meier curve for PFS is in Figure 1. (See Table 2 and Figure 1.)
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OS data were not mature at the time of the analysis. There were 9 deaths in the sunitinib arm and 21 deaths in the placebo arm. A statistically significant difference in ORR favoring sunitinib over placebo was observed.
Upon disease progression, subjects were unblinded and placebo subjects could have been offered access to open-label sunitinib in a separate extension study. As a result of the early study closure, remaining subjects were unblinded and offered access to open-label sunitinib in an extension study. A total of 59 subjects from the placebo arm received Sunitinib malate (Sutent) in an extension study.
Results from the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire (EORTC QLQ-C30) showed that the overall global health-related quality of life and the five functioning domains (physical, role, cognitive, emotional and social) were maintained for subjects on sunitinib treatment as compared to placebo with limited adverse symptomatic effects.
Renal cell carcinoma: Treatment-naïve MRCC: A Phase 3 randomized study comparing single-agent sunitinib with IFN-α was conducted in subjects with treatment-naïve MRCC. The primary objective was to compare PFS in subjects receiving sunitinib versus subjects receiving IFN-α. Secondary objectives included TTP, ORR, OS, safety and PROs. Seven hundred fifty (750) subjects were randomized (1:1) to receive either 50 mg sunitinib once daily on Schedule 4/2 or to receive IFN-α administered subcutaneously at 9 MIU three times a week. Subjects were treated until disease progression or withdrawal from the study for another reason.
The ITT population included 750 subjects, 375 randomized to sunitinib and 375 randomized to IFN-α. Baseline age, gender, race and Eastern Cooperative Oncology Group (ECOG) performance status were comparable and balanced between the sunitinib and IFN-α groups. Demographics and patient characteristics are shown in Table 3. 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 subjects had multiple (2 or more) metastatic sites at baseline (80% versus 77%, respectively). (See Table 3.)
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The median duration of treatment was 11.1 months (range: 0.4 - 46.1) for sunitinib treatment and 4.1 months (range: 0.1 - 45.6) for IFN-α treatment. Dose interruptions occurred in 202 (54%) subjects on sunitinib and 141 (39%) subjects on IFN-α. Dose reductions occurred in 194 (52%) subjects on sunitinib and 98 (27%) subjects on IFN-α. Discontinuation rates due to adverse reactions were 20% for sunitinib and 23% for IFN-α. Subjects were treated until disease progression or withdrawal from the study. The primary efficacy endpoint was PFS. A planned interim analysis showed a statistically significant advantage for sunitinib over IFN-α in the primary endpoint of PFS, with PFS for sunitinib more than double that of IFN-α (47.3 weeks and 22.0 weeks, respectively). The secondary endpoint of ORR was more than four times higher for sunitinib than IFN-α (27.5% and 5.3%, respectively). Data were not mature enough to determine the overall survival benefit; at the time of the interim analysis, 374 of 750 (50%) subjects enrolled continued on study, 248 of 375 (66%) on the sunitinib arm and 126 of 375 (34%) on the IFN-α arm.
At the time of the final analysis there was a statistically-significant advantage for sunitinib over IFN-α in the endpoint of PFS (see Table 4 and Figure 2). In the pre-specified stratification factors of lactate dehydrogenase (LDH) (>1.5 ULN versus ≤1.5 ULN), ECOG performance status (0 versus 1), and prior nephrectomy (yes versus no), the HR favored sunitinib over IFN-α. Core radiology assessment was discontinued after the primary endpoint had been met. The ORR as determined by the investigator's assessment was 46% (95% CI: 41, 51) for the sunitinib arm and 12% (95% CI: 9, 16) for the IFN-α arm [p < 0.001] (see Table 4).
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 262 of 750 subjects (35%) with no known risk factors, median PFS was 64.1 weeks in the sunitinib arm and 34.1 weeks in the IFN-α arm (HR: 0.447; 95% CI: 0.313, 0.640); for the 424 subjects (56%) with 1 or 2 risk factors, median PFS was 46.6 weeks in the sunitinib arm and 16.1 weeks in the IFN-α arm (HR: 0.547; 95% CI: 0.423, 0.707); and for the 47 subjects (6%) with ≥3 risk factors, median PFS was 12.1 weeks in the sunitinib arm and 5.7 weeks in the IFN-α arm (HR: 0.679; 95% CI: 0.330, 1.398).
As shown in Figure 3, sunitinib treatment was associated with longer survival compared to IFN-α. The median OS was 114.6 weeks for the sunitinib arm (95% CI: 100.1, 142.9) and 94.9 weeks for the IFN-α arm (95% CI: 77.7, 117.0) [HR: 0.821; 95% CI: 0.673, 1.001; p=0.0510 by log-rank test, p=0.013 by Wilcoxon test]. In the stratified analysis (LDH > versus ≤1.5 x ULN, ECOG performance status 0 versus ≥1, and absence or presence of prior nephrectomy), the HR was 0.818 (95% CI: 0.669, 0.999; p=0.049 by log-rank test). The median OS for the IFN-α arm included 25 subjects who discontinued IFN-α treatment because of disease progression and crossed over to treatment with sunitinib. Following discontinuation from the study, 213 subjects on the IFN-α arm received post-study cancer treatment, including 32% who received sunitinib; 182 subjects on the sunitinib arm received post-study cancer treatment, including 11% who received sunitinib. In post-hoc analyses censoring subjects who crossed over from IFN-α treatment to sunitinib treatment, median OS at the time of crossover was 114.6 versus 86.7 weeks (unstratified hazard ratio: 0.808; p=0.0361 by log-rank test; p=0.0081 by Wilcoxon test). When excluding subjects who received post-study anticancer therapy, median OS was 121.9 versus 61.3 weeks on sunitinib versus IFN-α (HR: 0.647; 95% CI: 0.482,0.867; p=0.0033 by log-rank test; p=0.0013 by Wilcoxon test). (See Table 4, Figures 2 and 3.)
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PRO were measured using the Functional Assessment of Cancer Therapy-Advanced Kidney Cancer Symptom Index (FKSI) and the Functional Assessment of Cancer Therapy-General (FACT-G). PRO endpoints include the FKSI score, its Disease Related Symptoms subscale (FKSI-DRS) score, the FACT-G total score and its four subscale scores (Physical Well-Being [PWB], Social/Family Well-Being [SWB], Emotional Well-Being [EWB] and Functional Well-Being [FWB]. The FKSI-DRS was pre-specified as the primary PRO endpoint and 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 subjects. Subjects treated with sunitinib reported statistically significant better FKSI-DRS index scores (p ≤0.0071), FKSI scores (p ≤0.0133), FACT-G total scores (p ≤0.0244), PWB (p ≤0.0208), and FWB (p ≤0.0044) than subjects treated with IFN-α at all post-baseline assessment time points up to 20 cycles of treatment. For PWB, SWB, and EWB, the statistical significance level increased above the 0.05 level after cycle 13, cycle 15 day 1, and cycle 10, respectively. Compared to the pre-established minimum clinically important differences for these endpoints, the between treatment differences for kidney cancer related symptoms (FKSI at all post-baseline timepoints and FKSI-DRS after cycle 3, day 1) and overall quality of life (FACT-G) at all post-baseline time points were considered clinically meaningful.
Cytokine-refractory MRCC: A Phase 2 study of sunitinib was conducted in subjects who were refractory to prior cytokine therapy with interleukin-2 or IFN-α. Sixty-three (63) subjects received a starting dose of 50 mg of sunitinib orally, once daily on Schedule 4/2. The primary efficacy endpoint was ORR based on RECIST. Secondary endpoints included assessment of TTP, PFS, duration of response (DR), and OS.
In this study the ORR was 36.5% (95% CI: 24.7%, 49.6%), the median TTP/PFS was 37.7 weeks (95% CI: 24.0, 46.4).
A confirmatory, open-label, single-arm, multi-center study evaluating the efficacy and safety of sunitinib was conducted in subjects with MRCC who were refractory to prior cytokine therapy. One hundred and six (106) subjects received at least one 50 mg dose of sunitinib on Schedule 4/2. The primary efficacy endpoint of this study was ORR. Secondary endpoints included TTP, PFS, DR, and OS.
In this study the ORR was 34.0% (95% CI: 25.0%, 43.8%). The median TTP, PFS, DR, and OS had not yet been reached.
The pharmacokinetics of sunitinib and sunitinib malate were evaluated in 135 healthy volunteers and 266 subjects with solid tumors.
Maximum plasma concentrations (Cmax
) are generally observed between 6 - 12 hours (Tmax
) following oral administration. Food has no effect on the bioavailability of sunitinib.
Binding of sunitinib and its primary active metabolite to human plasma protein in vitro
was 95% and 90%, respectively, with no apparent concentration dependence in the range of 100 - 4000 ng/mL. The apparent volume of distribution (Vd/F) for sunitinib was large (2230 L), indicating distribution into the tissues. In the dosing range of 25 - 100 mg, the area under the plasma concentration-time curve (AUC) and Cmax
increased proportionately with dose.
The calculated in vitro
Ki values for all CYP isoforms tested (CYP1A2, CYP2A6, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, CYP2E1, CYP3A4/5 AND CYP4A9/11) indicated that sunitinib and its primary active metabolite are unlikely to have any clinically relevant drug-drug interactions with drugs that may be metabolized by these enzymes.
studies indicate that sunitinib neither induces nor inhibits major CYP enzymes, including CYP3A4 (see Interactions).
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.
Excretion is primarily via feces (61%) with renal elimination of drug and metabolites 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 were not found in plasma. Total oral clearance (CL/F) ranged from 34-62 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 desethyl metabolite were approximately 40-60 hours, and 80 - 110 hours, respectively.
Pharmacokinetics in special patient groups:
Hepatic Insufficiency: Sunitinib and its primary metabolite are mainly metabolized by the liver. Systemic exposures after a single dose of sunitinib 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. Sunitinib was not studied in subjects with severe (Child-Pugh Class C) hepatic impairment.
Renal Insufficiency: Population pharmacokinetic analyses have shown that sunitinib pharmacokinetics were unaltered in subjects with calculated creatinine clearances in the range of 42-347 mL/min. Systemic exposures after a single dose of Sunitinib malate (Sutent) were similar in subjects with severe renal impairment (CLcr
<30 mL/min) compared to subjects with normal renal function (CLcr
>80 mL/min). Although sunitinib and its primary metabolite were not eliminated through hemodialysis in subjects with ESRD, the total systemic exposures were lower by 47% for sunitinib and 31% for its primary metabolite compared to subjects with normal renal function.
Cardiac Electrophysiology: QT interval prolongation was investigated in a Phase 1 trial with 24 evaluable subjects, aged 20-87 years, with advanced malignancies. At therapeutic plasma concentrations, the maximum QTcF mean change from baseline was 9.6 msec (90% CI upper limit of 15.1 msec). At approximately twice the therapeutic concentrations, the maximum QTcF mean change from baseline was 15.4 msec (90% CI upper limit of 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 version 3.0). No patient presented with a cardiac arrhythmia (see Precautions).
Plasma Pharmacokinetics: Following administration of a single oral dose in healthy volunteers, the elimination half-lives of sunitinib and its primary active metabolite are approximately 40-60 hours, and 80-110 hours, respectively. With repeated daily administration, sunitinib accumulates 3- to 4-fold while the primary active 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 are 62.9-101 ng/mL which are target concentrations predicted from preclinical data to inhibit receptor phosphorylation in vitro
and result in tumor stasis/growth reduction in vivo
. 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 all solid tumor populations tested and in healthy volunteers.
Population Pharmacokinetics: Population pharmacokinetic analyses of demographic data indicate that there are no clinically relevant effects of age, body weight, creatinine clearance, gender, race or ECOG score on the pharmacokinetics of sunitinib or the primary active metabolite.
Weight, performance status: Population pharmacokinetic analyses of demographic data indicate that no starting dose adjustments are necessary for weight or ECOG performance status.
Gender: Available data indicate that females could have about 30% lower apparent clearance (CL/F) of sunitinib than males; this difference, however, does not necessitate starting dose adjustments.
Toxicology: Preclinical Safety Data:
In rat and monkey repeated-dose toxicity studies up to 9-months duration, the primary target organ effects were identified in the gastrointestinal tract (emesis and diarrhea in monkeys); adrenal gland (cortical congestion and/or hemorrhage in rats and monkeys, with necrosis followed by fibrosis in rats); hemolymphopoietic system (bone marrow hypocellularity, and lymphoid depletion of thymus, spleen, and lymph node); exocrine pancreas (acinar cell degranulation with single-cell necrosis); salivary gland (acinar hypertrophy); bone joint (growth plate thickening); uterus (atrophy); and ovaries (decreased follicular development). All findings occurred at clinically relevant sunitinib plasma exposure levels. Additional effects, observed in other studies included: QTc interval prolongation, LVEF reduction, and testicular tubular atrophy, increased mesangial matrix in kidney, hemorrhage in GI tract and oral mucosa, and hypertrophy of anterior pituitary cells. Changes in the uterus (endometrial atrophy) and bone growth plate (physeal thickening or dysplasia of cartilage) are thought to be related to the pharmacological action of sunitinib. Most of these findings were reversible after 2 to 6 weeks without treatment.
Genotoxicity: The genotoxic potential of sunitinib was assessed in vitro
and in vivo
. Sunitinib was not mutagenic in bacteria using metabolic activation provided by rat liver. Sunitinib did not induce structural chromosome aberrations in human peripheral blood lymphocyte cells in vitro
. Polyploidy (numerical chromosome aberrations) was observed in human peripheral blood lymphocytes in vitro
, both in the presence and absence of metabolic activation. Sunitinib was not clastogenic in rat bone marrow in vivo
. The major active metabolite was not evaluated for genetic toxicity potential.
Carcinogenicity: In a 1-month, oral gavage dose-range finding study (0, 10, 25, 75, or 200 mg/kg/day) with continuous daily dosing in rasH2 transgenic mice, carcinoma and hyperplasia of Brunner's glands of the duodenum were observed at the highest dose (200 mg/kg/day) tested.
A 6-month, oral gavage carcinogenicity study (0, 8, 25, or 75 [reduced to 50] mg/kg/day), with daily dosing was conducted in rasH2 transgenic mice. Gastroduodenal carcinomas, an increased incidence of background hemangiosarcomas, and/or gastric mucosal hyperplasia were observed at doses of ≥25 mg/kg/day following 1- or 6-months duration (≥7.3 times the AUC in subjects administered the RDD).
In a 2-year rat carcinogenicity study (0, 0.33, 1, or 3 mg/kg/day), administration of sunitinib in 28-day cycles followed by 7-day dose-free periods resulted in increases in the incidence of pheochromocytomas and hyperplasia in the adrenal medulla of male rats given 3 mg/kg/day following >1 year of dosing (≥7.8 times the AUC in subjects administered the RDD). Brunner's glands carcinoma occurred in the duodenum at ≥1 mg/kg/day in females and at 3 mg/kg/day in males, and mucous cell hyperplasia was evident in the glandular stomach at 3 mg/kg/day in males, which occurred at ≥0.9, 7.8 and 7.8 times the AUC in subjects administered the RDD, respectively. The relevance to humans of the neoplastic findings observed in the mouse (rasH2 transgenic) and rat carcinogenicity studies with sunitinib treatment is unclear.
Reproductive and developmental toxicity: No effects on fertility were observed in male rats dosed for 58 days prior to mating with untreated females. No reproductive effects were observed in female rats treated for 14 days prior to mating with untreated males, at doses resulting in systemic exposures approximately 5 times the systemic exposure in humans. However, in repeated-dose toxicity studies performed in rats and monkeys, effects on female fertility were observed in the form of follicular atresia, degeneration of corpora lutea, endometrial changes in the uterus and decreased uterine and ovarian weights at clinically relevant systemic exposure levels. Moreover, in repeat-dose toxicity studies conducted in rats, effects on male fertility were observed in the form of tubular atrophy in the testes, reduction of spermatozoa in epididymides and colloid depletion in prostate and seminal vesicles at plasma exposure levels 25 times the systemic exposure in humans. Not all the effects observed in male rats were reversible at the end of the recovery period (6 weeks).
In rats, treatment-related embryo-fetal mortality was evident as significant reductions in the number of live fetuses, increased numbers of resorptions (early and total), corresponding increased post-implantation loss, and total litter loss in 8 of 28 pregnant females at plasma exposure levels 5.5 times the systemic exposure in humans. In rabbits, reductions in gravid uterine weights and number of live fetuses were due to increases in the number of resorptions (early and total), increases in post-implantation loss, and complete litter loss in 4 of 6 pregnant females at plasma exposure levels 3 times the systemic exposure in humans.
Sunitinib treatment in rats during organogenesis resulted in developmental effects at ≥5 mg/kg/day consisting of increased incidence of fetal skeletal malformations, predominantly characterized as retarded ossification of thoracic/lumbar vertebrae. Developmental effects in rats occurred at plasma exposure levels 6 times the systemic exposure in humans. In rabbits, developmental effects consisted of increased incidence of cleft lip at plasma exposure levels approximately equal to that observed in clinic, and cleft lip and cleft palate at plasma exposure levels 2.7 times the systemic exposure in humans.
A definitive rabbit embryo-fetal development toxicity study was not conducted as embryo-fetal effects were clearly demonstrated in the rat and reported in the preliminary study conducted in rabbits.