Regorafenib Tablets

Dosage Forms And Strengths

STIVARGA is a 40 mg, light pink, oval-shaped, film-coated tablet, debossed with 'BAYER' on one side and '40' on the other side.

Tablets are supplied in packages containing three bottles, with each bottle containing 28 tablets, for a total of 84 tablets per package (NDC 50419-171-03).

Storage And Handling

Store STIVARGA at 25°C (77°F); excursions are permitted from 15 to 30°C (59 to 86°F) [see USP Controlled Room Temperature].

Store tablets in the original bottle and do not remove the desiccant. Keep the bottle tightly closed after first opening.

Discard any unused tablets 7 weeks after opening the bottle. Dispose of unused tablets in accordance with local requirements.

Manufactured for Bayer HealthCare Pharmaceuticals Inc., Whippany, NJ 07981 USA. Revised: Apr 2017

The following serious adverse reactions are discussed elsewhere in the labeling:

• Hepatotoxicity [see WARNINGS AND PRECAUTIONS]
• Infections [(see WARNINGS AND PRECAUTIONS]
• Hemorrhage [see WARNINGS AND PRECAUTIONS]
• Gastrointestinal Perforation or Fistula [see WARNINGS AND PRECAUTIONS]
• Dermatological Toxicity [see WARNINGS AND PRECAUTIONS]
• Hypertension [see WARNINGS AND PRECAUTIONS]
• Cardiac Ischemia and Infarction [see WARNINGS AND PRECAUTIONS]
• Reversible Posterior Leukoencephalopathy Syndrome (RPLS) [see WARNINGS AND PRECAUTIONS]

Clinical Trials Experience

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rate observed in practice.

The data described in the WARNINGS AND PRECAUTIONS section reflect exposure to STIVARGA in more than 4800 patients who were enrolled in four randomized, placebo-controlled trials (n=1142), an expanded access program (CONSIGN, n=2864), or single arm clinical trials (single agent or in combination with other agents). There were 4518 patients who received STIVARGA as a single agent; the distribution of underlying malignancies was 80% CRC, 4% GIST, 10% HCC, 6% other solid tumors; and 74% were White, 11% Asian, and 15% race not known. Among these 4518 patients, 83% received STIVARGA for at least 21 days and 20% received STIVARGA for 6 months or longer.

In randomized placebo-controlled trials (CORRECT, GRID, RESORCE and CONCUR), the most frequently observed adverse drug reactions ( ≥ 20%) in patients receiving STIVARGA are pain (including gastrointestinal and abdominal pain), HFSR, asthenia/fatigue, diarrhea, decreased appetite/food intake, hypertension, infection, dysphonia, hyperbilirubinemia, fever, mucositis, weight loss, rash, and nausea.

Colorectal Cancer

The safety data described below, except where noted, are derived from a randomized (2:1), double-blind, placebo-controlled trial (CORRECT) in which 500 patients (median age 61 years; 61% men) with previously-treated metastatic colorectal cancer (CRC) received STIVARGA as a single agent at the dose of 160 mg daily for the first 3 weeks of each 4 week treatment cycle and 253 patients (median age 61 years; 60% men) received placebo. The median duration of therapy was 1.7 months (range 2 days, 10.8 months) for patients receiving STIVARGA. Due to adverse reactions, 61% of the patients receiving STIVARGA required a dose interruption and 38% of the patients had their dose reduced. Adverse reactions that resulted in treatment discontinuation occurred in 8.2% of STIVARGA-treated patients compared to 1.2% of patients who received placebo. Hand-foot skin reaction (HFSR) and rash were the most common reasons for permanent discontinuation of STIVARGA.

Table 1 provides the incidence of adverse reactions ( ≥ 10%) in patients in CORRECT.

Table 1: Adverse drug reactions reported in ≥ 10% of patients treated with STIVARGA in CORRECT and reported more commonly than in patients receiving placeboa

Table 2 provides laboratory abnormalities observed in CORRECT.

Table 2: Laboratory test abnormalities reported in CORRECT

Gastrointestinal Stromal Tumors

The safety data described below are derived from a randomized (2:1), double-blind, placebo-controlled trial (GRID) in which 132 patients (median age 60 years; 64% men) with previously-treated GIST received STIVARGA as a single agent at a dose of 160 mg daily for the first 3 weeks of each 4 week treatment cycle and 66 patients (median age 61 years; 64% men) received placebo. The median duration of therapy was 5.7 months (range 1 day, 11.7 months) for patients receiving STIVARGA. Dose interruptions for adverse events were required in 58% of patients receiving STIVARGA and 50% of patients had their dose reduced. Adverse reactions that resulted in treatment discontinuation were reported in 2.3% of STIVARGA-treated patients compared to 1.5% of patients who received placebo.

Table 3 provides the incidence of adverse reactions ( ≥ 10%) in patients in GRID.

Table 3: Adverse reactions reported in ≥ 10% patients treated with STIVARGA in GRID and reported more commonly than in patients receiving placeboa

Table 4 provides laboratory abnormalities observed in GRID.

Table 4: Laboratory test abnormalities reported in GRID

Hepatocellular Carcinoma

The safety data described below are derived from a randomized (2:1), double-blind, placebo-controlled trial (RESORCE) in which patients with previously-treated HCC received either STIVARGA (n=374) 160 mg orally on days 1-21 of each 4 week treatment cycle or placebo (n=193). The median age was 63 years, 88% were men, 98% had Child-Pugh A cirrhosis, 66% had an ECOG performance status (PS) of 0 and 34% had PS of 1. The median duration of therapy was 3.5 months (range 1 day to 29.4 months) for patients receiving STIVARGA. Of the patients receiving STIVARGA, 33% were exposed to STIVARGA for greater than or equal to 6 months and 14% were exposed to STIVARGA for greater than or equal to 12 months. Dose interruptions for adverse events were required in 58.3% of patients receiving STIVARGA and 48% of patients had their dose reduced. The most common adverse reactions requiring dose modification (interruption or dose reduction) were HFSR/PPES (20.6%), blood bilirubin increase (5.9%), fatigue (5.1%) and diarrhea (5.3%). Adverse reactions that resulted in treatment discontinuation were reported in 10.4% of STIVARGA-treated patients compared to 3.6% of patients who received placebo; the most common adverse reactions requiring discontinuation of STIVARGA were HFSR/PPES (1.9%) and AST increased (1.6%).

Table 5 provides the incidence of adverse reactions ( ≥ 10%) in patients in RESORCE.

Table 5: Adverse reactions reported in ≥ 10% of patients treated with STIVARGA in RESORCE and reported more commonly than in patients receiving placeboa

Other clinically significant adverse reactions observed in less than 10% of STIVARGA-treated patients were: alopecia (7%), hypothyroidism (6.4%), pancreatitis (1.6%), exfoliative rash (1.3%), tremor (1.3%), erythema multiforme (0.8%), myocardial ischemia (0.8%), gastrointestinal fistula (0.3%), and myocardial infarction (0.3%).

Table 6 provides laboratory abnormalities observed in RESORCE.

Table 6: Laboratory test abnormalities reported in RESORCE

Postmarketing Experience

The following adverse reaction has been identified during postapproval use of STIVARGA. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure:

• hypersensitivity reaction

Mechanism Of Action

Regorafenib is a small molecule inhibitor of multiple membrane-bound and intracellular kinases involved in normal cellular functions and in pathologic processes such as oncogenesis, tumor angiogenesis, metastasis and tumor immunity. In in vitro biochemical or cellular assays, regorafenib or its major human active metabolites M-2 and M-5 inhibited the activity of RET, VEGFR1, VEGFR2, VEGFR3, KIT, PDGFR-alpha, PDGFR-beta, FGFR1, FGFR2, TIE2, DDR2, TrkA, Eph2A, RAF-1, BRAF, BRAF V600E, SAPK2, PTK5, Abl and CSF1R at concentrations of regorafenib that have been achieved clinically. In in vivo models, regorafenib demonstrated anti-angiogenic activity in a rat tumor model and inhibition of tumor growth in several mouse xenograft models including some for human colorectal carcinoma, gastrointestinal stromal and hepatocellular carcinoma. Regorafenib also demonstrated anti-metastatic activity in a mouse xenograft model and two mouse orthotopic models of human colorectal carcinoma.

Pharmacodynamics

The effect of multiple doses of STIVARGA (160 mg once daily for 21 days) on the QTc interval was evaluated in an open-label, single-arm study in 25 patients with advanced solid tumors. No large changes in the mean QTc interval (i.e., > 20 msec) were detected in the study.

Pharmacokinetics

Following a single 160 mg dose of STIVARGA in patients with advanced solid tumors, regorafenib reaches a geometric mean peak plasma level (Cmax) of 2.5 μg/mL at a median time of 4 hours and a geometric mean area under the plasma concentration vs. time curve (AUC) of 70.4 μg*h/mL. The AUC of regorafenib at steady-state increases less than dose proportionally at doses greater than 60 mg. At steady-state, regorafenib reaches a geometric mean Cmax of 3.9 μg/mL and a geometric mean AUC of 58.3 μg*h/mL. The coefficient of variation of AUC and Cmax is between 35% and 44%.

The mean relative bioavailability of tablets compared to an oral solution is 69% to 83%.

In a food-effect study, 24 healthy men received a single 160 mg dose of STIVARGA on three separate occasions: under a fasted state, with a high-fat meal and with a low-fat meal. A high-fat meal (945 calories and 54.6 g fat) increased the mean AUC of regorafenib by 48% and decreased the mean AUC of the M-2 and M-5 metabolites by 20% and 51%, respectively, as compared to the fasted state. A low-fat meal (319 calories and 8.2 g fat) increased the mean AUC of regorafenib, M-2 and M-5 by 36%, 40% and 23%, respectively as compared to fasted conditions. STIVARGA was administered with a low-fat meal in the CORRECT and GRID studies [see DOSAGE AND ADMINISTRATION, Clinical Studies].

Regorafenib undergoes enterohepatic circulation with multiple plasma concentration peaks observed across the 24-hour dosing interval. Regorafenib is highly bound (99.5%) to human plasma proteins.

Following a single 160 mg oral dose of STIVARGA, the geometric mean (minimum to maximum) elimination half-lives for regorafenib and the M-2 metabolite in plasma are 28 hours (14 to 58 hours) and 25 hours (14 to 32 hours), respectively. M-5 has a longer mean (minimum to maximum) elimination half-life of 51 hours (32 to 70 hours).

Regorafenib is metabolized by CYP3A4 and UGT1A9. The main circulating metabolites of regorafenib measured at steady-state in human plasma are M-2 (N-oxide) and M-5 (N-oxide and N-desmethyl). Both metabolites have similar in vitro pharmacological activity and steady-state concentrations as regorafenib. M-2 and M-5 are highly protein bound (99.8% and 99.95%, respectively).

Approximately 71% of a radiolabeled dose was excreted in feces (47% as parent compound, 24% as metabolites) and 19% of the dose was excreted in urine (17% as glucuronides) within 12 days after administration of a radiolabeled oral solution at a dose of 120 mg.

Specific Populations

Age, sex, race and weight had no clinically meaningful effect on the pharmacokinetics of regorafenib.

Based on a population pharmacokinetic analysis, no clinically important differences in the mean total exposure of regorafenib, including M-2 and M-5, were noted amongst patients with normal liver function (total bilirubin and AST ≤ ULN, n=744), mild hepatic impairment (total bilirubin ≤ ULN and AST > ULN or total bilirubin > ULN to ≤ 1.5x ULN, n=437), and moderate hepatic impairment (total bilirubin > 1.5x to ≤ 3x ULN and any AST, n=36). The pooled analysis included 391 patients with HCC of whom 116, 249, and 26 were categorized as having normal liver function, mild, and moderate hepatic impairment, respectively. The pharmacokinetics of regorafenib were not evaluated in patients with severe hepatic impairment (total bilirubin > 3x ULN).

The pharmacokinetics of regorafenib, M-2, and M-5 was evaluated in 6 patients with severe renal impairment (CLcr 1529 mL/min) and 18 patients with normal/mild renal function (CLcr ≥ 60 mL/min) following the administration of STIVARGA at a dose of 160 mg daily for 21 days. No differences in the mean steady-state exposure of regorafenib, M-2, or M-5 were observed in patients with severe renal impairment compared to patients with normal renal function. The pharmacokinetics of regorafenib has not been studied in patients with end-stage renal disease on dialysis.

Drug Interaction Studies

Effect of Regorafenib on Cytochrome P450 Substrates: In vitro studies suggested that regorafenib is an inhibitor of CYP2C8, CYP2C9, CYP2B6, CYP3A4 and CYP2C19; M-2 is an inhibitor of CYP2C9, CYP2C8, CYP3A4 and CYP2D6, and M-5 is an inhibitor of CYP2C8. In vitro studies suggested that regorafenib is not an inducer of CYP1A2, CYP2B6, CYP2C19, and CYP3A4 enzyme activity.

Patients with advanced solid tumors received single oral doses of CYP substrates, 2 mg of midazolam (CYP3A4), 40 mg of omeprazole (CYP2C19) and 10 mg of warfarin (CYP2C9) or 4 mg of rosiglitazone (CYP2C8) one week before and two weeks after STIVARGA at a dose of 160 mg once daily. No clinically meaningful effect was observed in the mean AUC of rosiglitazone (N=12) or the mean omeprazole (N=11) plasma concentrations measured 6 hours after dosing or the mean AUC of midazolam (N=15). The mean AUC of warfarin (N=8) increased by 25% [see WARNINGS AND PRECAUTIONS].

Effect of CYP3A4 Strong Inducers on Regorafenib: Twenty-two healthy men received a single 160 mg dose of STIVARGA alone and then 7 days after starting rifampin. Rifampin, a strong CYP3A4 inducer, was administered at a dose of 600 mg daily for 9 days. The mean AUC of regorafenib decreased by 50% and mean AUC of M-5 increased by 264%. No change in the mean AUC of M-2 was observed [see DRUG INTERACTIONS].

Effect of CYP3A4 Strong Inhibitors on Regorafenib: Eighteen healthy men received a single 160 mg dose of STIVARGA alone and then 5 days after starting ketoconazole. Ketoconazole, a strong CYP3A4 inhibitor, was administered at a dose of 400 mg daily for 18 days. The mean AUC of regorafenib increased by 33% and the mean AUC of M-2 and M-5 both decreased by 93% [see DRUG INTERACTIONS].

Effect of Neomycin on Regorafenib: Twenty-seven healthy men received a single 160 mg dose of STIVARGA and then 5 days after starting neomycin. Neomycin, a non-absorbable antibiotic, was administered at a dose of 1 gram three times daily for 5 days. No clinically meaningful effect on the mean AUC of regorafenib was observed; however, the mean AUC of M-2 decreased by 76% and the mean AUC of M-5 decreased by 86%. The decreased exposure of M-2 and M-5 may result in a decreased efficacy of STIVARGA. The effects of other antibiotics on the exposure of regorafenib and its active metabolites have not been studied.

Effect of Regorafenib on UGT1A1 Substrates: In vitro studies showed that regorafenib, M-2, and M-5 competitively inhibit UGT1A9 and UGT1A1 at therapeutically relevant concentrations. Eleven patients received irinotecan-containing combination chemotherapy with STIVARGA at a dose of 160 mg. The mean AUC of irinotecan increased by 28% and the mean AUC of SN-38 increased by 44% when irinotecan was administered 5 days after the last of 7 daily doses of STIVARGA.

Effect of Regorafenib on BCRP Substrates: Administration of regorafenib (160 mg for 14 days) prior to administration of a single dose of rosuvastatin (5 mg), a BCRP substrate, resulted in a 3.8-fold increase in mean exposure (AUC) of rosuvastatin and a 4.6-fold increase in Cmax [see DRUG INTERACTIONS].

Animal Toxicology And/Or Pharmacology

In a chronic 26-week repeat dose study in rats there was a dose-dependent increase in the finding of thickening of the atrioventricular valve. At a dose that resulted in an exposure of approximately 12% of the human exposure at the recommended dose, this finding was present in half of the examined animals.

Clinical Studies

Colorectal Cancer

The clinical efficacy and safety of STIVARGA were evaluated in an international, multicenter, randomized (2:1), double-blind, placebo-controlled trial [Study “Patients with metastatic COloRectal cancer treated with REgorafenib or plaCebo after failure of standard Therapy” (CORRECT); NCT 01103323)] in 760 patients with previously-treated metastatic colorectal cancer. The major efficacy outcome measure was overall survival (OS); additional efficacy outcome measures included progression-free survival (PFS) and overall tumor response rate.

Patients were randomized to receive 160 mg regorafenib orally once daily (N=505) plus best supportive care (BSC) or placebo (N=255) plus BSC for the first 21 days of each 28-day cycle. STIVARGA was administered with a low-fat breakfast that contains less than 30% fat [see DOSAGE AND ADMINISTRATION , CLINICAL PHARMACOLOGY]. Treatment continued until disease progression or unacceptable toxicity.

Baseline demographics were: median age 61 years, 61% men, 78% White, and all patients had an ECOG performance status of 0 or 1. The primary sites of disease were colon (65%), rectum (29%), or both (6%). History of KRAS evaluation was reported for 729 (96%) patients; 430 (59%) of these patients were reported to have KRAS mutation. The median number of prior lines of therapy for metastatic disease was 3. All patients received prior treatment with fluoropyrimidine-, oxaliplatin-, and irinotecan-based chemotherapy, and with bevacizumab. All but one patient with KRAS mutation-negative tumors received panitumumab or cetuximab.

The addition of STIVARGA to BSC resulted in a statistically significant improvement in survival compared to placebo plus BSC (see Table 7 and Figure 1).

Table 7: Efficacy Results from CORRECT

Figure 1: Kaplan-Meier Curves of Overall Survival

Gastrointestinal Stromal Tumors

The efficacy and safety of STIVARGA were evaluated in an international, multicenter, randomized (2:1), double-blind, placebo-controlled trial [Study “GIST Regorafenib In progressive Disease” (GRID); NCT 01271712] in 199 patients with unresectable, locally advanced or metastatic gastrointestinal stromal tumor (GIST), who had been previously treated with imatinib mesylate and sunitinib malate. Randomization was stratified by line of therapy (third vs. four or more) and geographic region (Asia vs. rest of the world).

The major efficacy outcome measure of GRID was progression-free survival (PFS) based on disease assessment by independent radiological review using modified RECIST 1.1 criteria, in which lymph nodes and bone lesions were not target lesions and progressively growing new tumor nodule within a pre-existing tumor mass was progression. The key secondary outcome measure was overall survival.

Patients were randomized to receive 160 mg regorafenib orally once daily (N=133) plus best supportive care (BSC) or placebo (N=66) plus BSC for the first 21 days of each 28-day cycle. Treatment continued until disease progression or unacceptable toxicity. In GRID, the median age of patients was 60 years, 64% were men, 68% were White, and all patients had baseline ECOG performance status of 0 (55%) or 1 (45%). At the time of disease progression as assessed by central review, the study blind was broken and all patients were offered the opportunity to take STIVARGA at the investigator's discretion. Fifty-six (85%) patients randomized to placebo and 41 (31%) patients randomized to STIVARGA received open-label STIVARGA.

A statistically significant improvement in PFS was demonstrated among patients treated with STIVARGA compared to placebo (see Table 8 and Figure 2). There was no statistically significant difference in overall survival at the time of the planned interim analysis based on 29% of the total events for the final analysis.

Table 8: Efficacy Results for GRID

Figure 2: Kaplan-Meier Curves of Progression-Free Survival for GRID

Hepatocellular Carcinoma (HCC)

The clinical efficacy and safety of STIVARGA were evaluated in an international, multicenter, randomized (2:1), double-blind, placebo-controlled trial [Study “REgorafenib after SORafenib in patients with hepatoCEllular carcinoma” (RESORCE); NCT 01774344]. The study enrolled adults with Child-Pugh A and Barcelona Clinic Liver Cancer Stage Category B or C hepatocellular carcinoma, with documented disease progression following sorafenib. The median duration of previous sorafenib treatment was 7.8 months; patients who permanently discontinued sorafenib due to toxicity or were unable to tolerate sorafenib doses of 400 mg once daily were ineligible.

Patients were randomized to receive 160 mg regorafenib orally once daily plus best supportive care (BSC) or matching placebo plus BSC for the first 21 days of each 28-day cycle until disease progression or unacceptable toxicity. Randomization was stratified by geographical region (Asia vs rest of world), ECOG performance status (0 vs 1), alphafetoprotein levels ( < 400 ng/mL vs ≥ 400 ng/mL), extrahepatic disease (presence vs absence), and macrovascular invasion (presence vs absence). The major efficacy outcome measure was overall survival (OS). Additional outcome measures were progression-free survival (PFS), overall tumor response rate (ORR) and duration of response as assessed by investigators using RECIST 1.1 and using modified RECIST (mRECIST) for HCC. Patients continued therapy with STIVARGA until clinical or radiological disease progression or unacceptable toxicity.

The characteristics of the study population were a median age of 63 years (range 19 to 85 years); 88% male; 41% Asian, 36% White, and 21% not reported; 66% had ECOG performance status (PS) of 0 and 34% had ECOG PS of 1; 98% had Child-Pugh A and 2% had Child-Pugh B. Risk factors for underlying cirrhosis included hepatitis B (38%), alcohol use (25%), hepatitis C (21%), and non-alcoholic steato hepatitis (7%). Macroscopic vascular invasion or extra-hepatic tumor spread was present in 81% of patients. Barcelona Clinic Liver Cancer (BCLC) was stage C in 87% and stage B in 13% of patients. All patients received prior sorafenib and 61% received prior loco-regional transarterial embolization or chemoinfusion procedures.

Efficacy results are summarized in Table 9 and Figure 3 below.

Table 9: Efficacy Results from Study RESORCE

Figure 3: Kaplan-Meier Curve of Overall Survival from Study RESORCE

You should not use regorafenib if past use has caused severe bleeding, or if you have severe liver disease.

To make sure regorafenib is safe for you, tell your doctor if you have:

• liver disease;
• heart disease, high blood pressure;
• bleeding or blood clotting disorder such as hemophilia;
• a history of recent heart attack or stroke (including "mini-stroke"); or
• if you have recently had surgery.

FDA pregnancy category D. Do not use regorafenib if you are pregnant. It could harm the unborn baby. Use effective birth control, and tell your doctor if you become pregnant during treatment.

Use birth control to prevent pregnancy while you are receiving regorafenib, whether you are a man or a woman. Tell your doctor right away if a pregnancy occurs while either parent is taking regorafenib. Keep using birth control for at least 2 weeks after your treatment ends.

It is not known whether regorafenib passes into breast milk or if it could harm a nursing baby. Tell your doctor if you are breast-feeding a baby.