WARNING: HEPATOTOXICITY

Transcription

1 Version.16 NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines ) Colon Cancer Overall management of Colon Cancer from diagnosis through recurrence is described in the NCCN Guidelines f Colon Cancer. Visit NCCN.g to view the complete list of treatment options and the complete library of NCCN Guidelines. Indication STIVARGA (regafenib) is indicated f the treatment of patients with metastatic colectal cancer (CRC) who have been previously treated with fluopyrimidine-, oxaliplatin- and irinotecan-based chemotherapy, an anti-vegf therapy, and, if KRAS wild type, an anti-egfr therapy. Imptant Safety Infmation WARNING: HEPATOTOXICITY Severe and sometimes fatal hepatotoxicity has been observed in clinical trials. Monit hepatic function pri to and during treatment. Interrupt and then reduce discontinue STIVARGA f hepatotoxicity as manifested by elevated liver function tests hepatocellular necrosis, depending upon severity and persistence. Please see additional Imptant Safety Infmation on pages 6 and 7, as well as accompanying full Prescribing Infmation, including Boxed Warning provided by Bayer HealthCare Pharmaceuticals, Inc.

2 Colon Cancer NCCN Guidelines Version.16 CONTINUUM OF CARE - CHEMOTHERAPY FOR ADVANCED OR METASTATIC DISEASE: 1 (PAGE 1 of 9) Patient appropriate f intensive therapy Initial Therapy FOLFOX CapeOX 4 FOLFOX + bevacizumab 5,6 CapeOX 4 + bevacizumab 5,6 FOLFOX + cetuximab panitumumab 6,7 (KRAS/NRAS WT gene only) 8,9 Additional options on COL-C of 9 through COL-C of 9 F patients not appropriate f intensive therapy, see COL-C 4 of 9 Subsequent Therapy FOLFIRI 1 FOLFIRI 1 + (bevacizumab 1 [preferred] 5,6 ziv-aflibercept 11,1 ramucirumab 11,1 ) Irinotecan 1 Irinotecan 1 + (bevacizumab 1 [preferred] 5,6 ziv-aflibercept 11,1 ramucirumab 11,1 ) FOLFIRI 1 + (cetuximab panitumumab) 6,1-16 (KRAS/NRAS WT gene only) 8 (Cetuximab panitumumab) 6,1-16 (KRAS/NRAS WT gene only) 8 + irinotecan 1 FOLFIRI 1 FOLFIRI 1 + (bevacizumab 1 [preferred] 5,6 ziv-aflibercept 11 ramucirumab) 1 Irinotecan 1 Irinotecan 1 + (bevacizumab 1 [preferred] 5,6 ziv-aflibercept 11,1 ramucirumab 11,1 ) (Cetuximab panitumumab) 6,1-16 (KRAS/NRAS WT gene only) 8 + irinotecan; 1 f patients not able to tolerate combination, consider single agent (cetuximab panitumumab) 6,1-16 (KRAS/NRAS WT gene only) 8 Regafenib 17 Trifluridine + tipiracil* Regafenib 17 Trifluridine + tipiracil* Regafenib 17 Trifluridine + tipiracil* *TAS-1 Regafenib 17 Trifluridine + tipiracil* Regafenib (if not given previously) Trifluridine + tipiracil* (if not given previously) Clinical trial Best supptive care 18 See footnotes on COL-C 5 of 9 Note: All recommendations are categy A unless otherwise indicated. Clinical Trials: NCCN believes that the best management of any cancer patient is in a clinical trial. Participation in clinical trials is especially encouraged. Version.16, 11/4/15 National Comprehensive Cancer Netwk, Inc. 15, All rights reserved. The NCCN Guidelines and this illustration may not be reproduced in any fm without the express written permission of NCCN. COL-C 1 OF 9 This is not the complete listing of treatment options. Visit NCCN.g to view the complete list of treatment options and the complete library of NCCN Guidelines. Please see STIVARGA (regafenib) Imptant Safety Infmation on pages 6 and 7, as well as accompanying full Prescribing Infmation, including Boxed Warning provided by Bayer HealthCare Pharmaceuticals, Inc.

3 Colon Cancer NCCN Guidelines Version.16 CONTINUUM OF CARE - CHEMOTHERAPY FOR ADVANCED OR METASTATIC DISEASE: 1 (PAGE of 9) Initial Therapy Subsequent Therapy Patient appropriate f intensive therapy FOLFIRI 1 FOLFIRI 1 + bevacizumab 5,6 FOLFIRI 1 + cetuximab panitumumab 6,7 (KRAS/NRAS WT gene only) 8,9 FOLFOX CapeOX 4 FOLFOX + bevacizumab 5,6 CapeOX 4 + bevacizumab 5,6 (Cetuximab panitumumab) 6,1-16 (KRAS/NRAS WT gene only) 8 + irinotecan; 1 f patients not able to tolerate combination, consider single agent (cetuximab panitumumab) 6,1-16 (KRAS/NRAS WT gene only) 8 FOLFOX CapeOX 4 FOLFOX + bevacizumab 5,6 CapeOX 4 + bevacizumab 5,6 (Cetuximab panitumumab) 6,1-16 (KRAS/NRAS WT gene only) 8 + irinotecan; 1 f patients not able to tolerate combination, consider single agent (cetuximab panitumumab) 6,1-16 (KRAS/NRAS WT gene only) 8 Regafenib 17 Trifluridine + tipiracil* FOLFOX CapeOX 4 Regafenib 17 Trifluridine + tipiracil* Regafenib 17 Trifluridine + tipiracil* Regafenib 17 Trifluridine + tipiracil* Regafenib (if not given previously) Trifluridine + tipiracil* (if not given previously) Clinical trial Best supptive care 18 Additional options on COL-C 1 of 9 through COL-C of 9 F patients not appropriate f intensive therapy, see COL-C 4 of 9 *TAS-1 See footnotes on COL-C 5 of 9 Note: All recommendations are categy A unless otherwise indicated. Clinical Trials: NCCN believes that the best management of any cancer patient is in a clinical trial. Participation in clinical trials is especially encouraged. Version.16, 11/4/15 National Comprehensive Cancer Netwk, Inc. 15, All rights reserved. The NCCN Guidelines and this illustration may not be reproduced in any fm without the express written permission of NCCN. COL-C OF 9 This is not the complete listing of treatment options. Visit NCCN.g to view the complete list of treatment options and the complete library of NCCN Guidelines. Please see STIVARGA (regafenib) Imptant Safety Infmation on pages 6 and 7, as well as accompanying full Prescribing Infmation, including Boxed Warning provided by Bayer HealthCare Pharmaceuticals, Inc.

4 Colon Cancer NCCN Guidelines Version.16 CONTINUUM OF CARE - CHEMOTHERAPY FOR ADVANCED OR METASTATIC DISEASE: 1 (PAGE 4 of 9) Initial Therapy Subsequent Therapy Patient not appropriate f intensive therapy Infusional 5-FU + leucovin Capecitabine ± bevacizumab Cetuximab (KRAS/NRAS WT gene only) 8,9 (categy B) Panitumumab (KRAS/NRAS WT gene only) 8,9 (categy B) Improvement in functional status No improvement in functional status Consider initial therapy as COL-C 1 of 9 through COL-C of 9 Best supptive care See NCCN Guidelines f Palliative Care See footnotes on COL-C 5 of 9 Note: All recommendations are categy A unless otherwise indicated. Clinical Trials: NCCN believes that the best management of any cancer patient is in a clinical trial. Participation in clinical trials is especially encouraged. Version.16, 11/4/15 National Comprehensive Cancer Netwk, Inc. 15, All rights reserved. The NCCN Guidelines and this illustration may not be reproduced in any fm without the express written permission of NCCN. COL-C 4 OF 9 This is not the complete listing of treatment options. Visit NCCN.g to view the complete list of treatment options and the complete library of NCCN Guidelines. Please see STIVARGA (regafenib) Imptant Safety Infmation on pages 6 and 7, as well as accompanying full Prescribing Infmation, including Boxed Warning provided by Bayer HealthCare Pharmaceuticals, Inc.

5 Colon Cancer NCCN Guidelines Version.16 CHEMOTHERAPY FOR ADVANCED OR METASTATIC DISEASE (PAGE 5 of 9) 1 F chemotherapy references, see Chemotherapy Regimens and References (COL-C 6-9). PET-CT should not be used to monit progress of therapy. CT with contrast MRI is recommended. Discontinuation of oxaliplatin should be strongly considered from FOLFOX CapeOX after 4 months of therapy ( sooner if significant neurotoxicity develops grade ) with other drugs maintained (fluopyrimidine + bevacizumab) until time of tum progression. Oxaliplatin may be reintroduced if it was discontinued previously f neurotoxicity rather than disease progression. Tournigand C, Cervantes A, Figer A, et al. OPTIMOX1: A randomized study of FOLFOX4 FOLFOX7 with oxaliplatin in a stop-and-go fashion in advanced colectal cancer - A GERCOR Study. J Clin Oncol 6;4:94-4. There are no data to suppt the routine use of Ca/Mg infusion to prevent oxaliplatin-related neurotoxicity and therefe it should not be done. 4 The majity of safety and efficacy data f this regimen have been developed in Europe, where a capecitabine starting dose of 1 mg/m twice daily f 14 days, repeated every 1 days, is standard. Evidence suggests that Nth American patients may experience greater toxicity with capecitabine (as well as with other fluopyrimidines) than European patients, and may require a lower dose of capecitabine. The relative efficacy of CapeOx with lower starting doses of capecitabine has not been addressed in large-scale randomized trials. 5 There is an increased risk of stroke and other arterial events, especially in those aged 65 years. The use of bevacizumab may interfere with wound healing. 6 Combination therapy involving cytotoxics, anti-egfrs, and anti-vegfs is not recommended. Hecht JR, Mitchell E, Chidiac T, et al. A randomized phase IIIB trial of chemotherapy, bevacizumab, and panitumumab compared with chemotherapy and bevacizumab alone f metastatic colectal cancer. J Clin Oncol 9;7:67-8. Tol J, Koopman M, Cats A, et al. Chemotherapy, bevacizumab, and cetuximab in metastatic colectal cancer. N Engl J Med 9;6(6): If cetuximab panitumumab is used as initial therapy, then neither cetuximab n panitumumab should be used in second subsequent lines of therapy. 8 See Principles of Pathologic Review (COL-A 4 of 5) - KRAS, NRAS, and BRAF Mutation Testing. 9 There are insufficient data to guide the use of anti-egfr therapy in the first-line setting with active chemotherapy based on BRAF V6E mutation status. 1 Irinotecan should be used with caution and with decreased doses in patients with Gilbert s disease elevated serum bilirubin. There is a commercially available test f UGT1A1. Guidelines f use in clinical practice have not been established. 11 There are no data to suggest activity of FOLFIRI-ziv-aflibercept FOLFIRIramucirumab in a patient who has progressed on FOLFIRI-bevacizumab, vice versa. Ziv-aflibercept and ramucirumab have only shown activity when given in conjunction with FOLFIRI in FOLFIRI-naïve patients. 1 Bevacizumab is the preferred anti-angiogenic agent based on toxicity and/ cost. 1 Cetuximab is indicated in combination with irinotecan-based therapy as single-agent therapy f patients who cannot tolerate irinotecan. 14 EGFR testing has no demonstrated predictive value; therefe, routine EGFR testing is not recommended. No patient should be included excluded from cetuximab panitumumab therapy on the basis of EGFR test results. 15 There are no data, n is there a compelling rationale, to suppt the use of panitumumab after clinical failure on cetuximab, the use of cetuximab after clinical failure on panitumumab. As such, the use of one of these agents after therapeutic failure on the other is not recommended. 16 Evidence increasingly suggests that BRAF V6E mutation makes response to panitumumab cetuximab, as single agents in combination with cytotoxic chemotherapy, highly unlikely. 17 Regafenib trifluridine + tipiracil are treatment options f patients who have progressed through all available regimens (eg, KRAS/NRAS mutant KRAS/ NRAS WT with previous exposure to anti-egfr inhibit.) 18 Single-agent combination therapy with capecitabine, mitomycin, gemcitabine has not been shown to be effective in this setting. 19 Infusional 5-FU is preferred. Patients with diminished creatinine clearance may require dose modification of capecitabine. 1 A treatment option f patients not able to tolerate oxaliplatin irinotecan. The use of single-agent capecitabine as a salvage therapy after failure on a fluopyrimidine-containing regimen has been shown to be ineffective; therefe, this is not recommended. Note: All recommendations are categy A unless otherwise indicated. Clinical Trials: NCCN believes that the best management of any cancer patient is in a clinical trial. Participation in clinical trials is especially encouraged. Version.16, 11/4/15 National Comprehensive Cancer Netwk, Inc. 15, All rights reserved. The NCCN Guidelines and this illustration may not be reproduced in any fm without the express written permission of NCCN. COL-C 5 OF 9 This is not the complete listing of treatment options. Visit NCCN.g to view the complete list of treatment options and the complete library of NCCN Guidelines. Please see STIVARGA (regafenib) Imptant Safety Infmation on pages 6 and 7, as well as accompanying full Prescribing Infmation, including Boxed Warning provided by Bayer HealthCare Pharmaceuticals, Inc.

6 Colon Cancer NCCN Guidelines Version.16 Indication From Bayer HealthCare Pharmaceuticals, Inc. STIVARGA (regafenib) is indicated f the treatment of patients with metastatic colectal cancer (CRC) who have been previously treated with fluopyrimidine-, oxaliplatin- and irinotecan-based chemotherapy, an anti-vegf therapy, and, if KRAS wild type, an anti-egfr therapy. Imptant Safety Infmation WARNING: HEPATOTOXICITY Severe and sometimes fatal hepatotoxicity has been observed in clinical trials. Monit hepatic function pri to and during treatment. Interrupt and then reduce discontinue STIVARGA f hepatotoxicity as manifested by elevated liver function tests hepatocellular necrosis, depending upon severity and persistence. Hepatotoxicity: Severe drug-induced liver injury with fatal outcome occurred in. of 1 STIVARGA-treated patients across all clinical trials. In metastatic colectal cancer (mcrc), fatal hepatic failure occurred in 1.6 of patients in the STIVARGA arm and.4 of patients in the placebo arm; all the patients with hepatic failure had metastatic disease in the liver. Liver Function Moniting: Obtain liver function tests (ALT, AST, and bilirubin) befe initiation of STIVARGA and monit at least every weeks during the first months of treatment. Thereafter, monit monthly me frequently as clinically indicated. Monit liver function tests weekly in patients experiencing elevated liver function tests until improvement to less than times the upper limit of nmal (ULN) baseline values. Temparily hold and then reduce permanently discontinue STIVARGA, depending on the severity and persistence of hepatotoxicity as manifested by elevated liver function tests hepatocellular necrosis. Hemrhage: STIVARGA caused an increased incidence of hemrhage. The overall incidence (Grades 1-5) was 1 with STIVARGA compared to 8 with placebo in mcrc. Fatal hemrhage occurred in 4 of 6 (.6) STIVARGA-treated patients and involved the respiraty, gastrointestinal, genitourinary tracts. Permanently discontinue STIVARGA in patients with severe life-threatening hemrhage and monit INR levels me frequently in patients receiving warfarin. Dermatological Toxicity: STIVARGA caused an increased incidence of hand-foot skin reaction (HFSR) (also known as palmar-plantar erythrodysesthesia [PPE]) and severe rash, frequently requiring dose modification. The overall incidence of HFSR was increased with STIVARGA compared to placebo in mcrc (45 vs 7). The incidence of Grade HFSR (17 vs ), Grade rash (6 vs <1), serious adverse reactions of erythema multifme (. vs ), and Stevens-Johnson syndrome (. vs ) was higher in STIVARGA-treated patients. Toxic epidermal necrolysis occurred in.17 of 1 STIVARGA-treated patients across all clinical trials. Withhold STIVARGA, reduce the dose, permanently discontinue depending on the severity and persistence of dermatologic toxicity. Hypertension: STIVARGA caused an increased incidence of hypertension ( with STIVARGA vs 8 with placebo in mcrc). Hypertensive crisis occurred in.5 of 1 STIVARGA-treated patients across all clinical trials. Do not initiate STIVARGA until blood pressure is adequately controlled. Monit blood pressure weekly f the first 6 weeks of treatment and then every cycle, me frequently, as clinically indicated. Temparily permanently withhold STIVARGA f severe uncontrolled hypertension. Continued on next page This is not the complete listing of treatment options. Visit NCCN.g to view the complete list of treatment options and the complete library of NCCN Guidelines. Please see STIVARGA (regafenib) Imptant Safety Infmation on next page, as well as accompanying full Prescribing Infmation, including Boxed Warning provided by Bayer HealthCare Pharmaceuticals, Inc.

7 Colon Cancer NCCN Guidelines Version.16 From Bayer HealthCare Pharmaceuticals, Inc., Continued Cardiac Ischemia and Infarction: STIVARGA increased the incidence of myocardial ischemia and infarction (1. with STIVARGA vs.4 with placebo). Withhold STIVARGA in patients who develop new acute cardiac ischemia infarction, and resume only after resolution of acute cardiac ischemic events if the potential benefits outweigh the risks of further cardiac ischemia. Reversible Posteri Leukoencephalopathy Syndrome (RPLS): RPLS occurred in 1 of 1 STIVARGA-treated patients across all clinical trials. Perfm an evaluation f RPLS in any patient presenting with seizures, headache, visual disturbances, confusion, altered mental function. Confirm the diagnosis of RPLS with MRI and discontinue STIVARGA in patients who develop RPLS. Gastrointestinal Perfation Fistula: Gastrointestinal perfation fistula occurred in.6 of 1 patients treated with STIVARGA across all clinical trials; this included 4 fatal events. Permanently discontinue STIVARGA in patients who develop gastrointestinal perfation fistula. Wound Healing Complications: Treatment with STIVARGA should be stopped at least weeks pri to scheduled surgery. Resuming treatment after surgery should be based on clinical judgment of adequate wound healing. STIVARGA should be discontinued in patients with wound dehiscence. Embryo-Fetal Toxicity: STIVARGA can cause fetal harm when administered to a pregnant woman. Use effective contraception during treatment and up to months after completion of therapy. If this drug is used during pregnancy, if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to the fetus. Nursing Mothers: Because many drugs are excreted in human milk and because of the potential f serious adverse reactions in nursing infants from STIVARGA, a decision should be made whether to discontinue nursing discontinue the drug, taking into account the imptance of the drug to the mother. Most Frequently Observed Adverse Drug Reactions in mcrc ( ): The most frequently observed adverse drug reactions ( ) in STIVARGA-treated patients vs placebo-treated patients in mcrc, respectively, were: asthenia/fatigue (64 vs 46), decreased appetite and food intake (47 vs 8), HFSR/PPE (45 vs 7), diarrhea (4 vs 17), mucositis ( vs 5), weight loss ( vs 1), infection (1 vs 17), hypertension ( vs 8), and dysphonia ( vs 6). This is not the complete listing of treatment options. Visit NCCN.g to view the complete list of treatment options and the complete library of NCCN Guidelines. Please see STIVARGA (regafenib) Imptant Safety Infmation on pri page, as well as accompanying full Prescribing Infmation, including Boxed Warning provided by Bayer HealthCare Pharmaceuticals, Inc.

8 Indication STIVARGA (regafenib) is indicated f the treatment of patients with metastatic colectal cancer (CRC) who have been previously treated with fluopyrimidine-, oxaliplatin- and irinotecan-based chemotherapy, an anti-vegf therapy, and, if KRAS wild type, an anti-egfr therapy. Imptant Safety Infmation WARNING: HEPATOTOXICITY Severe and sometimes fatal hepatotoxicity has been observed in clinical trials. Monit hepatic function pri to and during treatment. Interrupt and then reduce discontinue STIVARGA f hepatotoxicity as manifested by elevated liver function tests hepatocellular necrosis, depending upon severity and persistence. Please see additional Imptant Safety Infmation on pages 6 and 7, as well as accompanying full Prescribing Infmation, including Boxed Warning provided by Bayer HealthCare Pharmaceuticals, Inc. The National Comprehensive Cancer Netwk (NCCN ) appreciates that suppting companies recognize NCCN s need f autonomy in the development of the content of NCCN resources. All NCCN Guidelines are produced completely independently. NCCN Guidelines are not intended to promote any specific therapeutic modality. The distribution of this flash card is suppted by Bayer HealthCare Pharmaceuticals, Inc. 16 National Comprehensive Cancer Netwk GL-N PP-9-US-1976 /16

9 HIGHLIGHTS OF PRESCRIBING INFORMATION These highlights do not include all the infmation needed to use STIVARGA safely and effectively. See full prescribing infmation f STIVARGA. STIVARGA (regafenib) tablets, f al use Initial U.S. Approval: 1 WARNING: HEPATOTOXICITY See full prescribing infmation f complete boxed warning. Severe and sometimes fatal hepatotoxicity has been observed in clinical trials. (5.1) Monit hepatic function pri to and during treatment. (5.1) Interrupt and then reduce discontinue Stivarga f hepatotoxicity as manifested by elevated liver function tests hepatocellular necrosis, depending upon severity and persistence. (.) RECENT MAJOR CHANGES Dosage and Administration (.1) 4/ INDICATIONS AND USAGE Stivarga is a kinase inhibit indicated f the treatment of patients with: Metastatic colectal cancer (CRC) who have been previously treated with fluopyrimidine-, oxaliplatin- and irinotecan-based chemotherapy, an anti- VEGF therapy, and, if KRAS wild type, an anti-egfr therapy. (1.1) Locally advanced, unresectable metastatic gastrointestinal stromal tum (GIST) who have been previously treated with imatinib mesylate and sunitinib malate. (1.) DOSAGE AND ADMINISTRATION Recommended Dose: 16 mg ally, once daily f the first 1 days of each 8-day cycle. (.1) Take Stivarga with a low-fat meal. (.1, 1.) DOSAGE FORMS AND STRENGTHS mg film-coated tablets () CONTRAINDICATIONS None WARNINGS AND PRECAUTIONS Hemrhage: Permanently discontinue Stivarga f severe lifethreatening hemrhage. (5.) FULL PRESCRIBING INFORMATION: CONTENTS* WARNING: HEPATOTOXICITY 1 INDICATIONS AND USAGE 1.1 Colectal Cancer 1. Gastrointestinal Stromal Tums DOSAGE AND ADMINISTRATION.1 Recommended Dose. Dose Modifications DOSAGE FORMS AND STRENGTHS 4 CONTRAINDICATIONS 5 WARNINGS AND PRECAUTIONS 5.1 Hepatotoxicity 5. Hemrhage 5. Dermatological Toxicity 5.4 Hypertension 5.5 Cardiac Ischemia and Infarction 5.6 Reversible Posteri Leukoencephalopathy Syndrome (RPLS) 5.7 Gastrointestinal Perfation Fistula 5.8 Wound Healing Complications 5.9 Embryo-Fetal Toxicity 6 ADVERSE REACTIONS 6.1 Clinical Trials Experience 6. Postmarketing Experience 7 DRUG INTERACTIONS 7.1 Effect of Strong CYPA4 Inducers on Regafenib 7. Effect of Strong CYPA4 Inhibits on Regafenib Dermatological toxicity: Interrupt and then reduce discontinue Stivarga depending on severity and persistence of dermatologic toxicity. (5.) Hypertension: Temparily permanently discontinue Stivarga f severe uncontrolled hypertension. (5.4) Cardiac ischemia and infarction: Withhold Stivarga f new acute cardiac ischemia/infarction and resume only after resolution of acute ischemic events. (5.5) Reversible Posteri Leukoencephalopathy Syndrome (RPLS): Discontinue Stivarga. (5.6) Gastrointestinal perfation fistulae: Discontinue Stivarga. (5.7) Wound healing complications: Stop Stivarga befe surgery. Discontinue in patients with wound dehiscence. (5.8) Embryofetal toxicity: Can cause fetal harm. Advise women of potential risk to a fetus. (5.9, 8.1) ADVERSE REACTIONS The most common adverse reactions ( ) are asthenia/fatigue, HFSR, diarrhea, decreased appetite/food intake, hypertension, mucositis, dysphonia, infection, pain (not otherwise specified), decreased weight, gastrointestinal and abdominal pain, rash, fever, and nausea. (6) To rept SUSPECTED ADVERSE REACTIONS, contact Bayer HealthCare Pharmaceuticals Inc. at FDA at 1-8- FDA DRUG INTERACTIONS Strong CYPA4 inducers: Avoid strong CYPA4 inducers. (7.1) Strong CYPA4 inhibits: Avoid strong CYPA4 inhibits. (7.) USE IN SPECIFIC POPULATIONS Nursing Mothers: Discontinue drug nursing, taking into consideration the imptance of the drug to the mother. (8.) See 17 f PATIENT COUNSELING INFORMATION and FDAapproved patient labeling. Revised: 4/15 8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy 8. Nursing Mothers 8.4 Pediatric Use 8.5 Geriatric Use 8.6 Hepatic Impairment 8.7 Renal Impairment 8.8 Females and Males of Reproductive Potential 1 OVERDOSAGE 11 DESCRIPTION 1 CLINICAL PHARMACOLOGY 1.1 Mechanism of Action 1. Pharmacokinetics 1.6 Cardiac Electrophysiology 1 NONCLINICAL TOXICOLOGY 1.1 Carcinogenesis, Mutagenesis, Impairment of Fertility 1. Animal Toxicology and/ Pharmacology 14 CLINICAL STUDIES 14.1 Colectal Cancer 14. Gastrointestinal Stromal Tums 16 HOW SUPPLIED/STORAGE AND HANDLING 16.1 How Supplied 16. Stage and Handling 17 PATIENT COUNSELING INFORMATION *Sections subsections omitted from the full prescribing infmation are not listed. 1

10 FULL PRESCRIBING INFORMATION WARNING: HEPATOTOXICITY Severe and sometimes fatal hepatotoxicity has been observed in clinical trials [see Warnings and Precautions (5.1)]. Monit hepatic function pri to and during treatment [see Warnings and Precautions (5.1)]. Interrupt and then reduce discontinue Stivarga f hepatotoxicity as manifested by elevated liver function tests hepatocellular necrosis, depending upon severity and persistence [see Dosage and Administration (.)]. 1 INDICATIONS AND USAGE 1.1 Colectal Cancer Stivarga is indicated f the treatment of patients with metastatic colectal cancer (CRC) who have been previously treated with fluopyrimidine-, oxaliplatin- and irinotecan-based chemotherapy, an anti-vegf therapy, and, if KRAS wild type, an anti-egfr therapy. 1. Gastrointestinal Stromal Tums Stivarga is indicated f the treatment of patients with locally advanced, unresectable metastatic gastrointestinal stromal tum (GIST) who have been previously treated with imatinib mesylate and sunitinib malate. DOSAGE AND ADMINISTRATION.1 Recommended Dose The recommended dose is 16 mg regafenib (four 4 mg tablets) taken ally once daily f the first 1 days of each 8- day cycle. Continue treatment until disease progression unacceptable toxicity. Take Stivarga at the same time each day. Swallow tablet whole with water after a low-fat meal that contains less than 6 calies and less than fat [see Clinical Pharmacology (1.)]. Do not take two doses of Stivarga on the same day to make up f a missed dose from the previous day.. Dose Modifications Interrupt Stivarga f the following: NCI CTCAE Grade hand-foot skin reaction (HFSR) [palmar-plantar erythrodysesthesia (PPE)] that is recurrent does not improve within 7 days despite dose reduction; interrupt therapy f a minimum of 7 days f Grade HFSR Symptomatic Grade hypertension Any NCI CTCAE Grade 4 adverse reaction Reduce the dose of Stivarga to 1 mg: F the first occurrence of Grade HFSR of any duration After recovery of any Grade 4 adverse reaction F Grade aspartate aminotransferase (AST)/alanine aminotransferase (ALT) elevation; only resume if the potential benefit outweighs the risk of hepatotoxicity Reduce the dose of Stivarga to 8 mg: F re-occurrence of Grade HFSR at the 1 mg dose

11 After recovery of any Grade 4 adverse reaction at the 1 mg dose (except hepatotoxicity) Discontinue Stivarga permanently f the following: Failure to tolerate 8 mg dose Any occurrence of AST ALT me than times the upper limit of nmal (ULN) Any occurrence of AST ALT me than times ULN with concurrent bilirubin me than times ULN Re-occurrence of AST ALT me than 5 times ULN despite dose reduction to 1 mg F any Grade 4 adverse reaction; only resume if the potential benefit outweighs the risks DOSAGE FORMS AND STRENGTHS Stivarga is a 4 mg, light pink, oval shaped, film-coated tablet, debossed with BAYER on one side and 4 on the other side. 4 CONTRAINDICATIONS None 5 WARNINGS AND PRECAUTIONS 5.1 Hepatotoxicity Severe drug induced liver injury with fatal outcome occurred in. of 1 Stivarga-treated patients across all clinical trials. Liver biopsy results, when available, showed hepatocyte necrosis with lymphocyte infiltration. In Study 1, fatal hepatic failure occurred in 1.6 of patients in the regafenib arm and in.4 of patients in the placebo arm; all the patients with hepatic failure had metastatic disease in the liver. In Study, fatal hepatic failure occurred in.8 of patients in the regafenib arm [see Adverse Reactions (6.1)]. Obtain liver function tests (ALT, AST and bilirubin) befe initiation of Stivarga and monit at least every two weeks during the first months of treatment. Thereafter, monit monthly me frequently as clinically indicated. Monit liver function tests weekly in patients experiencing elevated liver function tests until improvement to less than times the ULN baseline. Temparily hold and then reduce permanently discontinue Stivarga depending on the severity and persistence of hepatotoxicity as manifested by elevated liver function tests hepatocellular necrosis [see Dosage and Administration (.)]. 5. Hemrhage Stivarga caused an increased incidence of hemrhage. The overall incidence (Grades 1-5) was 1 and 11 in Stivargatreated patients compared to 8 and in placebo-treated patients in Studies 1 and. Fatal hemrhage occurred in 4 of 6 (.6) of Stivarga-treated patients in Studies 1 and and involved the respiraty, gastrointestinal, genitourinary tracts. Permanently discontinue Stivarga in patients with severe life-threatening hemrhage. Monit INR levels me frequently in patients receiving warfarin [see Clinical Pharmacology (1.)].

12 5. Dermatological Toxicity Stivarga caused increased incidences of adverse reactions involving the skin and subcutaneous tissues (7 versus 4 in Study 1 and 78 versus 4 in Study ), including hand-foot skin reaction (HFSR) also known as palmar-plantar erythrodysesthesia (PPE), and severe rash requiring dose modification. The overall incidence of HFSR was higher in Stivarga-treated patients, (45 versus 7 in Study 1 and 67 versus 1 in Study ), than in the placebo-treated patients. Most cases of HFSR in Stivarga-treated patients appeared during the first cycle of treatment (69 and 71 of patients who developed HFSR in Study 1 and Study, respectively). The incidence of Grade HFSR (17 versus in Study 1 and versus in Study ), Grade rash (6 versus <1 in Study 1 and 7 versus in Study ), serious adverse reactions of erythema multifme (. vs. in Study 1) and Stevens Johnson Syndrome (. vs. in Study 1) was higher in Stivarga-treated patients [see Adverse Reactions (6.1)]. Toxic epidermal necrolysis occurred in.17 of 1 Stivarga-treated patients across all clinical trials. Withhold Stivarga, reduce the dose, permanently discontinue Stivarga depending on the severity and persistence of dermatologic toxicity [see Dosage and Administration (.)]. Institute supptive measures f symptomatic relief. 5.4 Hypertension Stivarga caused an increased incidence of hypertension ( versus 8 in Study 1 and 59 versus 7 in Study ) [see Adverse Reactions (6.1)]. Hypertensive crisis occurred in.5 of 1 Stivarga-treated patients across all clinical trials. The onset of hypertension occurred during the first cycle of treatment in most patients who developed hypertension (7 in Study 1 and Study ). Do not initiate Stivarga unless blood pressure is adequately controlled. Monit blood pressure weekly f the first 6 weeks of treatment and then every cycle, me frequently, as clinically indicated. Temparily permanently withhold Stivarga f severe uncontrolled hypertension [see Dosage and Administration (.)]. 5.5 Cardiac Ischemia and Infarction Stivarga increased the incidence of myocardial ischemia and infarction in Study 1 (1. versus.4) [see Adverse Reactions (6.1)]. Withhold Stivarga in patients who develop new acute onset cardiac ischemia infarction. Resume Stivarga only after resolution of acute cardiac ischemic events, if the potential benefits outweigh the risks of further cardiac ischemia. 5.6 Reversible Posteri Leukoencephalopathy Syndrome (RPLS) Reversible Posteri Leukoencephalopathy Syndrome (RPLS), a syndrome of subctical vasogenic edema diagnosed by characteristic finding on MRI, occurred in one of 1 Stivarga-treated patients across all clinical trials. Perfm an evaluation f RPLS in any patient presenting with seizures, headache, visual disturbances, confusion altered mental function. Discontinue Stivarga in patients who develop RPLS. 5.7 Gastrointestinal Perfation Fistula Gastrointestinal perfation fistula occurred in.6 of 1 patients treated with Stivarga across all clinical trials; this included four fatal events. In Study,.1 (4/188) of Stivarga-treated patients who were treated during the blinded open-label ption of the study developed gastrointestinal fistula perfation; of these, two cases of gastrointestinal perfation were fatal. Permanently discontinue Stivarga in patients who develop gastrointestinal perfation fistula. 4

13 5.8 Wound Healing Complications No fmal studies of the effect of regafenib on wound healing have been conducted. Since vascular endothelial growth fact recept (VEGFR) inhibits such as regafenib can impair wound healing, treatment with regafenib should be stopped at least weeks pri to scheduled surgery. The decision to resume regafenib after surgery should be based on clinical judgment of adequate wound healing. Regafenib should be discontinued in patients with wound dehiscence. 5.9 Embryo-Fetal Toxicity Stivarga can cause fetal harm when administered to a pregnant woman. Regafenib was embryolethal and teratogenic in rats and rabbits at exposures lower than human exposures at the recommended dose, with increased incidences of cardiovascular, genitourinary, and skeletal malfmations. If this drug is used during pregnancy, if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to a fetus [see Use in Specific Populations (8.1)]. 6 ADVERSE REACTIONS The following serious adverse reactions are discussed elsewhere in the labeling: Hepatotoxicity [See Warnings and Precautions (5.1)] Hemrhage [See Warnings and Precautions (5.)] Dermatological Toxicity [See Warnings and Precautions (5.)] Hypertension [See Warnings and Precautions (5.4)] Cardiac Ischemia and Infarction [See Warnings and Precautions (5.5)] Reversible Posteri Leukoencephalopathy Syndrome (RPLS) [See Warnings and Precautions (5.6)] Gastrointestinal Perfation Fistula [See Warnings and Precautions (5.7)] 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 most frequently observed adverse drug reactions ( ) in patients receiving Stivarga are asthenia/fatigue, HFSR, diarrhea, decreased appetite/food intake, hypertension, mucositis, dysphonia, infection, pain (not otherwise specified), decreased weight, gastrointestinal and abdominal pain, rash, fever, and nausea. The most serious adverse drug reactions in patients receiving Stivarga are hepatotoxicity, hemrhage, and gastrointestinal perfation. 6.1 Clinical Trials Experience Colectal Cancer The safety data described below, except where noted, are derived from a randomized (:1), double-blind, placebocontrolled trial (Study 1) in which 5 patients (median age 61 years; 61 men) with previously-treated metastatic colectal cancer received Stivarga as a single agent at the dose of 16 mg daily f the first weeks of each 4 week treatment cycle and 5 patients (median age 61 years; 6 men) received placebo. The median duration of therapy was 7. (range., 47.) weeks f patients receiving Stivarga. Due to adverse reactions, 61 of the patients receiving Stivarga required a dose interruption and 8 of the patients had their dose reduced. Drug-related adverse reactions that resulted in treatment discontinuation were repted in 8. of Stivarga-treated patients compared to 1. of patients who 5

14 received placebo. Hand-foot skin reaction (HFSR) and rash were the most common reasons f permanent discontinuation of Stivarga. Table 1 compares the incidence of adverse reactions ( 1) in patients receiving Stivarga and repted me commonly than in patients receiving placebo (Study 1). Table 1 Adverse drug reactions ( 1) repted in patients treated with Stivarga in Study 1 and repted me commonly than in patients receiving placebo Adverse Reactions General disders and administration site conditions Asthenia/fatigue Pain Fever All Stivarga (N=5) Grade 15 All Placebo (N=5) Grade Metabolism and nutrition disders Decreased appetite and food intake Skin and subcutaneous tissue disders HFSR/PPE Rash a Gastrointestinal disders Diarrhea Mucositis Investigations Weight loss <1 1 Infections and infestations Infection Vascular disders Hypertension Hemrhage b 1 Respiraty, thacic and mediastinal disders Dysphonia 6 Nervous system disders Headache 1 <1 7 a The term rash represents repts of events of drug eruption, rash, erythematous rash, generalized rash, macular rash, maculo-papular rash, papular rash, and pruritic rash. b Fatal outcomes observed <1 <1 <1 6

15 Labaty Abnmalities Labaty abnmalities observed in Study 1 are shown in Table. Table Labaty test abnmalities repted in Study 1 Labaty Parameter All Stivarga (N=5 a ) Grade b 4 All Placebo (N=5 a ) Grade b Blood and lymphatic system disders Anemia Thrombocytopenia 41 <1 17 <1 Neutropenia 1 Lymphopenia Metabolism and nutrition disders Hypocalcemia 59 1 < Hypokalemia <1 Hyponatremia Hypophosphatemia Hepatobiliary disders Hyperbilirubinemia Increased AST Increased ALT <1 Renal and urinary disders Proteinuria 6 <1 4 <1 Investigations Increased INR c 4 4 N/A 17 N/A Increased Lipase Increased Amylase 6 <1 17 <1 a based on number of patients with post-baseline samples which may be less than 5 (regafenib) 5 (placebo). b Common Terminology Criteria f Adverse Events (CTCAE), v.. c International nmalized ratio: No Grade 4 denoted in CTCAE, v.. Gastrointestinal Stromal Tums The safety data described below are derived from a randomized (:1), double-blind, placebo-controlled trial (Study ) in which 1 patients (median age 6 years; 64 men) with previously-treated GIST received Stivarga as a single agent at a dose of 16 mg daily f the first weeks of each 4 week treatment cycle and 66 patients (median age 61 years; 64 men) received placebo. The median duration of therapy was.9 (range.1, 5.9) weeks f patients receiving Stivarga. Dose interruptions f adverse events were required in 58 of patients receiving Stivarga and 5 of patients had their dose reduced. Drug-related adverse reactions that resulted in treatment discontinuation were repted in. of Stivargatreated patients compared to 1.5 of patients who received placebo. Table compares the incidence of adverse reactions ( 1) in GIST patients receiving Stivarga and repted me commonly than in patients receiving placebo (Study ). 4 7

16 Table Adverse reactions ( 1) repted in patients treated with Stivarga in Study and repted me commonly than in patients receiving placebo Adverse Reactions Stivarga (N=1) Grade Placebo (N=66) Grade Skin and subcutaneous tissue disders HFSR/PPE Rash a Alopecia General disders and administration site conditions Asthenia/Fatigue Fever Vascular disders Hypertension Hemrhage Gastrointestinal disders Diarrhea Mucositis Nausea All Vomiting Respiraty, thacic and mediastinal disders Dysphonia 9 9 Infections and infestations Infection 5 5 Metabolism and nutrition disders Decreased appetite and food intake Hypothyroidism b 1 18 Nervous system disders Headache 16 9 Investigations Weight loss 14 8 Musculoskeletal and connective tissue disders Musculoskeletal stiffness 14 a The term rash represents repts of events of rash, erythematous rash, macular rash, maculo-papular rash, papular rash and pruritic rash <1 <1 All b Hypothyroidism incidence based on subset of patients with nmal TSH and no thyroid supplementation at baseline. 8

17 Labaty Abnmalities Labaty abnmalities observed in Study are shown in Table 4. Table 4 Labaty test abnmalities repted in Study Labaty Parameter Blood and lymphatic system disders Thrombocytopenia Neutropenia Lymphopenia Metabolism and nutrition disders Hypocalcemia Hypokalemia Hypophosphatemia Hepatobiliary disders Hyperbilirubinemia Increased AST Increased ALT All Stivarga (N=1 a ) Grade b All Placebo (N=66 a ) Grade b Renal and urinary disders Proteinuria - c - c Investigations Increased Lipase a based on number of patients with post-baseline samples which may be less than 1 (regafenib) 66 (placebo). b CTCAE, v4.. c No Grade 4 denoted in CTCAE, v Postmarketing Experience The following adverse reaction has been identified during postapproval use of Stivarga. Because these reactions are repted voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency establish a causal relationship to drug exposure: hypersensitivity reaction 7 DRUG INTERACTIONS 7.1 Effect of Strong CYPA4 Inducers on Regafenib Co-administration of a strong CYPA4 inducer (rifampin) with a single 16 mg dose of Stivarga decreased the mean exposure of regafenib, increased the mean exposure of the active metabolite M-5, and resulted in no change in the mean exposure of the active metabolite M-. Avoid concomitant use of Stivarga with strong CYPA4 inducers (e.g. rifampin, phenytoin, carbamazepine, phenobarbital, and St. John s Wt) [see Clinical Pharmacology (1.)]. 9

18 7. Effect of Strong CYPA4 Inhibits on Regafenib Co-administration of a strong CYPA4 inhibit (ketoconazole) with a single 16 mg dose of Stivarga increased the mean exposure of regafenib and decreased the mean exposure of the active metabolites M- and M-5. Avoid concomitant use of Stivarga with strong inhibits of CYPA4 activity (e.g. clarithromycin, grapefruit juice, itraconazole, ketoconazole, nefazodone, posaconazole, telithromycin, and viconazole) [see Clinical Pharmacology (1.)]. 8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy Pregnancy Categy D [see Warnings and Precautions (5.9)] Risk Summary Based on its mechanism of action, Stivarga can cause fetal harm when administered to a pregnant woman. There are no adequate and well-controlled studies with Stivarga in pregnant women. Regafenib was embryolethal and teratogenic in rats and rabbits at exposures lower than human exposures at the recommended dose, with increased incidences of cardiovascular, genitourinary, and skeletal malfmations. If this drug is used during pregnancy if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to a fetus. Animal Data In embryo-fetal development studies, a total loss of pregnancy (1 resption of litter) was observed in rats at doses as low as 1 mg/kg (approximately 6 of the recommended human dose, based on body surface area) and in rabbits at doses as low as 1.6 mg/kg (approximately 5 of the human exposure at the clinically recommended dose measured by AUC). In a single dose distribution study in pregnant rats, there was increased penetration of regafenib across the blood-brain barrier in fetuses compared to dams. In a repeat dose study with daily administration of regafenib to pregnant rats during ganogenesis, findings included delayed ossification in fetuses at doses >.8 mg/kg (approximately 5 of the recommended human dose based on body surface area) with dose-dependent increases in skeletal malfmations including cleft palate and enlarged fontanelle at doses 1 mg/kg (approximately 1 of the clinical exposure based on AUC). At doses 1.6 mg/kg (approximately 11 of the recommended human dose based on body surface area), there were dosedependent increases in the incidence of cardiovascular malfmations, external abnmalities, diaphragmatic hernia, and dilation of the renal pelvis. In pregnant rabbits administered regafenib daily during ganogenesis, there were findings of ventricular septal defects evident at the lowest tested dose of.4 mg/kg (approximately 7 of the AUC in patients at the recommended dose). At doses of.8 mg/kg (approximately 15 of the human exposure at the recommended human dose based on AUC), administration of regafenib resulted in dose-dependent increases in the incidence of additional cardiovascular malfmations and skeletal anomalies as well as significant adverse effects on the urinary system including missing kidney/ureter; small, defmed and malpositioned kidney; and hydronephrosis. The proption of viable fetuses that were male decreased with increasing dose in two rabbit embryo-fetal toxicity studies. 8. Nursing Mothers It is unknown whether regafenib its metabolites are excreted in human milk. In rats, regafenib and its metabolites are excreted in milk. Because many drugs are excreted in human milk and because of the potential f serious adverse reactions in nursing infants from Stivarga, a decision should be made whether to discontinue nursing discontinue the drug, taking into account the imptance of the drug to the mother. 1

19 8.4 Pediatric Use The safety and efficacy of Stivarga in pediatric patients less than 18 years of age have not been established. In 8-day repeat dose studies in rats there were dose-dependent findings of dentin alteration and angiectasis. These findings were observed at regafenib doses as low as 4 mg/kg (approximately 5 of the AUC in humans at the recommended dose). In 1-week repeat dose studies in dogs there were similar findings of dentin alteration at doses as low as mg/kg (approximately 4 of the AUC in humans at the recommended dose). Administration of regafenib in these animals also led to persistent growth and thickening of the femal epiphyseal growth plate. 8.5 Geriatric Use Of the 6 Stivarga-treated patients enrolled in Studies 1 and, 7 were 65 years of age and over, while 8 were 75 and over. No overall differences in safety efficacy were observed between these patients and younger patients. 8.6 Hepatic Impairment Stivarga is eliminated mainly via the hepatic route. No clinically imptant differences in the mean exposure of regafenib the active metabolites M- and M-5 were observed in patients with hepatocellular carcinoma and mild (Child-Pugh A) moderate (Child-Pugh B) hepatic impairment compared to patients with nmal hepatic function [see Clinical Pharmacology (1.)]. No dose adjustment is recommended in patients with mild moderate hepatic impairment. Closely monit patients with hepatic impairment f adverse reactions [see Warnings and Precautions (5.1)]. Stivarga is not recommended f use in patients with severe hepatic impairment (Child-Pugh Class C), as it has not been studied in this population. 8.7 Renal Impairment No clinically relevant differences in the mean exposure of regafenib and the active metabolites M- and M-5 were observed in patients with mild renal impairment (CLcr 6-89 ml/min) compared to patients with nmal renal function following regafenib 16 mg daily f 1 days [see Clinical Pharmacology (1.)]. No dose adjustment is recommended f patients with mild renal impairment. Limited pharmacokinetic data are available from patients with moderate renal impairment (CLcr -59 ml/min). Stivarga has not been studied in patients with severe renal impairment end-stage renal disease. 8.8 Females and Males of Reproductive Potential Contraception Use effective contraception during treatment and up to months after completion of therapy. Infertility There are no data on the effect of Stivarga on human fertility. Results from animal studies indicate that regafenib can impair male and female fertility [see Nonclinical Toxicology (1.1)]. 1 OVERDOSAGE The highest dose of Stivarga studied clinically is mg per day. In the event of suspected overdose, interrupt Stivarga, institute supptive care, and observe until clinical stabilization. 11

20 11 DESCRIPTION Stivarga (regafenib) has the chemical name 4-[4-({[4-chlo--(trifluomethyl) phenyl] carbamoyl} amino)-- fluophenoxy]-n-methylpyridine--carboxamide monohydrate. Regafenib has the following structural fmula: Regafenib is a monohydrate and it has a molecular fmula C 1H 15ClF 4N 4O H O and a molecular weight of 5.8. Regafenib is practically insoluble in water, slightly soluble in acetonitrile, methanol, ethanol, and ethyl acetate and sparingly soluble in acetone. Stivarga tablets f al administration are fmulated as light pink oval shaped tablets debossed with "BAYER" on one side and "4" on the other. Each tablet contains 4 mg of regafenib in the anhydrous state, which cresponds to mg of regafenib monohydrate, and the following inactive ingredients: cellulose microcrystalline, croscarmellose sodium, magnesium stearate, povidone, and colloidal silicon dioxide. The film-coating contains the following inactive ingredients: ferric oxide red, ferric oxide yellow, lecithin (soy), polyethylene glycol 5, polyvinyl alcohol, talc, and titanium dioxide. 1 CLINICAL PHARMACOLOGY 1.1 Mechanism of Action Regafenib is a small molecule inhibit of multiple membrane-bound and intracellular kinases involved in nmal cellular functions and in pathologic processes such as oncogenesis, tum angiogenesis, and maintenance of the tum microenvironment. In in vitro biochemical cellular assays, regafenib its maj human active metabolites M- and M-5 inhibited the activity of RET, VEGFR1, VEGFR, VEGFR, KIT, PDGFR-alpha, PDGFR-beta, FGFR1, FGFR, TIE, DDR, TrkA, EphA, RAF-1, BRAF, BRAF V6E, SAPK, PTK5, and Abl at concentrations of regafenib that have been achieved clinically. In in vivo models, regafenib demonstrated anti-angiogenic activity in a rat tum model, and inhibition of tum growth as well as anti-metastatic activity in several mouse xenograft models including some f human colectal carcinoma. 1. Pharmacokinetics Absption Following a single 16 mg dose of Stivarga in patients with advanced solid tums, regafenib reaches a geometric mean peak plasma level (C max) of.5 µg/ml at a median time of 4 hours and a geometric mean area under the plasma concentration vs. time curve (AUC) of 7.4 µg*h/ml. The AUC of regafenib at steady-state increases less than dose proptionally at doses greater than 6 mg. At steady-state, regafenib reaches a geometric mean C max of.9 µg/ml and a geometric mean AUC of 58. µg*h/ml. The coefficient of variation of AUC and C max is between 5 and 44. The mean relative bioavailability of tablets compared to an al solution is 69 to 8. 1