CENTER FOR DRUG EVALUATION AND
`CENTER FOR DRUG EVALUATION AND
`RESEARCH
`RESEARCH
`
`APPLICATION NUMBER:
`APPLICATION NUMBER:
`22-334
`22-334
`
`CLINICAL PHARMACOLOGY AND
`CLINICAL PHARMACOLOGY AND
`BIOPHARMACEUTICS REVIEW(S)
`BIOPHARMACEUTIC S REVIEW! S 2
`
`

`

`NDA
`Submission Date:
`Brand Name:
`Generic Name:
`Formulation:
`OCP Reviewer:
`Pharmacometrics Reviewer:
`OCP Team Leader:
`Pharmacometrics Team Leader:
`OCP Division:
`ORM Division:
`Sponsor:
`Submission Type; Code:
`Dosing regimen:
`Indication:
`
`Clinical Pharmacology Review
`22-334
`27 June 2008
`Afinitor(B
`everolimus
`5 mg and 10 mg tablets
`Julie M. Bullock, Pharm.D.
`Nitin Mehrotra, Ph.D.
`Brian Booth, Ph.D.
`Chrstoffer Tomoe, Ph.D.
`Division of Clinical Pharmacology 5
`Division of Drug Oncology Products
`Novartis
`Original NDA; 000
`i 0 mg once daily
`treatment of advanced renal cell carcinoma
`
`OCP Briefing held on February 19,2009 attended by: Amna Ibrahim, Pengfei Song, Ramana
`Uppoor, Phil Colangelo, Jun Yang, Aakanksha Khandelwal, Sarah Schrieber, Nam Atiqur
`Rahman, Gil Burckart, Rosane Charlab-Orbach, Gerlie Gieser, Qi Liu, Chris Tornoe, Ping Zhao,
`Lilian Zhang, Anthony Murgo, Ellen Maher, Qin Ryan, Partha Roy.
`Table of contents
`i Executive Summar .........................................................................................................................4
`1.1 Recommendations ...............................................................................................................4
`1.2 Clinical Pharmacology Summary ........................................................................................ 5
`2 Question Based Review ...................................................................................................................6
`2.1 General Attributes ..............................................................................;................................6
`2.2 General Clinical Pharmacology ...........................................................................................6
`2.3 Intrinsic Factors .................................................................................................................19
`2.4 Extrinsic Factors................................................................................................................24
`2.5 General Biopharmaceutics.................................................................................................33
`2.6 Analytical Section .............................................................................................................36
`3 Detailed Labeling Recommendations ............................................................................................39
`4 Appendices.....................................................................................................................................45
`4.1 CMC Response..................................................................................................................45
`4.2 Pharmacometric review .....................................................................................................49
`List of Tables
`TABLE 1. clinical pharacology studies using the transplant tablets in healthy volunteers and transplant
`patients. ................................................................................................................................................7
`
`TABLE 2. Clinical pharmacology studies using the oncology tablets in healthy volunteers and patients
`with cancer. .... ....... ...... ...... ...... .... ....... ........... ..... ... ...... ... .... .... ............. .... ........ ...... ..... ...................... .....7
`
`TABLE 3. Phase 1 and 2 studies of everolimus for other cancer indications. .............................................8
`
`TABLE 4. Effcacy endpoints of the dose finding and effcacy trials for advanced RCC. .........................9
`
`NDA 22-334 Review - Everolimus
`1
`
`

`

`TABLE 5. Weeks 2-5 Pre-dose everolimus concentrations following 5 to 70 mg weekly doses.............. 12
`
`TABLE 6. Mean:: SD single- and multiple-dose pharmacokinetic parameters following a 5 or 10 mg oral
`everolimus dose in patients with cancer. ............ ... ........... ..... ..... .............. ...... ........ ..... ..... ... ...... ... ...... 13
`
`TABLE 7. Everolimus pharmacokinetic parameters on Cycle 1 Day 1 (single dose) and Cycle 1 Day 15
`(multiple dose) in patients with advanc'ed renal cell carcinoma receiving 10 mg QD. ......................14
`TABLE 8. Mean:: SD single dose PK parameters of 10-mg everolimus in healthy volunteers (study
`C21 19) and patients with cancer (C2101).......................................................................................... 15
`TABLE 9: Free fraction and bound fraction of(3H)-everolimus in serum (sponsors table)..................... 15
`
`TABLE 10. Mean:: SD and relative amounts for everolimus and metabolites in blood (taken from Dr.
`Lee's review)......................................................................................................................................18
`
`TABLE 11. Single and multiple dose pharmacokinetic parameters of everolimus in Japanese and multiple
`dose pharacokinetics in Caucasian solid tumor patients. ............. ..... ..... ................... ............ .......... 20
`
`TABLE 12. Effect of
`
`moderate hepatic impairment on everolimus pharmacokinetic parameters following
`a single dose of2 mg (taken from Jang-Ike's review)..............~.........................................................23
`
`TABLE 13: Permeability Coefficient (Pelf) ofeverolimus in Caco-2 monolayers....................................26
`TABLE 14: Drug-Drug interaction studies................................................................................................27
`
`TABLE 15. Effect ofatorvastatin or pravastatin on everolimus PK (taken from Dr. Lee's Review)........
`
`28
`
`TABLE 16. Effect of everolimus on the pharmacokinetics of atorvastatin and pravastatin (Taken from
`Dr. Lee's review)................................................................................................................................29
`TABLE 17. Effect ofCYP3A induction by rifampin on everolimus pharacokinetics (Taken from Dr.
`Lee's review) ......................................................................................................................................30
`
`TABLE 18. Everolimus PK parameters following 5 days ofketoconazole administration (taken from Dr.
`Lee's review). .....................................................................................................................................31
`
`TABLE 19. Everolimus pharmacokinetics in combination with erythromycin (taken from Dr. Lee's
`review)................................................................................................................................................32
`TABLE 20. Everolimus pharacokinetic parameters following co-administration with verapamii....... 33
`TABLE 21. Mean:: SD pharmacokinetic parameters of everolimus in healthy subjects following single
`oral doses of 10 mg. ....... ... .............. ..... ........... ......... ......... ................ ...... ........ ... ..... ...... ...... ........ .......34
`
`TABLE 22. Ratios of
`
`Geometric means (test/reference) and 90% confidence intervals for primary PK
`parameters. .........................................................................................................................................34
`TABLE 23. Analytical methods for determination of everolimus............................................................. 37
`
`TABLE 24. Summary of in-process performance ofthe analytical methods used for the measurement of
`everolimus blood concentrations in oncology studies........................................................................ 38
`
`List of Figures
`FIGUR 1. Kaplan Meier plots for progression free survival for placebo and treatment groups. Ql, Q2,
`Q3 and Q4 are quariles based on steady state trough concentrations. ....................... .......... ............. 10
`FIGURE 2. Percent adverse events in the four Cirough quartiles. The concentration ranges are 1.4-12.4,
`12.5-19, 1.-30.6 and 30.7 to 135 ng/ml for 1,2,3 and 4, respectively. ........................................... 10
`FIGURE 3. Mean week 4 everolimus vs. time concentrations (right: 24 hours; left 264 hours) for subjects
`
`NDA 22-334 Review - Everolimus
`2
`
`

`

`with cancer who received once weekly doses. ................. .... ......... ........... ........ ................... ...... ... ...... 13
`
`FIGURE 4: Distribution ofeH)everolimus between human blood components (Sponsors figure)..........
`
`16
`FIGURE 5: Proposed biotransformation pathways for everolimus (Sponsors figure) ..............................17
`
`FIGURE 6: Dose proportionality ofCmax and AUCO-tau for everolimus given once-weekly in patients
`with advanced solid tumors over the dose range of 5 to 70 mg. .. ........... ........... .............. ... ...... ......... 19
`FIGUR 7. Everolimus AUCt and Cmax versus dose for Asian (Japanese) and Caucasian subjects with
`solid tumors. ...... ........ ......... ..... .................. ..... ...... ...... ........... ........ .... ....... ............ ... ... ....... ............ .....20
`
`FIGURE 8. Multiple dose CL/F versus various liver function parameters for 5 and 10 mg everolimus in
`Caucasian (blue circles) and Japanese (red triangles) patients with solid tumors. ............................. 21
`
`FIGURE 9. No effect of
`
`baseline creatinine clearance on oral clearance of everolimus. .......................... 22
`
`FIGUR 10. No effect of
`
`hepatic function ((Left) total bilrubin and (Right) serum albumin) on oral
`clearance of everolimus. ........... .................. ..... ...... ...... .................... ... ... ........ ...... ......... ........ ..............24
`
`FIGURE 11: Inhibition of Rho 123 efflux by RADOO 1 ....... ............ ..... ............ ... ... ........... ........ ........... .....26
`
`Appears ThIs Way
`On Originai
`
`NDA 22-334 Review - Everolimus
`3
`
`

`

`1 EXECUTIVE SUMMARY
`
`Everolimus is an inhibitor ofthe human kinase mammalian target of rapamycin (mTOR). The
`current submission is the original NDA for everolimus for the treatment of advanced renal cell
`carcinoma (RCC). Everolimus has also been evaluated under two NDAs for transplant
`indications.
`
`for the decrease in everolimus exposure. For strong CYP3A4 inhibitors because of
`
`To support the efficacy in advanced renal cell carcinoma, the sponsor conducted one
`randomized, controlled phase 3 study. Patients in the phase 3 study were randomized to receive
`best supportive care plus placebo or 10 mg of everolimus daily. Progression free survival was
`the primary endpoint and the median PFS for the everolimus treatment arm ranged from 3.71 to
`5.52 months compared to 1.87 months for patients receiving placebo.
`Everolimus is a CYP3A4 substrate. Multiple drug-drug interaction studies were conducted
`under the NDAs for the transplant indications. Based on the results from the drug-drug
`interaction studies with ketoconazole, erythromycin and verapamil no dose adjustments wil be
`provided in the label since the increases in everolimus exposures can not be adjusted by lowering
`the dose to 5 mg QD. For strong CYP3A4 inducers, a dose increase to 20 mg would compensate
`the
`significant increase in exposure labeling instructions co-administration is not recommended. b(4)
`Currently, for moderate CYP3A4 inhibitors generic - tatements wil be
`proposed until the sponsor can develop a2.5 mg dose for market.
`A study in patients with normal hepatic function and patients with moderate hepatic impairment
`supported the labeling recommendation of a 50% dose reduction for patients with moderate
`hepatic impairment. Patients with severe hepatic impairment have not been studied and that
`everolimus should not be used in this patient population.
`The IRT review ofthe thorough QT study suggested that everolimus has a low potential to
`prolong the QT interval. IRT proposed labeling has been added to the package insert.
`1.1 RECOMMNDATIONS
`
`The Office of
`
`Clinical PharmacologylDivision of
`
`Clinical Pharmacology 5 has reviewed the
`information contained in NDA 22-334. This NDA is considered acceptable from a clinical
`pharmacology perspective.
`Post Marketing Requirements
`
`1. A study in patients with severe hepatic impairment.
`
`2. Make available a 2.5 mg formulation.
`Labeling Recommendations
`Please refer to Section 3 - Detailed Labeling Recommendations
`
`Reviewer: Julie M. Bullock, Pharm.D.
`Deputy Director & Acting Team Leader: Brian Booth, Ph.D.
`Cc: DDOP: CSO - C Cottrell; MTL - E Maher; MO - Q Ryan
`DCP- Reviewers - J Bullock, N Mehrotra; PM TL - C Tomoe; Acting TL & DDD - B Booth;
`5: DD - A Rahman
`
`NDA 22-334 Review - Everolimus
`4
`
`

`

`1.2 CLINICAL PHARMACOLOGY SUMMAY
`
`After administration of
`
`Everolimus is a derivative ofrapamycin which acts as a signal transduction inhibitor. It targets
`mTOR (mammalian target ofrapamycin), which regulates protein synthesis and cell growth, cell
`proliferation, angiogenesis and survivaL. Everolimus is being developed for oral use in the
`treatment of advanced renal cell carcinoma (RCC). Prior to it's development for RCC,
`everolimus has been under investigation as an immun su ressant for transplantation under bl4)
`NDAf.- '(allogeneic kidney transplant) and NDA 1-628 (allogeneic heart transplant).
`IL______..!J
`The applicant has conducted several phase 1 studies in healthy volunteers, transplant patients,
`patients with solid tumors and patients with advanced renal cell carcinoma to evaluate the safety
`and pharmacokinetics of everolimus. The Tmax of everolimus typically occurs 1-2 hours
`following oral administration the concentrations of everolimus decreased over time with a half-
`life of approximately 39 hours after a single 10 mg oral dose. The AUC of everolimus is dose
`proportional over the dose range of 5 - 70 mg. Cmax rose in a roughly dose-proportional
`manner from 5 to 10 mg/week, but increased less than dose-proportionally at doses of 20 mg and
`higher. There are no significant differences between the pharmacokinetics in healthy volunteers
`and patients. A high-fat meal decreased AUC of everolimus by 16%.
`radio-labeled everolimus in transplant patients, approximately 80% ofthe
`total radioactivity was eliminated in the feces. No parent drug was detectable in urine and feces,
`indicating metabolism was the main clearance mechanism of everolimus. Following oral
`administration, everolimus is the main circulating component in human blood. Six metabolites of
`everolimus have been detected in human blood, these metabolites were also identified in animal
`species used in toxicity studies. These metabolites and showed approximately 100-times less
`activity than everolimus itself. A hepatic impairment study in patients with moderate hepatic
`impairment showed that the average AUC was twice that found in patients with normal hepatic
`function. A 50% dose reduction for patients with moderate hepatic impairment is recommended.
`Everolimus is a substrate ofCYP3A4 and p-glycoprotein (p-gp). Drug-drug interaction studies
`indicate a 62% reduction in everolimus exposure (AUC), when administered with rifampin.
`Coadministration of everolimus with three different CYP3A4 inhibitors (ketoconazole,
`eryhromycin, verapamil) increased the exposure (A UC) of everolimus over the range of 1371 to
`124%. In vitro everolimus inhibited CYP3A and 2D6, however, based on Ki values a significant
`effect on the metabolism of CYP3A or 2D6 is not expected. Everolimus was not found to induce
`any cytochrome P-450 enzymes in vitro.
`Results from two phase 1 studies in patients with advanced solid tumors were used to support
`dose selection and dose-response. These studies investigated the biochemical activity of
`everolimus based on a biomarker (p70 ribosomal S6 kinase 1 inhibition). A near complete
`inhibition of S6 phosphorylation in both skin and tumor samples at doses of 10 mg/day and 50
`mg/week led to the recommendation that these doses should be explored further. The 10 mg/day
`dose was further evaluated in multiple phase 2 trials and was determined to have the desired anti
`tumor activity and safety profie for use in the phase 3 triaL.
`
`NDA 22-334 Review - Everolimus
`5
`
`

`

`2 QUESTION BASED REVIEW
`
`2.1 GENERAL
`
`ATTRIBUTES
`
`drug substance and the formulation of
`
`2.1.1 What are the highlights of the chemistry and physical-chemical properties of the
`the drug product as they relate to clinical
`pharmacology and biopharmaceutics review?
`Physico-chemical properties
`1. Structural formula:
`
`HiC..o
`
`Hie
`
`O~
`
`~.c"o""":yo
`
`c~.
`
`2. Established name: everolimus
`3. Molecular Weight: 958.25 g/mol
`4. Molecular Formula: C53H83NOl4
`5. Chemical Name: (1 R,9S, 12S, 15R, 16E, 18R, 19R,21 R,23 S,24 E,26E,28E,30S,32S,3 5R),-1, 18-
`dihydroxy-12-f (1 R)-2-( (1 S,3R,4 R)-4-(2-hydroxyethoxy )-3-methoxycyclohexyl)-1-methy lethyl)-
`19,30-dimethoxy-15,17,21,23,29,35-hexamethyl-11,36-dioxa-4-azatricyclo(30.3.1.0.,9)-
`hexatriaconta-16,24,26,28-tetraene-2,3, 1 0, 14,20-peritaone
`2.1.2 What are the proposed mechanisms of action and therapeutic indications?
`Everolimus is a signal transduction inhibitor targeting mammalian target ofrapamycin (mTOR),
`an enzyme that regulates cell growth, proliferation, angiogenesis and survivaL. The proposed
`indication is for the treatment of advanced renal cell carcinoma.
`2.1.3 What are the proposed dosage and route of administration?
`The sponsors proposed dose of everolimus is 10 mg once daily at the same time every day.
`
`The labeling wil recommend that everolimus should be taken at the same time every day
`
`2.2 GENERAL CLINICAL PHARCOLOGY
`
`2.2.1 What are the design features of the clinical pharmacology and clinical studies used
`to support dosing or claims?
`Clinical Pharmacology Studies
`Multiple clinical pharmacology studies conducted for the transplant indication were submitted to
`support part ofthe clinical pharmacology of everolimus for treatment of advanced renal cell
`
`bl4l
`
`NDA 22-334 Review - Everolimus
`6
`
`

`

`"lA)
`
`carcinoma and al e studies have been reviewed previously by Dr. Jang-Ik Lee under
`NDAs¡ . ,j& Portions oftheses trials listed in TABLE 1 wil be used to support
`labeling for the oncology indications. b(4)
`TABLE 1. clinical pharmacology studies using the transplant tablets in healthy volunteers and
`ransp an pa ien s.
`Study
`Study
`population
`renal transplant
`
`tIt t t
`
`Design
`
`W107
`
`W303
`
`healthy subjects
`
`A2302
`A2304
`
`A2408
`
`A2409
`A2410
`
`W302
`A2301
`
`B2303
`
`healthy subjects
`healthy subjects
`
`healthy subjects
`
`healthy subjects
`healthy subjects
`
`healthy subjects
`healthy subjects
`
`healthy subjects
`
`ADME study. Single 3 mg radiolabeled dose of everolimus
`administered simultaneously with Neoral(I
`DDI study. atorvastatin (CYP3A4 substrate), pravastatin (non-
`CYP3A4 substrate)
`DDI study. Rifampin (CYP3A4 and p-gp induær)
`DDI study. Cyclosporine (CYP3A4 substrate, Pgp inhibitor)
`DDI study. Eryhromycin (moderate CYP3A4 inhibitor, Pgp
`inhibitor)
`DDI study. Ketoconazole (CYP3A4 inhibitor)
`DDI study. Verapamil (moderate CYP3A4 inhibitor, Pgp
`inhibitor)
`Food effect study.
`Relative BA of transplant tablets.
`hepatic impairment study.
`
`Design
`
`To support the clinical pharmacology and dose finding of everolimus in patients with advanced
`renal cell carcinoma the sponsor submitted multiple studies in cancer patients and healthy
`volunteers (TABLE 2).
`TABLE 2. Clinical pharmacology studies using the oncology tablets in healthy volunteers and
`patients with cancer
`Study
`Study
`Population
`solid tumors
`
`C2101
`Part 1
`
`C2102
`
`solid tumors
`
`C2107
`
`solid tumors
`
`C1101
`
`solid tumors
`
`C2118
`
`C2119
`
`healthy subjects
`(females)
`healthy subjects
`
`Phase 1, dose finding, open label triaL. Part 1: 8 cohorts receiving either weekly
`regimens (5, 10, 20, 30, 50, 70 mg) or daily regimens (5 and 10 mg) over a 4-week
`period.
`Phase 1 dose finding study of monotherapy RAD001 given at 5,10,20,30,50, and
`70 mçi weekly or 5 and 10 mg QD.
`Phase 1, non-randomized, open labeL.
`Daily (5 and 10 ma) and weekly (20, 50, 70 ma)
`Phase 1, open-label, dose-escalation study of everolimus administered on a
`continuous once-daily schedule (2.5, 5, and 10 ma daily) in aduit Jaoanese oatients.
`Phase 1 cardiac safety with everolimus 20 mg, 50 mg, moxifloxacin, and plaæbo.
`
`Phase 1 bioequivalence of a single 10 mg dose of RAD001 administered as either 5
`mg market formulation (MF) tablet, 5 mg final market image (FMI) tablet or 10 mg
`FMI tablet
`
`Additional phase 1 and 2 studies were conducted but do not pertain to the advanced renal cell
`carcinoma indication. These studies wil mostly be used for intrinsic factor covariate analysis
`and safety.
`
`NDA 22-334 Review - Everolimus
`7
`
`

`

`TABLE 3 Phase 1 and 2 studies of everolimus for other cancer indications
`Study
`Study
`Design
`Population
`solid tumors
`
`Part 2: Gemcitabine drug-drug interaction evaluation
`
`C2101
`Part 2
`C2106
`C2104
`C2108
`
`prostate cancer
`solid tumors
`breast cancer
`
`C2207
`
`Ph+ CML
`
`C2222
`
`breast cancer
`
`nhase 1 optimal dose study for prostate cancerleeklV and daily doses).
`Phase 1 everolimus 115 and 30 mçi weeklv) in combination with paclitaxel therapy.
`Phase 1 b in postmenopausal women with metastatic or loco regionally recurring
`breast cancer. Everolimus 5, 10 rna QD or 30 rna weeklv + letrozole 2.5 mQ QD.
`Phase 1, everolimus (2.5 or 5 mg QD) in combination with imatinib at 600 or 800
`mo/dav.
`Phase 2 double-blind, placebo-controlled, multi-center. Patients received daily
`administration of either everolimus 10 mg + letrozole 2.5 mg or placebo + letrozole
`2.5 rna for 4 months prior to underaoina breast conservina surQerv or mastèctomy.
`Phase 2, non-randomized, open label, multi-center study with 10 rna QD everolimus.
`Phase 2 expanded two-stage, single-arm study. Patients received everolimus 10
`mg QD or everolimus 10 mg QD + Sandostatin LAR(ß Depot.
`
`C2235
`C2239
`
`NSCLC
`pancreatic
`neuroendocrine
`tumor
`Pivotal Study
`Study C2240 was a randomized, double-blind, placebo controlled, phase 3 study in advanced
`renal cell carcinoma patients.
`
`the following treatments:
`
`Eligible patients were enrolled in a 2: 1 fashion to receive one of
`
`· Everolimus 10 mg QD + best supportive care
`· Placebo + best supportive care.
`The primary efficacy endpoint was progression free survival (PFS). Ofthe 410 patients
`randomized, 272 were in the everolimus group and 138 were in the placebo group. At the time
`ofthe interim analysis the median progression-free survival (based on central radiological
`review) was 4.01 months in the everolimus group (95% CI, 3.71 to 5.52 months) and 1.87
`months in the placebo group (95% CI, 1.81 to 1.94 months). On 25 February 2008 the
`independent data monitoring committee recommended stopping the study early due to the
`statistically significant efficacy results favoring everolimus treatment. All sites with patients
`receiving placebo were notified on 28 February 2008 to cross these patients over to open-label
`everolimus.
`
`The most commonly occurring (~ 10%) adverse events related to everolimus treatment were:
`stomatitis, rash, fatigue, anemia, asthenia, diarrhea, anorexia, nausea, mucosal inflammation,
`hypercholesterolemia, cough, vomiting, and dry skin.
`2.2.2 What is the basis for selecting the response endpoints or biomarkers and how are
`they measured in clinical pharmacology and clinical studies?
`Biomarkers
`mTOR signaling is effected through phosphorylation of substrates p70 ribosomal S6 kinase 1
`(S6Kl) and eukaryotic initiation factor 4E binding protein (4E-BPl). In a rat pancreatic tumor
`model, doses of everolimus that inhibited tumor growth also dramatically inhibited mTOR
`signaling in the tumor, skin, and peripheral blood mononuclear cells (PBMCs). In this model,
`decreases in p4E-BPl were consistently observed in all three tissues. Striking reductions in pS6
`were demonstrated only in tumor.
`Results of an in vitro kinase assay using 40S ribosomal subunits as substrate, revealed a
`significant and consistent inhibition ofS6Kl signaling in tumor, skin, and PBMCs. These
`factors were therefore thought to serve as biomarkers for monitoring mTOR inhibition and were
`
`NDA 22-334 Review - Everolimus
`8
`
`

`

`used in the dose finding trail C21 07.
`
`Clinical Endpoints
`The clinical efficacy of everolimus in patients with advanced RCC has been demonstrated in the
`pivotal phase 3 study (C2240) and was supported by 3 dose-finding phase 1 pharmacokinetic
`studies in patients with advanced solid tumors. The design and endpoints from these studies are
`listed below in TABLE 4.
`
`TABLE 4. Efficacy endpoints of
`
`the dose finding and efficacy trials for advanced RCC.
`
`Study Study desiuoi objective._ and populatíon Efficacy endpoints No of patients
`Everolimus Total
`10mg
`
`Pivotal, ph3Be~ni study
`rC2240i Phase-III randomized, double.blind, placebo
`'Contmlle, effcacy and safety in patients
`wit mRCC oftr railure of VEGFf- TKf
`theipy
`Dose selection triar8i
`lC2101 Phß5e.1 dose-escalatin study in patints
`Part 11 wrt advanced solld tumor
`C2102j
`(C2107J Phase-! invesigation of saf6-ty, tolerablfty,
`and molecuiar plimiacodynamk: effect in
`pants witi advanced sGjd tumors
`~C1101i Phase-I dose-escalatin study in Japanese
`patients with advanced saUd tumors
`
`Primary PFS
`Secondary ORR,
`OS,QoL
`
`272
`
`410
`
`ORR
`
`ORR
`
`ORR,PFS
`
`33
`
`12
`
`92
`
`55
`
`9
`
`2.2.3 Are the active moieties in the plasma (or other biological fluid) appropriately
`identified and measured to assess pharmacokinetic parameters and exposure
`response relationships?
`Yes. Please refer to Section 2.6 AnalyticaL.
`
`2.2.4 Exposure-response
`
`2.2.4.1 What are the characteristics of
`
`the exposure-response relationships (dose-
`response, concentration-response) for effcacy?
`Preliminary PK-PD studies suggested that concentrations between 10-35 ng/ml are needed in
`order for everolimus to effect downstream effectors. The reviewer, divided the trough
`concentrations from the available patients into quartiles and performed a Kaplan Meier analysis
`(with four quartiles as different strata) to assess the exposure response for efficacy based on
`progression free survivaL. The survival curves of patients in different concentration-quartile
`groups were not significantly different (see FIGURE 1). However, the drug clearly seems to be
`effective as all the four survival curves for treatment were well differentiated from the placebo
`group.
`
`Appears This Way
`On Original
`
`NDA 22-334 Review - Everolimus
`9
`
`

`

`1.0
`
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`
`0.0
`
`o
`
`2
`
`4
`
`6
`
`8
`
`10
`
`Follow up time in months
`
`FIGUR 1. Kaplan Meier plots for progression free survival for placebo and treatment groups.
`Ql, Q2, Q3 and Q4 are quartiles based on steady state trough concentrations.
`2.2.4.2 What are the characteristics of the exposure-response relationships (dose-
`response, concentration-response) for safety?
`To assess the exposure-safety relationship, the patients for whom the trough concentrations were
`available from the pivotal trial (C2240) were divided into quartiles and % subjects having
`adverse events were plotted against each quartile. Adverse events to be assessed were selected
`based on the clinical relevance and after discussion with the medical reviewer. GI disorders and,
`skin and subcutaneous infections were two ofthe most common adverse events observed.
`the adverse events FIGUR 2).
`
`However, there was no trend observed in case of either of
`
`8.5 16.1 26.3 41.4
`
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`
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`8.5 16.1 26:3
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`80
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`60
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`in 20
`i 0
`oic.:;
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`60
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`8.5 16.1 26.3
`Median Steady state trough concentrations (ng/ml)
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`FIGURE 2. Percent adverse events in the four Ctrough quartiles. The concentration ranges are
`1.4-12.4, 12.5-19, 1.1-30.6 and 30.7 to 135 ng/ml for 1,2,3 and 4, respectively.
`
`NDA 22-334 Review - Everolimus
`10
`
`

`

`2.2.4.3 Does this drug prolong the QT or QTc interval?
`A thorough QT (TQT) study was conducted and reviewed by the IRT. The TQT study was a
`single-dose, randomized, blinded (everolimus versus placebo), 4-period crossover study in 59
`the two-sided 90% CI for the ~~QTcF for
`the study was
`
`moxif1oxacin was greater than 5 ms, indicating that the assay sensitivity of
`
`healthy volunteers. The largest lower bound of
`
`established. The results from the IRT analysis are below:
`
`Table 1: The Point E,stimates and the 900/0 CIs Corresponding to the Largest Upper
`Bounds for RAOOl (20 mg and 50 mg) and the Largest Lower Bounds for
`Moxit1oxacin (FA Analvsis)
`90%CI
`Treatment
`titiQTcF
`Time (li)
`RAOOl 20 llg
`3 'i
`12li
`( 1.6, 5.9)
`"'
`RADOOl 50 lll?
`4.7
`(2.5,6.8)
`12li
`Moxifloxadn 400 mg*
`4li
`12.8
`(10.9,14.6)
`* Multiple endpoint adjustment is not applied. The l.gest lov,-er botmd after Bomerron adjus-tment
`was9.84ms.
`
`achieved with administering higher doses because of
`
`The upper bound of the 2-sided 90% CI for the mean difference between RADOO 1 (20 mg and
`50 mg) and placebo were below 10 ms, the threshold for regulatory concern as described in ICH
`E14 guidance. However, the exposures achieved with the 50-mg dose do not cover the increase
`in RADOOI exposures due to CYP3A4 and PgP inhibition. Higher exposure could not be
`the less than dose proportional increases in
`RADOO 1 exposure. There was no relationship between RADOO 1 concentrations and QTc
`changes within the current exposure range.
`For more details please see the posted IRT review in DFS by Dr. Joanne Zhang. The IRT had
`labeling recommendations which can be found in Section 3 - Detailed labeling
`recommendations.
`2.2.4.4 Is the dose and dosing regimen selected by the sponsor consistent with the known
`relationship between dose-concentration-response, and are there any unresolved
`dosing or administration issues?
`
`which functions in Gl of
`
`the cell-cycle, through phosphorylation of
`
`An oral dose of 10 mg everolimus daily is proposed by the sponsor based on safety data from
`multiple trials and efficacy data from the phase 3 comparator triaL. During the phase 1 trial
`(C2101) peripheral blood mononucleocyte (PBMC) derived p70 S6 kinase 1 (S6Kl) activity was
`analyzed fOll0'Ying 5 - 30 mg weekly doses. S6Kl is a primary downstream target ofmTOR
`the 40S ribosomal protein
`S6, to increase the translation of mRNAs largely encoding ribosomal proteins and other elements
`ofthe translational machinery. Through inhibition ofmTOR function, rapamycin blocks these
`essential translational events resulting in inhibition of G 1 progression and contributes to the
`anti proliferative activity of everolimus.
`Inhibition ofthe S6Kl in PBMCs was observed 24 hrs after everolimus administration and
`evidence of dose-dependent effects on the recovery ofPBMC-derived S6Kl activity was
`observed by the sponsor. As S6Kl activity in PBMCs was found to be sufficiently inhibited for
`at least 7 days at a 20-mg weekly dose, this was considered to be a suitable starting dose for
`subsequent trials.
`In study C21 07, the pharmacodynamic effects of everolimus were determined in patients with
`
`NDA 22-334 Review - Everolimus
`11
`
`

`

`high inhibition of
`
`patients on the weekly schedule, inhibition of
`
`advanced tumors receiving weekly (20, 50, or 70 mg) or daily (5 or 10 mg) administration of
`everolimus. The downstream PD markers (total (T) and phosphorylated (P)) of 4E-BPl, S6, eIF-
`4G in tumor tissues and skin samples were assessed. The daily regimen was associated with a
`phosphorylation ofS6 and eIF-4G at both 5 mg/day and 10 mg/day. In
`phosphorylation ofS6 was complete and sustained
`at all dose levels while that of eIF-4G was completed and sustained at 50 mg/week but not at 20
`mg/week.
`The sponsor also performed PK-PD modeling using biomarker data (S6Kl) to select the
`optimum dosing regimen. Model based simulations suggested that a 20-30 mg weekly dose
`would be associated with an anti-tumor effect and that daily administration (l0 mg QD) would
`
`exert greater effect than doses of 50 or 70 mg given weekly.
`
`1,2, 3
`
`The molecular results from these two studies led to the recommendation to explore doses of 10
`mg/day. The multiple phase 2 studies supported the safety and efficacy ofthis chosen dose.
`2.2.5 Pharmacokinetic characteristics of the drug and its major metabolites
`2.2.5.1 What are the single dose and multiple dose PK parameters?
`Phase 1 - solid tumors
`The sponsor combined the once-weekly (QW) and daily (QD) dosing data from 36 patients from
`two phase 1 trials in cancer patients (C2102 and C2101) to characterize the pharmacokinetic
`these phase 1 studies, everolimus was administered
`without chemotherapy in sequential cohorts at escalating doses of 5, 10, 20, and 30 mg/week
`(QW). Additional dose levels of 50 and 70 mg/week and 5 and 10 mg/day (QD) were added to
`the dose es