Clinical Review
`
`Herceptin@
`BLA 98-0369
`
`FDA Clinical Review of
`
`BLA 98-0369
`
`Herceptin@
`Trastuzumab
`(rhuMAb HER2)
`
`-
`
`Date of Submission: May 4, 1998
`Date of Approval:
`September 25, 1998
`
`Sponsor: Genentech, Inc.
`
`Food and Drug Administration
`Center for Biologics Evaluation and Research
`
`IMMUNOGEN 2178, pg. 1
`Phigenix v. Immunogen
`IPR2014-00676
`
`

`

`Clinical Review
`
`Herceptin@
`BLA 98-0369
`
`FDA Review Team
`
`Product/Chair:
`
`Julia Goldstein, MD
`
`Clinical/Primary:
`Clinical/Secondary:
`
`Susan Jerian, MD
`Genevieve Schechter, MD
`
`Statistical:
`
`Teresa Neeman, PhD
`
`Pharm/Tox:
`
`M. David Green, PhD
`
`Portions ofthe reviews of the statistical, product and
`plzarn~acoZogy/toxicoZogy sections have been included
`in
`the clinical review in order to improve the logicalflow
`of
`the content andprovide
`the reader with a comprehensive
`overview of the subj’ect.
`
`IMMUNOGEN 2178, pg. 2
`Phigenix v. Immunogen
`IPR2014-00676
`
`

`

`Clinical Review
`
`HerceptinGD
`BLA 98-0369
`
`Table of Contents
`
`Topic
`1 .O Background of the Product
`2.0
`Sponsor’s Proposed
`Indication
`3 .O Clinical Pharmacology Review
`4.0 Methodology
`of the Clinical Review
`5.0 Clinical Trial H0649g-Phase 2
`5.1 Title H0649g
`5.2 Study Design and Conduct H0649g
`5.3 Results - Efficacy H0649g
`5.4 Results - Safety H0649g
`6.0 Clinical Trial H0648g-Phase 3
`6.1 Title H0648g
`6.2 Title H0659g
`6.3 Study Design and Conduct H0648g
`6.4 Study H0659g
`of Data Review H0648g
`6.5 Methodology
`-
`6.6 Results Efficacy H0648g
`6.7 Results - Safety H0648g
`7.0 Relationship Between Level of HEFWneu Protein
`Overexpression
`and Clinical Benefit
`8.0 Overall Efficacy for all Phase 2 and 3 studies
`9.0 Reviewer’s Conclusions
`10.0 Appendix A: Patient Summaries
`11 .O Appendix B: Pharmacology/Toxicology
`12.0 Appendix C: Abbreviations
`13.0 Appendix D: Definitions
`for the Oncologic Drugs Advisory
`14.0 Appendix E: Questions
`Committee Meeting September 2, 1998
`15.0 Final FDA Clinical Reviewer Recommendation
`
`-
`
`Figure
`Figure 1.
`Figure 2.
`Figure 3.
`Figure 4.
`Figure 5.
`Figure 6.
`Figure 7.
`Figure 8.
`
`Figure 9.
`
`Kaplan-Meier Estimates Survival H0649g
`Time to Progression, All Patients H0648g
`Time to Progression, AC Patients H0648g
`Time to Progression, Tax01 Patients H0648g
`Survival Plot, All Patients H0648g
`Survival Plot, AC Patients H0648g
`Survival Plot, Tax01 Patients H0648g
`Summary of Cardiotoxicity Events
`H0648g and H0649g
`Kaplan-Meier Estimates of Cardiac Toxicities
`by Cumulative AC Dose
`
`3
`
`Page
`06
`09
`10
`14
`18
`18
`18
`21
`27
`31
`31
`31
`31
`36
`37
`37
`60
`
`73
`77
`79
`83
`92
`96
`98
`
`100
`105
`
`Page
`27
`50
`51
`52
`56
`57
`58
`
`69
`
`71
`
`IMMUNOGEN 2178, pg. 3
`Phigenix v. Immunogen
`IPR2014-00676
`
`

`

`Clinical Review
`
`Figure
`Figure 10.
`
`Figure 11.
`
`Figure 12.
`
`Kaplan-Meier Estimates of Cardiac Toxicities
`by Cumulative AC Dose
`Time to Progression 2+ Patients H0648g and
`H0649g
`Time to Progression 3+ Patients H0648g and
`H0649g
`
`Herceptina
`BLA 98-0369
`
`Page
`(3/4)
`
`71
`
`75
`
`76
`
`Page
`19
`22
`24
`26
`
`26
`28-30
`33
`39
`40
`45
`
`45
`
`46
`
`46
`47
`
`49
`
`49
`
`54
`
`54
`
`55
`55
`
`60
`
`60
`
`Table
`Table 1.
`Table 2.
`Table 3.
`Table 4.
`Table 5.
`
`Table 6.
`Table 7.
`Table 8.
`Table 9.
`Table 10.
`Table 11.
`
`Table 12.
`
`Table 13.
`
`Table 14.
`Table 15.
`
`Table 16.
`
`Table 17.
`
`Table 18.
`
`Table 19.
`
`Table 20.
`Table 2 1.
`
`Table 22.
`
`of Therapy H0649g
`
`Selection Criteria H0649g
`Reasons for Discontinuation
`Demographics H0649g
`Primary Endpoint H0649g - FDA derived data set
`Secondary Endpoint H0649g - Sponsor derived
`data set
`Adverse Events H0649g
`Comparison of original and final protocol H0648g
`Demographics H0648g
`Sites of metastatic Disease H0648g - FDA analysis
`Concomitant
`therapy by study arm H0648g
`Cumulative dose for anthracyclines
`and
`paclitaxel H0648g
`Patients who stopped
`therapy prior to completing
`6 cycles of chemotherapy H0648g
`Patients who completed chemotherapy
`and
`then stopped Herceptin H0648g
`Reasons for stopping
`therapy H0648g
`Time to Progression
`- Sponsor derived data set
`H0648g
`Time to Progression
`H0648g
`Response
`rate and duration of response
`derived data set H0648g
`Response
`rate and duration of response
`derived data set H0648g
`Time to Treatment Failure - Sponsor derived
`data set H0648g
`Survival H0648g
`Responding patients relative to IHC score of
`protein over-expression
`Proportion of patients who had tumor response:
`2+ vs 3+
`
`- FDA derived data set
`
`- Sponsor
`
`- FDA
`
`IMMUNOGEN 2178, pg. 4
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`IPR2014-00676
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`

`

`Clinical Review
`
`Table 23.
`
`Table 24.
`
`Table 25.
`
`Table 26.
`
`Table 27.
`
`Table 28.
`
`Table 29.
`
`Table 30.
`Table 3 1.
`
`Table 32.
`
`Adverse events H0648g - Listing as percent of
`those enrolled and treated
`Adverse events H0648g - Listing by number of
`moderate and severe events
`Selected
`toxicity events - FDA derived data
`set H0648g
`of patients who developed
`Profile/demographics
`cardiotoxicity H0648g
`Incidence of cardiotoxicity
`class I-IV by
`cumulative dose range H0648g
`Incidence of cardiotoxicity
`class III-IV by
`cumulative dose range H0648g
`Percent of patients
`testing 2+ or 3+ by IHC
`H0648g and H0649g
`Response
`rate by IHC score H0648g and H0649g
`Median time to progression of 2+ vs 3+ patients
`enrolled on H0648g
`Efficacy results for all Herceptin studies
`submitted
`to the BLA
`
`Herceptin@
`BLA 98-0369
`
`61-62
`
`63-64
`
`65
`
`68
`
`70
`
`70
`
`73
`74
`
`74
`
`78
`
`IMMUNOGEN 2178, pg. 5
`Phigenix v. Immunogen
`IPR2014-00676
`
`

`

`Clinical Review
`
`Herceptin@
`BLA 98-0369
`
`1 .O BACKGROUND OF THE PRODUCT - HERCEPTIN@
`1.1 Introduction
`for
`It accounts
`in women.
`Breast cancer
`is one of the most common malignancies
`approximately
`l/3 of female cancer
`in the USA and therefore,
`remains a serious health
`care problem. Approximately
`2530%
`of breast and ovarian
`cancers
`overexpress
`HER2/neu. Abnormal expression of the HER2/neu
`is frequently observed
`in a number of
`primary
`tumors,
`suggesting
`that overexpression may contribute
`to transformation
`and
`tumorigenesis.
`HEIWneu overexpression
`has been correlated with poor clinical outcome
`in patients with breast and ovarian cancers. HER21neu overexpression
`appears
`to be
`associated with shorter disease-free
`inten.al,
`shorter overall survival, more rapid disease
`progression
`(higher
`incidence
`of metastasis),
`and
`resistance
`to chemotherapy
`in
`retrospective
`studies.
`
`1.2 HerceptinO
`humanized monoclonal
`DNA-derived
`is a recombinant
`Herceptin@
`(trastuzumab)
`antibody
`that targets
`the extracellular dc*main of the ErbB-2/HerYneu
`receptor.
`It was
`engineered
`by grafting
`the complementarity
`determining
`regions of the parental murine
`antibody
`(4D5) into the consensus
`framework of a human IgGl.
`
`systems at
`in cell culture
`from CHO cells maintained
`Herceptin@ has been produced
`trials sir,ce 1991. The entire cell culture process
`from
`Genentech
`for human clinical
`Master Cell Bank through final production contains no serum or other animal proteins.
`
`1.2.1 BACKGROUN?)
`
`The HER2 Receptor
`factor receptor 2 (ErbB-21 HER2p’85) is a member of Type I
`The human epidermal grov&
`family
`of growth
`factor
`tyrosine
`kinase
`receptors. The
`family
`also
`includes
`the
`endothelial growth factor receptor (EGFR), HER3, and HER4 receptors. These receptors
`are encoded by homeotic genes and share extensive
`sequence homology,
`suggesting
`a
`similar mechanism
`of activation
`and signaling.
`These receptors
`function by forming
`hetero- and homo-dimers with members of the family.
`
`The c-ErbB-21 HER2p’8S proto-oncogene
`glycoprotein
`encodes a 185 Kd trans-membrane
`that participates
`in an
`interactive
`network
`of receptor-receptor
`interactions.
`These
`interactions
`regulate cell fate, growth and proliferation, mainly
`through MAP and
`.--
`Kinases.
`
`6
`
`IMMUNOGEN 2178, pg. 6
`Phigenix v. Immunogen
`IPR2014-00676
`
`

`

`Clinical Review
`
`Herceptin@
`BLA 98-0369
`
`_-
`
`that HER2 acts as co-receptor
`Current data indicate
`prolonging
`and enhancing activation of proteins
`involved
`
`sub-unit,
`signaling
`or a shared
`in signal transduction pathways
`
`Normal Expression of Her2p’B” and Its Role in Embrvooenesis:
`in
`Immunohistochemistry
`staining showed
`that HER2/neu
`is normally widely expressed
`differentiated
`adult and in fetal tissues derived
`from
`the three embry’onic germ
`layers.
`High intensity staining was reported
`in the gastrointestinal
`tract (Press M. et al. Oncogene
`1990) and the proximal
`tubules and loop of Henle of the urinary
`tract (Gullick W. et al.
`Int. J. Cancer, 40246-254
`(1987).
`
`of
`that espression
`1995) demonstrated
`Recent studies (Lee I;. et al. Nature 378:394-396,
`the null allele died
`HERXneu
`is crucial for cardiac and CN> development. Mice carrying
`of cranial neural-
`at El 1 due to the lack of cardiac trabeculae
`formation. The development
`crest derived sensory ganglia as \vell as
`the motor nerves,
`\vas also compromised.
`(Lee
`K. et al. Nature 378:394-396
`(1995).
`
`Role of HER2”Is5 in Sirnal Transduction
`as the preferred partner of all
`The current
`literature supports a normal role for HERZneu
`the other fainily members
`(Karunagaran D. et al. Embo J:15: 253-264).
`Several
`ligands
`have been characterized
`that bind the EGFR, HER3 and HER4. EGF and
`transforming
`gro\\-th factor-alpha
`(TGF-alpha)
`arc among
`the ligands for EGFR, and heregulin/NDF
`(neu differentiation
`factor)
`is the ligand
`for HER3 and HER4. No specific
`ligand
`for
`HER2 has been found.
`
`induces a conformational
`receptors
`the respecti1.e
`to
`Ligand binding
`in turn results
`in a) ty.rosine autopl,.tsphorylation
`receptor,
`lvhich
`binding affinity for the other receptors.
`
`change of the
`and b) increased
`
`formation. As a result of
`in hetero/homodimer
`results
`increased binding affinity
`The
`tyrosine kinases become activated and transphosphorylate
`ligand binding,
`the intracellular
`initiate
`the signal
`transduction
`(e.g., HEIUp’*‘). These events
`the
`binding partner
`pathway. The ultimate step in all Erb family members’ activation
`is mitogenesis.
`
`HER 2 “*’ Overexprcssion
`correlated with
`of HER2/neu has invariably
`transformation
`In humans,
`the oncogenic
`protein overexpression. Due to its constituti\*e kinase activity, HER2/neu overexpression
`results
`in enhanced
`tyrosine phosphorylation
`activities. Constitutive
`tyrosine
`kinase
`activity
`leads to increased proliferation
`rate, resistance
`to TNFa, decreased expression of
`adhesion molecules
`(E-cadherines
`and
`integrins)
`and
`increased
`vascular
`endothelial
`growth factor (VEGF) secretion.
`
`Mechanism of action of HerccntinQB
`Herceptina
`acts in vitro by a dual mechanisms of action:
`a) Biochemical: Exerted by binding
`to the HER2p’8s receptor.
`
`7
`
`IMMUNOGEN 2178, pg. 7
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`IPR2014-00676
`
`

`

`Clinical Review
`
`HerceptinQ
`BLA 98-0369
`
`to HER2p1*5 blocks dimer formation and induces down-regulation
`Herceptin binding
`the receptor. Both events lead to the blockade of the signal transduction pathway.
`In addition, Herceptin has the following
`in vitro effects:
`l Cytostasis:
`inhibition of proliferation
`by interference with the mitogenic
`activity of the HERZneu
`receptor due to the induction of the CDK2 kinase
`inhibitor, ~27~’ and the retinoblastoma-related
`protein, p 130;
`l Reduction of the cellular resistance
`to TNFa;
`(E-cadherines,
`l Restoration
`of the expression
`of adhesion molecules
`integrins)
`involved
`in metastasis development
`and progression,
`l Reduction of VEGF production
`
`a2
`
`of
`
`to the FcgRIII of CD16+ cells.
`Exerted by Fc binding
`Immunological:
`b)
`In vitro studies demonstrated
`that HerceptinO,
`in the presence of PBMN, was able to
`mediate ADCC (antibody-dependent
`cell-mediated
`cytotoxicity). This effect was due to
`binding of the MAb to the FcgRIII present on the surface of cytotoxic cells (NK, CDS+ T
`cells, monocytes, macrophages,
`and activated PMN). It is postulated
`that in the in vivo
`setting, Herceptin@ may recruit immune cells to the tumor site.
`
`IMMUNOGEN 2178, pg. 8
`Phigenix v. Immunogen
`IPR2014-00676
`
`

`

`Clinical Review
`
`HerceptinQS
`BLA 98-0369
`
`2.0 SPONSOR’S PROPOSED IhaICATION
`
`Genentech,
`
`Inc. proposed
`
`that HerceptinQ be approved for the following
`
`indication(s):
`
`the treatment ofpatients with metastatic breast cancer who
`is indicatedfor
`“HerceptinB
`have tumors that overexpress HER2. ”
`
`IMMUNOGEN 2178, pg. 9
`Phigenix v. Immunogen
`IPR2014-00676
`
`

`

`Clinical Review
`
`Herceptin@
`BLA 98-0369
`
`3.0 Clinical Pharmacolopv
`
`Review of HerceptinB
`
`(MoAb) that selectively
`antibody
`is a recombinant humanized monoclonal
`Herceptin@
`is
`targets HER2/neu,
`the extracellular domain of the EGF receptor 2 protein. The MoAb
`an IgGl
`that contains human framework
`regions with the CDR of a murine antibody
`that
`binds to HER2/neu. Herceptin@ binds with high affinity to the HER2/neu protein,
`inhibits proliferation of human
`tumor cells that overexpresses HER2/neu
`in vitro and in
`vivo, and is a potent mediator of ADCC.
`
`in three Phase 1, three Phase 2, and one Phase 3
`Clinical pharmacokinetics were studied
`investigations
`in patients with metastatic breast cancer with tumors
`that over express
`the
`HElUneu
`gene product. Both single dose and multiple dose kinetics were studied.
`Pharmacokinetic
`data were collected as part of clinical safety and efficacy
`trials and no
`clinical studies were conducted
`to specifically
`investigate special populations,
`pharmacokinetics
`profiles or formulation
`issues.
`
`stimulation analysis, a weekly dose of 100
`From data used to perform a pharmacokinetics
`trough levels within the serum
`levels
`mg was selected for study and found to provide
`thought efficacious
`(10 to 20 pg/ml based on preclinical studies). A loading dose of 250
`mg was added to the dosing regimen
`to attain the target levels more quickly. Experience
`in early clinical development
`suggested
`that rather than administer a fixed dose of 250
`and 100 mg, a body weight adjusted dose of 4 mg/kg as a loading dose and 2 mg/kg as a
`maintenance dose would improve
`the consistency of response. Furthermore,
`a minimum
`target trough
`level of 20 pg/ml was selected as the lower limit of serum levels to be
`maintained upon repeated dosing.
`
`the
`the mechanisms of HerceptinQ clearance are not specifically established,
`Although
`presence of shed antigen from the HER2/neu
`receptor
`is known
`to increase
`the clearance
`of Herceptin@.
`
`The following
`
`studies investigated
`
`the pharmacokinetics
`
`of Herceptin@:
`
`Phase 1 studies
`
`1. HO407g: a single dose study of IO, 50, 100,250, and 500 mg
`
`2. H0452g: a multi-dose once weekly dosing regimen of 10, 50, 100,250, or 500 mg
`
`3. H0453g: a multi-dose once weekly dosing regimen of 10,50, 100,250 or 500 mg with
`cisplatin
`
`Phase 2 studies
`
`4. HO55 1 g: multi-dose given once weekly dosing regimen of 250 mg loading dose and
`
`10
`
`IMMUNOGEN 2178, pg. 10
`Phigenix v. Immunogen
`IPR2014-00676
`
`

`

`Clinical Review
`
`100 mg maintenance dose
`
`HerceptinB
`BLA 98-0369
`
`5. H0552g multi-dose given once weekly dosing regimen of 250 rng loading dose and
`100 mg maintenance dose with cisplatin
`
`Phase 3 studies
`
`loading dose and 2 mgkg
`study of 4 mgkg
`6. H0648g once weeklyr multi-dose
`maintenance d, se in patients given Herceptin@ 2nd chemotherapy
`
`study of 4 mgkg
`7. H0649g once \veekly, multi-dose
`maintenance dose in patients given HerceptinB
`
`loading dose and 2 mgkg
`
`Summary of Phamiacokinetics:
`
`the
`in Phase 1 and used to characterized
`Single dose studies \vere conducted
`in Phase 2. only
`pharmacokinetic
`profile of the hloAb.
`In multi-dose
`studies conducted
`\vithin 1 -hour of
`trough and peak samples were obtained. Peak samples were collected
`the end of HerceptinQ
`infusion.
`In addition
`to quantifjing
`levels of HerceptinO,
`all
`serum samples were also analyzed for shed antigen and antibodies
`to HerceptinO.
`In one
`Phase 2 studyp and one Phase 3 study. shed antigen was determined
`at irarious times \vhich
`included pretreatment
`samples.
`
`data were fit. to either a 1 or 2
`phannacokinetic
`le\rels of Hcrceptina.
`For strum
`compartment model as determined by the best tit of the data to the regression
`line. AUC,
`Cl and Css (steady-state concentrations) were determined using non-compartmental
`methods. Trough and peak serum le\cls v\.ere observed samples without modification.
`Half-life
`\vas determined by a standard technique using the slope of the terminal
`elimination phase.
`
`including dose
`of HerceptinO
`Various factors ivere found to modify, the pharmacokinetics
`and shed antigen. Early studies demonstrated
`that HerceptinO clearance
`(Clt) decreased
`with increasing dose as shown
`in the tables below. Concomitantly,
`half-life (t1/2)
`increased with decrea: 2s in Clt following
`increased dosage. Since the volume of
`distribution
`remained basically unchanged with increases
`in dose, it is likely that the
`changes
`in Clt and 1112 reflect an alteration
`in the elimination pathways of the Mo.4b
`rather than the extent of distribution. However, steady state serum levels were found to
`rise upon repeated dosing without an observable change in clearaxe
`suggesting
`that later
`rises in serum levels which occurred with repeated dosing may be due to alterations
`in
`distribc.:on
`rather than elimination.
`
`that an increased clearance of HerceptinR
`Additionally, Phase 1 studies revealed
`in patients. The association between shed antigen
`correlated with levels of shed antigen
`and Herceptin clearance was found to be continuous
`rather than a step function xith a
`specific cutoff such as 500 ng/ml. Given the dose selected for Phase 3 and the rise in
`
`IMMUNOGEN 2178, pg. 11
`Phigenix v. Immunogen
`IPR2014-00676
`
`

`

`Clinical Review
`
`Herceptina
`BLA 98-0369
`
`\vith repeated dosing, only about 9% of patients failed to
`levels of Herceptina
`trough
`achieve a level of 20 pg/ml or Herceptin@
`in a Phase 3 study. The percentage of patients
`with shed antigen levels >500 ng/mi Laried in the different studies between 0 and 24%.
`The highest percentage was observed
`In stud;. H0452g and the lowest percentage
`in study
`H0453g. The Phase 2 study H0649g demonstrated
`an elevated shed antigen
`level in 6.3%
`of the patients.
`
`Ninety-one per cent (177/l 95) of the patients given a maintenance dose of 2 mgkg
`obtained a trough serum le\rel of 20 &ml
`or higher at one or more sampling
`rimes as
`observed
`in HO6495 o\rer the first 8 \t.eeks. Trough serum concentrations
`at week 8 in
`studies H0618g and H0649g were greater thall predicted
`from simulations based on Phase
`2 data which suggests
`that later changes occur in the pharmacokinetics
`of HerceptinB
`upon repeated dosing. Serum concentrations
`achieved an observed steady-state
`level later
`(12 to 32 weeks) than would be predicted by their earlier pharmacokinetics
`(at
`approximately
`4 weeks) due to unknobvn factors.
`
`in the clinical study, but anJ
`levels were not found to be 1ndicatil.e of outcome
`Serum
`relationship of pharmacokinetics
`to -3tient outcome
`is likely confounded by several
`clinical factors such as disease burden and prior chemotherapy. No data are available
`regarding
`the possible relation between
`tumor burden, shed antigen and pharmacok..letics
`of Herceptin.
`
`the
`
`to investigate
`interaction studies were conducted
`No formal clinical drug-drug
`and cisplatin,
`potential
`influences bctkveen the pharmacokinctics
`of HerceptinB
`doxorubicin or epirubicin plus cyclophosphamide
`or paclitaxel.
`A comparison of serum
`levels of Herceptina
`given in combination
`lvith \kous
`chemotherapeutic
`agents did not
`suggest
`the possibility of any interactions except in combination with paclitaxel.
`Although not statistically significant. mean strum
`trough concentrations
`of HerccptinO
`\vith paclitasel
`\\.ere obscnped
`to bc consistently elevated
`\vhen compared
`cornbiruion
`serum of Herceptina
`levels \i.hen combined with AC. A non-clinical
`study in primates
`suggests
`that although
`the combination Herceptina with doxorubicin
`and
`cyclophosphamide
`does not effect the pharmacokinetics
`of HerceptinB or the
`chemotherapeutic
`agents, the pharmacokinetics
`of Herceptina
`are altered by paclitaxel.
`Clearance of Herceptina was statistically decreased when administered with paclitaxel.
`In the monkeys given Herceptina
`alone. clearance was 0.85+ 0.054 ml/hr/kg.
`ivhereas in
`the paclitaxel
`treated group it was 0.48~ 0.09 (X 2 SD). The non-clinical
`study used a
`different Posing regimen
`than that used clinically as the non-clinical
`study used an iv
`bolus administration
`of HerceptinO
`followed by a 60 minute
`iv infusion. No effect on
`paclitaxel pharrnacokinetics were observed
`in combination with HerceptinB
`in monkeys.
`
`in
`to
`
`the
`in formulation did not influence
`studies, changes
`Based on clinical and non-clinical
`pharmacokinetics
`of Herceptin m. Changing
`from a single-dose
`liquid to multiple-dose
`as
`lyophilized
`formulation did not appear to change the pharmacokinetics
`of HerceptinB
`Cmax and AUC were found to be similar in patients given either formulation
`in a Phase 3
`
`12
`
`IMMUNOGEN 2178, pg. 12
`Phigenix v. Immunogen
`IPR2014-00676
`
`

`

`Clinical Review
`
`HerceptinB
`BLA 98-0369
`
`of
`for a lack of effect on the pharmacokinetics
`study (H0648g). Additional evidence
`HerceptinO with changes
`in formulation or manufacturing was demonstrated
`in a series
`of non-clinical
`studies which were conducted using rhesus monkeys.
`These studies
`revealed no changes in pharmacokinetics
`incident to single dose vs multi-dose
`preparations,
`changes
`in the cell line used or scale-up for manufacturing
`purposes.
`
`Tables which summarize
`
`the pharmacokinetics
`
`of Herceptin follow:
`
`I
`I
`I
`I
`I
`for Herceptin as a 90 Minute
`Endpoints
`Table of Summary of Pharmacokinetic
`Infusion Across Studies H0452g, H0407g and H0453.
`
`I
`iv
`
`Dose, mg
`
`N
`
`t1/2, hr (days)
`
`Clt, ml/d/kg
`
`Vd, ml/kg
`
`Ctrough,
`ug/ml
`
`Cpcak,
`ugiml
`
`250/l 00
`6.2
`218 (9.1)
`82
`51
`18.3
`117
`for Herceptin given as 250 mg Loading
`Endpoints
`Table of Summary of Pharmacokinetic
`Dose plus a 100 mg Maintenance Dose (once weekly) Given in Studies HO55 1 g and
`H0552g. Crt-ough, Cpeak, Css were averaged across all observations.
`
`css,
`ug/ml
`
`102
`
`i
`
`Dose,
`m.&
`
`N
`
`t1/2, hr (d)
`
`Clt, ml/d/kg
`
`Vd, ml/kg
`
`Ctrough
`
`Cpeak
`
`CSS
`
`412
`159
`5.08
`141 (5.9)
`36.3
`53.6
`99.8
`of Herceptin@ Averaged
`from Studies H0648g and
`Summary of the Pharmacokinetics
`the effects of concomitant chemotherapy:
`doxorubicin
`H0649g. Study HO648 examined
`or paclitaxel. Crrough, Cpeak, Cm were observed
`or epirubicin plus cyclophosphamide
`at week 8 of repeated dosing.
`
`55.6
`
`in
`to augment serum levels of Herceptin@
`The potential contribution of paclitaxel
`agents, suggests caution
`in generalizing any
`comparison
`to other chemotherapeutic
`clinical benefit across a variety of chemotherapeutic
`agents.
`
`Please see Appendix B for details of the pre-clinical pharmacology/toxicology
`
`review.
`
`13
`
`IMMUNOGEN 2178, pg. 13
`Phigenix v. Immunogen
`IPR2014-00676
`
`

`

`Clinical Review
`
`Herceptin@
`BLA 98-0369
`
`4.0 METHODOLOGY OF THE CLINICAL REVIEW - OVERVIEW
`
`4.1 Clinical Studies
`This Biologics
`(BLA) for Herceptin@ was granted priority review
`License Application
`status and fast track designation;
`the sponsor was permitted
`to submit the contents
`in a
`rolling fashion with a complete application
`filed on May 4, 1998. Additional
`items have
`been submitted since that time. Some of these were planned (efficacy and safety updates)
`and some were responses
`to the requests of the FDA reviewers. The efficacy SAS data
`sets were updated at the end of May 1998. The safety data update was received
`in mid
`July 1998. A major efficacy update was received from the sponsor at the end of August
`1998. Requested
`imaging studies were received
`in mid September 1998.
`
`is a tabular summary of the studies conducted under IND 45 17 and which
`The following
`have been submitted
`to the BLA. Case Report Forms were submitted
`for studies H0648g
`and H0649g only.
`
`IMMUNOGEN 2178, pg. 14
`Phigenix v. Immunogen
`IPR2014-00676
`
`

`

`Clinical Review
`
`Studies submitted
`
`to the BLA:
`
`Study # Phase
`H0407g Phase 1
`
`H0452g Phase 1
`
`H0453g Phase 1
`
`H055lg Phase 2
`
`H0552g Phase 2
`
`Repimen
`Single dose
`10,50, 100,250,500 mg
`
`Weekly dosing
`10,50, 100,250,500 mg
`plus MTP’
`
`Weekly dosing
`10,50, 100,250,500 mg
`Plus Cisplatin 100 mgIm2
`plus MTP
`
`Weekly dosing
`250 mg load/l OOmg weekly
`plus MTP’
`
`Weekly dosing
`250 mg load/lOOmg weekly
`Plus Cisplatin 75 mdm2
`plus MTP’
`
`Herceptinm
`BLA 98-0369
`
`n=l6
`
`n=17
`
`Indication
`met. cancer
`Her2 (l-3+)
`
`met. cancer
`Her2 (l-3+)
`
`Accrual Status
`closed
`
`closed
`
`n=15
`
`met. cancer
`Her2 (l-3+)
`
`closed
`
`n=46
`
`met. breast ca.
`Her2 (2-3+)
`
`closed
`
`n=39
`
`met. breast ca
`Her2 (2-3+)
`
`closed
`
`lf’eekly dosing
`4 m&kg loud 2 mg/kg weekly
`Plus AC or Paclrtaxel vs chemo alone
`May go IO HO659g ot PD
`
`n=469
`
`met. breast ca
`Her2 (2-3 +)
`
`closed
`
`H0649g Phase 2
`
`Weekly dosing
`4 mg/kg load 2 mgfkg weekly
`Plus at PD 2 or 4 mg/kg f chemo
`
`n=222
`
`met. breast ca
`Her2 (2-3+)
`
`closed
`
`H0650g Phase 2
`
`Weekly dosing
`4 mg/kg
`load 2 mg/kg weekly
`
`n=62
`
`met. breast ca
`Her2 (2-3+)
`
`ongoing
`
`-
`H0659g Phase 2
`
`H0693g Phase 2
`
`8 mg/kg load 4 mg/kg weekly
`
`Weekly dosing
`4 mgfkg load 2 mglkg weekly
`f antitumor
`therapy
`
`Weekly dosing
`4 mg/kg
`load 2 mg/kg weekly
`f antitumor
`therapy
`
`n=l57
`
`met. breast ca
`Her2 (2-3+)
`
`ongoing
`
`n=163
`
`met. breast ca
`Her2 (any test)
`
`ongoing
`
`a MTP refers to a Maintenance Treatment Program which allowed the patient to continue to receive
`Herceptin@ weekly until progressive disease.
`
`15
`
`IMMUNOGEN 2178, pg. 15
`Phigenix v. Immunogen
`IPR2014-00676
`
`

`

`Clinical Review
`
`Herceptin@
`BLA 98-0369
`
`4.2 Analyses
`In
`Most analyses were conducted using the SAS data sets submitted by the sponsor.
`particular
`instances where the FDA chose to perform
`intensive
`review of the raw data in
`the CRF’s and patient narratives,
`the information was entered
`into separate FDA
`generated data sets from which analyses were performed. This was performed
`for
`selected adverse events (cardiac, hematologic,
`infectious, hospitalizions,
`pain, growth
`factor use, transfusions), determination
`of sites of disease (visceral, superficial
`(soft
`tissue) or bone), reasons for discontinuation
`of therapy, and determination
`of tumor
`response and time to progression.
`In addition, original imaging studies (e.g. CXR’s, CT
`scans, bone scans) of some patients were reviewed by the FDA.
`Instances where the
`FDA based analyses were performed are clearly noted in this document.
`
`’
`
`Response E\*aluation Committee
`
`(REC)
`
`in December 1996 after the protocols had been underway
`for
`The REC was established
`to
`It was a blinded committee
`(blinded
`to study and blinded
`over one and a half years.
`treatment arm) with a separate charter w.hich outlined procedures
`for acquisition of films
`from the siles, maintaining uniform criteria for determining
`response, and contacting
`the
`sites with results in a timely fashion. The committee was composed of 8 oncologists
`and 10 radiologists. Each reading team consisted of one oncologist and one radiologist.
`Internal Lralidation studies were conducted
`to ensure that inter-reader
`lpariability was >
`80% \jith a goal of 90%; we have not reviewed
`these inter-reader variability data. The
`readings occurred evev 2 weeks and in\!cstigators
`lvere notified of the results by fax.
`The charter outlined
`in great detail w-hat imaging studies w&e required, how frequently
`they should have been performed, and u*hat other ancillary data, such as pathology
`reports, should have been submitted
`to the REC. Since the tumor measurements
`obtained by the site impestigators were not collected on the ClWs, the REC elraluation
`was the only tumor measurement
`data available for rclriew. All patients were to be
`reviewed by the REC.
`
`b)
`
`Some elements of the REC charte;, however, were problematic:
`-
`a>
`(pleural effusions,
`The charter did not allow the REC to consider effusions
`ascites) as malignant unless there was cytopathologic
`evidence of
`malignancy.
`The charter did not allow the REC to consider new lesions on bone scans
`(either initial or sequentially
`increasing
`in number) as malignant unless there
`was a CT, MRI or plain X-ray confirmation.
`c>
`While the charter did require that the REC evaluate all sites of disease and all
`imaging studies,
`it did not require the REC to comment on other than the
`in
`indicator
`lesions selected; for example,
`there may be a progressive
`increase
`the size of a pleural effusion on sequential films, yet the data conveyed on the
`REC CRF’s did not indicate this finding.
`
`16
`
`IMMUNOGEN 2178, pg. 16
`Phigenix v. Immunogen
`IPR2014-00676
`
`

`

`Clinical Review
`
`Herceptin@
`BLA 98-0369
`
`4% of the
`in the charter, imaging studies of approximately
`Because of the problems
`patients enrolled on studies H0648g and H0649g were reviewed by the FDA. The
`conclusion of this film review was that, in general, the REC analysis was rigorous and in
`many cases conservative.
`In a small number of cases which fell into the problematic
`areas noted above, the FDA analysis differed with the REC analysis and in those cases
`the FDA analysis was used in calculating
`the endpoints.
`
`4.3 VaIidation
`treatment and
`Particular attention was placed upon validation of chemotherapy
`HerceptinO
`treatment. Herceptin
`treatment validation was complicated
`by the fact that
`the study began as a placebo controlled study and then was amended
`to become an open
`label trial; some patients who enrolled when the placebo therapy was in effect had vial lot
`numbers entered on their case report forms and some did not. The sponsor was asked and
`has supplied
`the codes for the blind and copies of the returned vial labels from those
`patients
`for whom no lot number was entered on the case report forms. Throughout
`the
`review process consistency between CW entries and SAS data sets was examined.
`
`4.4 Status of the Clinical Review
`for studies H0648g and H0649g. These
`This review
`is based primarily on data submitted
`are the only studies for which CRFs have been submitted.
`-
`-
`__. ___--m.
`
`17
`
`IMMUNOGEN 2178, pg. 17
`Phigenix v. Immunogen
`IPR2014-00676
`
`

`

`Clinical Review
`
`HerceptinO
`BLA 98-0369
`
`5.0 CLINICAL TRIAL H0649a - PHASE 2, SINGLE AIM STUDY
`
`5.1 Title H0649g
`A Multinational, Open-Label Study of Recombinant Humanized Anti-p1 85HEW
`Monoclonal Antibody
`(rhuMAb HER2) in Patients with HER2/neu Overexpression Who
`Have Relapsed Following One or Two Cytotoxic Chemotherapy Regimens
`for Metastatic
`Breast Cancer
`
`Conducted April 24, 1995 to June 4, 1997
`
`5.2 Study design and conduct H0649g
`
`5.2.1 Objectives H0649g
`rate defined as the sum
`Primary endpoints of this study were the overall response
`of the complete and partial responses and delineation of the safety profile of Herceptin@
`as a single agent in patients with metastaric breast cancer.
`time to progression,
`Secondary endpoints were the duration of response,
`treatment
`failure, smival,
`and quality of life. Please refer to Appendix D for all
`definitions..
`
`time to
`
`52.2 Desizn H0639g
`conducted at 54
`This is a Phase 2, open label, single arm study of HerceptinB
`in the North America, Europe, and Australia/New Zealand. The target enrollment
`centers
`was 200 patients.
`
`18
`
`IMMUNOGEN 2178, pg. 18
`Phigenix v. Immunogen
`IPR2014-00676
`
`

`

`Clinical Review
`
`Herceptinm
`BLA 98-0369
`
`5.2.3 Patient Selection H0649g
`in May 1996. Below
`The selection criteria for patients was amended
`the criteria from the original protocol and in its amended format.
`
`is a list of
`
`Final protocol - May 1996
`18 or older
`Metastatic Breast Cancer
`1 Progression
`following
`one or t~‘o
`/ regimens
`for metastatic disease.
`
`I
`
`I
`
`or FISH
`
`1 Acceptnblc only
`if both primary
`tumors are 2+ or 3+ or all
`metastatic sites are 2+ or 3+ for
`HER2 by IHC
`2+ or 3+ by
`immunohistochemistry
`eliminated
`Mass at least I cm in greatest
`dimension measurable
`in 2
`. dimensions by physical, CT,
`MRI, ultrasound, or photos.
`60% or bener
`eliminated
`eliminated
`eliminated
`eliminated
`eliminated
`eliminated
`eliminated
`
`eliminated
`
`if stable after radiation
`
`Allowed
`treatment
`therapy more than 30
`Stopped
`days prior to entry
`
`Age
`Diagnosis
`Prior chemotherapy
`cancer
`
`for breast
`
`- April 1995
`
`Bilateral breast ca