~enentech, Inc.
`
`460 Point San Bruno Boulevard
`South San Francisco. CA 940804990
`(41 51225- 1000
`FAX· (41 5) 225-6000
`
`November 16, 1995
`
`Ms. Sharon Risso
`Director
`DARP (HFM-585)
`Center for Biologics Evaluation and Research
`Food and Drug Administration
`1401 Rockville Pike
`Rockville, MD 20852-1448
`
`·.._...··
`
`Subject: BB-IND 4517 recombinant humanized Anti-p18SHER2 Monoclonal
`Antibody (rhuMAb HER2)
`Response to FDA Request for Information
`Protocol Amendment: Change in Protocol
`Serial No. 055
`
`Dear Ms. Risso:
`
`Reference is made to Genentech's lnvestigational New Drug Application,
`BB-IND No. 4517, recombinant humanized Anti-p185HER2 Monoclonal
`Antibody (rhuMAb HER2) for treating cancer patients with tumors that
`overexpress the HER2 proto-oncogene (submitted on April 20, 1992, Serial
`No. 000).
`
`Reference is also to made to a letter Genentech received from the Agency
`dated June 16, 1995, in which the Agency provided comments concerning
`information Genentech submitted on January 5, February 16, March 7, and
`March 14, 1995, as it pertains to the clinical program for rhuMAb HER2.
`
`Reference is also made a teleconference held with the Agency on
`October 30, 1995, to discuss proposed changes to pivotal trial H0648g. The
`proposed changes will allow entry of patients who have previously received
`doxorubicin as an adjuvant treatment for metastatic breast cancer. In the
`teleconference, Genentech agreed to provide the Agency with the Data Safety
`
`·...__,.··
`
`P~~T~I.\,V~ ORDER MATERIAL
`
`EXH1err
`.J._
`l!Jl#e1.i4v¥/
`31 1 11 3
`MARK RICHMAN. RPR
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`GENENTECH_0000034
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`..._..
`
`Ms. Sharon Risso
`November 16, 1995
`Page2
`
`Monitoring Board charter, curricula vitae of the DSMB members, and the
`statistical analysis plan. Those documents are under preparation and will be
`submitted as soon as they are available.
`
`The purpose of this submission is to submit the amended protocol for H0648g
`and to respond to the Agency's questions and comments about the trial. The
`protocol amendment with the list of changes is attached.
`
`Attachment: H0648g Amendment 1
`
`A Phase III, Multinational, Double-Blind Study Comparing Recombinant
`Humanized Anti-p18SHER2 Monoclonal Antibody (rhuMAb HER2) Plus
`Chemotherapy Compared with Placebo Plus Chemotherapy in Patients
`with HER2/ neu Overexpression Who Have Not Received Cytotoxic
`Chemotherapy for Metastatic Breast Cancer (Submitted March 7,
`1995/Serial No. 033.)
`
`'-.._/.
`
`For clarity, we have provided the Agency's questions and comments in bold
`followed by. Genentech's responses in normal type.
`
`1. With regard to the revised clinical protocol H0648g, entitled "A Phase 3,
`Multinational Double-Blind
`Study Comparing
`Recombinant
`Humanized Anti-plSSHERl Monoclonal Antibody (rhuMAb HER2) Plus
`Cyclophosphamide
`and
`Doxorubicin with
`Placebo
`Plus
`Cyclophosphamide and Doxorubicin
`in Patients with HER2/neu
`Overexpression Who Have Not Received Prior Cytotoxic Chemotherapy
`for Metastatic Bi:east Cancer", we have the following comments:
`
`a. The primary efficacy endpoint of this trial is time to progression,
`analyzed at 12 months after the last patient has been entered and
`will include all eligible patients. This endpoint must be supported
`by neutral or positive trends fn favor of the rhuMAb HER2 plus
`chemotherapy arm for the secondary endpoints of overall response
`rate, complete response rate, and quality of life assessment. If the
`effect of addition of the monoclonal antibody to the combination of
`cycloph~sphamide and doxorubicin results in a lowered response
`rate due to growth arrest rather than tumor reduc'tion, the benefit of
`such therapy will be of uncertain patient benefit. In the setting of
`metastatic disease, a durable complete or major partial response is
`expected to correlate with improvement in disease-related
`
`PROTECTIVE ORDER MATERIAL
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`·-
`
`Ms. Sharon Risso
`November 16, 1995
`Page3
`
`symptomatology while disease stabilization, even if prolonged, may
`not provide much symptomatic relief to the patient.
`
`We acknowledge that a positive result on time to progression as the
`primary efficacy endpoint for patients receiving rhuMAb HER2
`compared to those receiving placebo must be supported by neutral
`or positive trends in favor of response rates and quality of life in
`order to show a correlation of increased time to progression with
`·
`clinical benefit to the patient.
`
`h We note that there will be an interim analysis to estimate the
`treatment effect and determine whether the sample size or duration
`of follow-up should be adjusted. This is necessary because you have
`no data that suggest that addition of the monoclonal antibody will
`prolong the time to progression or, if it did, by what magnitude.
`The clinical impact of a delay in the median time to progression
`will need to be weighed against any adverse effects of the therapy.
`
`The purpose of the interim analysis is to verify the estimate of time
`to progression in the control group. In designing the trial, the
`number of patients and the duration of follow-up was based on the
`assumption that metastatic breast cancer patients treated with
`doxorubicin and cyclophosphamide had a median time to
`progression of 8 months. However, we do not know the median
`time to progression for patients with HER2 overexpressing tumors.
`
`At the time of the interim efficacy analysis, the Data Safety
`Monitoring Board (DSMB) will review the safety data as well. The
`follow-up period will not be extended if, in the opinion of the
`OSMB, there is an i~creased risk to patients of developing serious
`adverse events.
`
`c
`
`The protocol states that the dose mod.ification for non-hematologic
`toxicities will be carried out at the investigator's discretion. The
`protocol would be improved if uniform guidelines for dose
`adjustments were provided; however, since the protocol is blinded
`there should not be bias in the manner in which dose adjustments
`are made by individual investigators.
`
`PROTECTIVE ORDER MATERIAL
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`.._.··
`
`Ms. Sharon Risso
`November 16, 1995
`Page4
`
`We agree there should be no bias in dose reduction for non(cid:173)
`hematologic toxicities in this comparative study. To ensure
`compliance with the do.se and administration section of the package
`insert for branded doxorubicin, we are amending the protocol to
`introduce mandated dose reduction for increased bilirubin. (See
`Attachment 1, Section 5.4.). Additonal recommendations are made
`for dose reduction or delay for hematologic and other non(cid:173)
`hematologic toxicities. (See Appendix F.)
`
`d.
`
`Please confirm that all concomitant medications (including days of
`therapy and daily dose), blood transfusions, and hospitalizations
`will be recorded. The reason for initiation of new medications and
`the reasons for hospitalization and duration of hospitalization must
`also be recorded. In particular, the daily dose of narcotics or any
`other agents which may be used for palliation must be available i~
`order to attempt to interpret the quality of life data.
`
`We confirm that the concomitant medication case report form
`(CRF) designed for this study will collect the name of ill
`medications taken, the indication (i.e., the reasons for the initiation
`of new medications), total daily dose, and start and stop date of
`medication. If medications are taken on an as needed basis (PRN),
`sites have been instructed to enter the dose typically taken at each
`dosing. Sites have been instructed to list all medications used, as
`well as all blood transfusion information. Our Medical
`Information and Drug Experience (MIDE) safety database captures
`whether a serious ad.verse event involves a hospitalization, is life(cid:173)
`threatening, is a new cancer, etc. Our original CRFs collected the
`serious adverse event, but did not request duration of
`hospitalization information. At your request, we are amending the
`serious adverse event CRFs to capture the hospitalization
`information so as to adequately link the serious event with
`duration of hospitalization in our clinical database.
`
`e.
`
`Please clarify how you will analyze · quality of life assessments in
`patients who receive palliative, local radiotherapy or in whom
`other palliative measures are undertaken.
`
`· .. .._. . ...-
`
`··-""
`
`PROTECTIVE ORDER MATERIAL
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`..._.,.
`
`Ms. Sharon Risso
`November 16, 1995
`Pages
`
`The effect of the local radiotherapy on the quality of life can be
`positive or negative, depending on when the quality of life
`questionnaire is administered and when the· patient receives
`radiotherapy. Two sets of analysis will be performed: one ignoring
`the information on local radiotherapy and the other including the
`information on the local radiotherapy as a covariate.
`
`If you have any questions or comments concerning this submission, please
`contact Roxanne Bales, Senior Manager, Regulatory Affairs of my staff at
`(415) 225-1024.
`
`-·-
`
`·-·
`
`.._ ..
`
`PROTECTIVE ORDER MATERIAL
`5/4517-042 IUb ~
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`GENENTECH_0000038
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`".._/.
`
`...__ ..
`
`This submission contains information that constitutes trade secrets and/or is
`confidential within the meaning of the Federal Food, Drug and Cosmetic Act
`(21 U.S.C. §331 [j]), the Freedom of Information Act (5 U.S.C. §552[b][4] &
`18 U.S.C. Section 1905) and 21CFR601.50 and may not be revealed or
`disclosed without the prior written authorization of Genentech, Inc .
`
`PROTECTIVE ORDER MATERIAL
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`GENENTECH_0000039
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`DEPARTMENT OF HEALTH AND HUMAN SERVICES
`PUBLIC HEAL TH SERVICE
`FOOD AND DRUG ADMINISTRATION
`INVESTIGATIONAL NEW DRUG APPLICATION (IND)
`(TITLE 21, CODE OF FEDERAL REGULATIONS (CFR) Pert 312)
`
`'
`
`·..._ ~
`
`1 NAME OF SPONSOR
`Genentech, Inc.
`3 ADDRESS (Number, Street, City. State and Zip Ccdtl)
`
`460 Point San Bruno Boulevard
`South San Francisco, California 94080-4990
`
`Fenn~: a.e f\lo. 091()0014.
`E>tp/lafal Olds: Decerrbtlr31, 1~
`See a.e 5rldBmerton Rwatse.
`NOTE: No<*UJ mtr/ be~ or c:h::el
`n..algilbl beg.l'I Id an ND bht
`ln\lellgllb1ls ne«ect (21 CFR312.40).
`2 DATE OF SUBMISSION
`November 16, 1995
`4 TELEPHONE NUMBER
`(lndude AIM COOe).
`
`(415) 225-1557
`
`5 NAME(S) OF DRUG (Include all available narrw: Tftldfl, G8Ml1c, Chemical Qxfe)
`Recombinant Humanized Anti-p18SHB2 Monoclonal Antibody (rhuMAbHER2)
`
`e INONUMBER (/f Pf8~assigned)
`BB·IND4517
`
`7 INDICATION(S) (CoV9red by this submission)
`Treatment of Cancer Patients with Tumors that Overexpress the HERZ Proto-oncogene
`
`8 PHASE(S) OF CLINICAL INVESTIGATION TO BE CONDUCTED C PHASE 1 C PHASE2 • PliASE3 D OTHER
`
`(Sp«;itf)
`9 LIST NUMBERS OF ALL INVESTIGATIONAL NEW DRUG APPLICATIONS (21 CFR Part 312), NEW DRUG OR ANTIBIOTIC .APPLICATIONS
`(21 CFR Part 314), DRUG MASTER FILES (21CFR314.420). AND PRODUCT LICENSE APPLICATIONS (21 CFR Part 601) REFERRED TO IN THIS
`APPLICATION.
`
`_,.o IND submissions should be <?OnS8Ct.JflvBly numbef8d. The lnltlsl IND should be numbered
`•Serial Number: 000." The next submission (e.g., amendment, repolf, or correspondence)
`should be numbered •serial Number. 001. • Subsequent submissions should be numbered
`consecutively in the order in which they are submitted.
`
`SERIAi.. NUMBER:
`---
`0 5 5
`
`11 THIS SUBMISSION CONTAINS THE FOLLOWING: (Check all that apply)
`C INITIAL INVESTIGATIONAL NEW DRUG APPLICATION (IND)
`
`PROTOCOL M1ENDMENT(S):
`0 NEW PROTOCOL
`• CHANGE IN PROTOCOL
`0 NEW INVESTIGATOR
`
`INFORMATION AMENDMENT(S):
`D CHEMISTRY/MICROBIOLOGY
`C PHARMACOl..OGY/TOXICOLOGY
`OCLINICAL
`
`D RESPONSE TO CLINICAi.. HOLD
`
`IND SAFE'tY REPORT(S):
`C INITIAL WRITTEN REPORT
`C FOLLOW·UP TO A WRITTEN REPORT
`
`•RESPONSE TO FDA REQUEST FOR INFORMATION
`
`C ANNUAL REPORT
`
`C GENERAi.. CORRESPONDENCE
`
`C REQUEST FOR REINSTATEMENT OF IND THAT IS WITHDRAWN,
`INACTIVATED, TERMINATED OR DISCONTINUED
`
`COTHER
`
`{Sp«;ily)
`
`CHECK ONLY IF APPUCASLE
`JUSTIFICATION STATEMENT MUST BE SUBMITTED WITH APPLICATION FOR ANY CHECKED saow. REFER TO THE CITED CFR SECTION FOR
`FURTHER INFORMATION.
`
`C TREATMENT IND 21 CFR 312.35(b) C TREATMENT PROTOCOL 21 CFR 312.35(a) C CHARGE REQUESTINOTIFtCATION 21 CFR 312.7(d)
`
`CDR.IDBINDIOGD RECEIPT STAMP
`
`FOR FDA USE ONLY
`ODR RECEIPT STAMP
`
`'
`
`"'-
`
`IND NUMBER ASSIGNED
`
`DIVISION ASSIGNMENT
`
`PROTECTIVE ORDER MATE RIAL
`FORM FDA 1571 (6 92)
`
`PREVIOUS EDITlON OBSOLETE
`
`-
`
`· c c. -~ nnn nnAt'
`
`'"-
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`CONTENTS OF ~PPLICATION
`This application contains the following Items: (check an that apply)
`
`.
`
`181 1. Form FOA 1571
`[21CFR312.23(a)(1)]
`0 2. Table of contents [21 CFR 312.23{s)(2))
`O 3. Introductory statement {21 CFR 312.23(a)(3)}
`0 4. General lnvestlgatlonal plan {21 CFR 312.23(a)(3)J
`0 5. Investigator's brochure {21CFR312.23(a)(5)]
`6. Protocol(s) [21 CFR 312.23(s)(6)]
`181 a. Study protocol(s) [21 CFR 312.23(s)(6)]
`Ob. Investigator data [21 CFR312.23(a)(B)(lil)(b)] or completed Form(s) FDA 1572
`D c. Facilities data [21CFR312.23(a)(6)(iii)(b)] or completed Form(s) FDA 1572
`D d. Institutional Review Board data (21 CFR 312.23(a)(6)(/ll)(b)] or completed Form(s) FDA 1572
`D 7. Chemistry, manufacturing, and control data [21CFR312.23(s)(7)]
`O Environmental assessment or clalm for exclusion [21 CFR 312.23(a)(l)(lv)(e)]
`0 8. Pharmacology and toxloology data [21 CFR 312.23(a)(B)]
`0 9. Previous human experience {21CFR312.23(a)(9)]
`010. Additional information (21CFR312.23(a)(10)]
`
`13 IS At'lV PART OF THE CLINICAL STUDY TO BE CONDUCTED BY A CONTRACT RESEARCH ORGANIZATION? O YES ONO
`eves ONO
`IF YES, WILL ANY SPONSOR OBLIGATIONS BE TRANSFERRED TO THE CONTRACT RESEARCH ORGANIZATION?
`IF YES, ATTACH A STATEMENT CONTAINING THE NAME AND ADDRESS OF THE CONTRACT RESEARCH ORGANIZATION,
`toemFtCATION OF THE ct.INICAL STUDY, ANO A LISTING OF THE OBLIGATIONS TRANSFERRED.
`
`14 NAME ANO TITLE OF THE PERSON RESPONSIBLE FOR MONITORING THE CONDUCT ANO PROGRESS OF THE CLINICAL INVESTIGATIONS
`Tom Twaddell, MD.
`Assocute Director
`
`15 NAME(S) AND TITLE(S) OF THE PERSON(S) RESPONSIBLE FOR REVIEW AND EVALUATION OF INFORMATION RELEVANT TO THE SAFETY
`OFTHEDRUG
`Barry Sherman, m.D., Vice President, Medical Affairs
`Timothy G. Terrell, DVM, Ph.D., Director, Pathobiology and Toxicology
`
`I agree not to begin cllnlcal Investigations until 30 day• after FDA'• receipt of the IND unleaa I receive
`I also agree not to begin or continue cllnlcal
`earlier notification by FDA that the studies may begin.
`Investigations covered by the IND If those studies are placed on cllnlcal hold.
`I agree that an Institutional
`Review Board (IRB) that compllH with the requirement• Ht forth In 21 CFR Part 56 wlll be responsible for
`the Initial and continuing review and approval of each of the etudlea In the proposed cllnlcal Investigation.
`I
`agree to conduct the lnvestlgaflon In accordance with all other applicable regulatory requirements.
`
`16 NAMEOFSPONSORORSPONSOR'SAUTHORIZED ~7 SIGNATUR "2-!@°'12 0RS:;.: ·--.=•sAUTHORIZED
`
`REP
`
`ATIVE ~
`
`REPRESENTATIVE
`M. David Macfarlane, Ph.D.
`Vice President, Regulatory Affairs
`18 ADDRESS (Mlnber. Street Clty,StatesndZipC.ode)
`4.60 Point San Bruno Boulevard
`South San Francisco, California 94080-4990
`
`(WAIVING: A w111tully WM alilCliiiment le• criminal offew. U.S.C. Tiile 18, Sec.1001.)
`
`19 TELEPHONE NU
`(Include At.a Cod9)
`
`f1
`
`(415) 225-1557
`
`20 DATE
`
`~yr/
`
`·-......... .
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`TITLE:
`
`PROTOCOL AMENDMENT SUMMARY
`
`A PHASE Ill, MULTINATIONAL,
`DOUBLE·BLIND STUDY OF RECOMBINANT
`HUMANIZED ANTl·p1 e5HER2 MONOCLONAL
`ANTIBODY (rhuMAb HER2) PLUS
`CHEMOTHERAPY COMPARED WITH
`PLACEBO PLUS CHEMOTHERAPY IN
`PATIENTS WITH HER2/neu
`OVEREXPRESSION WHO HAVE NOT
`RECEIVED CYTOTOXIC CHEMOTHERAPY
`FOR METASTATIC BREAST CANCER
`
`PROTOCOL NUMBER:
`
`H0648g
`
`IND:
`
`BB-IND4517
`
`MEDICAL MONITOR:
`
`Thomas Twaddell, M.D.
`
`SPONSOR:
`
`Genentech, Inc.
`460 Point San Bruno Boulevard
`South San Francisco, CA 94080-4990 U.S.A.
`
`DATE FINAL:
`
`20 January 1995
`
`AMENDMENT ~:
`
`13 November 1995
`
`. CONFIDENTIAL
`This is a Genentech, Inc. document that contains confidential
`information. ·it is intended solely for the recipient clinical investigator(s)
`and must not be disclosed to any other party. This material can only be
`used for evaluating or conducting clinical investigations; any other
`proposed use requires written consent from Genentech, Inc.
`PROTECTIVE ORDER MATERIAL
`Protocol: rhuMAb HER2-Genentech, Inc.
`P H0648g·A1 .csumm Final
`
`O O t
`
`GENENTECH_0000042
`13NOV95
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`13 NOVEMBER 1995 AMENDMENT
`
`RATIONALE
`
`Protocol H0648g has been amended to:
`
`• Address comments and questions raised in recent correspondence
`from the FDA
`The exclusion criterion for hepatic function has been modified, and
`a dose reduction schedule for doxorubicin has been added that is
`consistent with FDA-approved product information.
`• Expand the patient population available for entry into this study by
`permitting prior anthracycline therapy (e.g., doxorubicin, epirubicin,
`mitoxantrone, idarubicin, or ~aunorubucin) in the adjuvant setting
`If, in the opinion of the investigator, paclitaxel represents the best
`therapy for this cohort of patients, they may receive paclitaxel. A
`dose reduction schedule for paclitaxel has also been added.
`• Clarify the study rationale because of the addition of paclitaxel
`• Clarify blood sampling requirements for serum pharmacokinetics,
`serum antibodies to rhuMAb HER2, and serum shed antigen
`• Add a supplemental questionnaire to examine pharmacoeconomic
`issues in both treatment groups
`• Address issues raised by the Data Safety Monitoring Board related
`to the interim analysis
`• Add a section pertaining to breaking the study blind, in compliance
`with regulatory reporting requirements and European Good Clinical
`Practice guidelines
`• Add a 60-day post-treatment follow-up to assess adverse events
`•
`Incorporate name and phone number changes of the contract
`research organization (CAO)
`Names and phone numbers of CAO contacts in Australia and
`New Zealand have been added.
`
`The title of the protocol has been simplified. The Introduction has been
`condensed because the identical information appears in the
`Investigator Brochure. Minor changes have been made to improve
`clarity and consistency. New information appears in italics. This
`amendment represents cumulative changes to the original final
`protocol.
`
`Q Q 2
`
`PROTECTIVE ORDER MATERIAL
`Protocol: rhuMAb HER2-Gen•ntech, Inc.
`1/P H0648g-A 1 Summ Final
`.
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`GENENTECH_0000043
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`SYNOPSIS
`
`PmvloUB/y BHd:
`
`'
`This protocol describes a Phase Ill randomized, placebo-controlled,
`double-blind, multinational study to determine the safety and efficacy of
`rhuMAb HER2 plus cyclophosphamide and doxorubicin compared with
`placebo plus cyclophosphamide and doxorubicin. Approximately
`450 patients with HER2/neu overexpression who have not received
`prior cytotoxic chemotherapy for metastatic breast cancer will be
`enrolled in the study and randomized to one of two treatment groups.
`
`rhuMAb HEA2 will be administered as a 4 mglkg .•. An equivalent
`amount of placebo will be administered on the same schedule ..•. After
`the completion of cytotoxic chemotherapy, rhuMAb HER2 or placebo
`will be continued weekly according to the original randomization until
`disease progression or study termination.
`
`The primary endpoint of the study will be time to disease progression.
`Complete and partial response rates and response duration will be
`determined and compared between the two groups ....
`
`Now8MdB:
`
`This protocol describes a Phase Ill, randomized, placebo-controlled,
`double-blind, multinational study in patients with HER2/neu
`overexpression who have not received cytotoxic chemotherapy for
`metastatic breast cancer. The objective of the study is to determine the
`safety and efficacy of recombinant humanized anti-p185HER2
`monoclonal antibody (rhuMAb HER2) used in addition to
`chemotherapy.
`
`All patients will receive either rhuMAb HER2 as a 4 ms;Vkg ... or an
`equivalent amount of placebo on the same schedule .... Patients who
`have net received anthracycline therapy (e.g., doxorubicin, epirubicin,
`mitoxantrone, idarubicin, or daunarubucin) in the adjuvant setting
`will receive cyclophosphamide (600 mg/m2) and doxorubicin
`(60 mg/m2) IV beginning on Day 1, then every 3 weeks on the day
`following rhuMAb HER2 administration, for a total of six cycles. If the
`patient received anthracycline therapy in the adjuvant setting and if,
`in the opinion of the investigator, the patient would benefit from
`003
`
`.
`PROTECTIVE ORDER MATERIAL
`Protocol: rhuMAb HER2-Genentech, Inc.
`2/P H0648g-A 1 Summ Final
`
`GENENTECH_0000044
`13NOV95
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`paclitaxel therapy, she may receive paclitaxel (175 mg/m2) over
`3 hours IV beginning on Day 1, then every 3 weeks on the day
`following administration of either rhuMAb HER2 or placebo, for a
`total of six cycles. At the Week 17 tumor evaluation, if the patient is
`continuing to benefit from the therapy and there is no dose-limiting
`toxicity (defined as WHO Grade 3 or 4 neuropathy), paclitaxel may be
`continued to a maximum of 10 cycles at the same dose every 3 weeks
`on the day following administration of either rhuMAb HER2 or
`placebo until disease progression or dose-limiting toxici"ty occurs.
`
`Approximately 450 patients will be enrolled in the study and
`randomized to either the rhuMAb HER2 or placebo arm, and will be
`stratified according to the type of metastatic disease: visceral (e.g.,
`liver or lung) versus superficial (e.g., skin, chest wall, and peripheral
`lymph node), and according to prior anthracycline therapy (yes/no).
`
`After the completion of cytotoxic chemotherapy, rhuMAb HER2 or
`placebo will be continued weekly according to the original
`randomization until disease progression or study termination. Patients
`will be evaluated for adverse events 60 days after discontinuing study
`drug and will be followed for survival information every 2 months.
`
`The primary endpoint of the study will be time to disease progression.
`Complete and partial response rates and response duration will be
`determined and compared between the rhuMAb HER2 and placebo
`treatment groups ....
`
`·......_,
`
`SECTION 1: INTRODUCTION
`
`In addition to condensing the text, the following revisions were made:
`
`SECTION 1.2: PRECLINICAL SIUDIES OF rhuMAb HER2
`
`Addtd:
`
`Characterization of the serum pharmacokinetics of rhuMAb HER2 in
`the presence of doxorubicin combined with cyclophosphamide or in the
`presence of doxorubicin or paclitaxel alone was conducted in female
`rhesus monkeys at doses that approximate human clinical doses on a
`body weight basis. Single-dose IV administration of rhuMAb HER2
`004
`
`PROTECTIVE ORDER MATERIAL
`Protocol: rhuMAb HER2--Genentech, Inc.
`3/P H0648g·A 1 Su mm Final
`
`GENENTECH_0000045
`13NOV95
`
`
`
`12 of 106
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`Celltrion v. Genentech
`IPR2017-01122
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`

`

`was well tolerated and did not alter the disposition of any agent
`administered.
`
`SECTION 1.4: STUDY RATIONALE
`
`previously Rud:
`
`Worldwide, doxorubicin-based regimens, especially those combined
`with cyclophosphamide, play an important role in therapy for the initial
`presentation of metastatic; breast cancer (25). In vivo nude mouse
`xenograft models utilizing HER2 transfected cell lines have
`demonstrated an additive effect in reducing tumor volume when
`rhuMAb HER2 is given in combination with doxorubicin, compared with
`rhuMAb HER2 or doxorubicin given alone (22). It is anticipated that, in
`a population of previously untreated patients with HER2
`overexpressing metastatic breast cancer, the addition of rhuMAb HEB2
`to a doxorubicin-based regimen will enhance efficacy compared with a
`doxorublcin-based regimen alone.
`
`Now Reads:
`
`Given the important role that HER2 plays in the pathogenesis and
`progression of breast cancer, it is vital to test the hypothesis that
`rhuMAb HER2 treatment is a valuable addition to standard
`chemotherapy. Cyclophosphamide and doxorubicin or paclitaxel are
`currently important chemotherapy agents in the treatment of breast
`cancer. In vivo nude mouse xenograft models utilizing HER2
`transfected cell lines have demonstrated an additive effect in reducing
`tumor volume when rhuMAb HER2 is given in combination with
`doxorubicin, compared with rhuMAb HER2 or doxorubicin given
`alone (20,23). Similar findings using a different in vivo model were
`reported with rhuMAb HER2 and paclitaxel (21,23). It is anticipated
`that, in a population of patients with HER2 overexpressing metastatic
`breast cancer, the addition of rhuMAb HER2 to cytotoxic chemotherapy
`will enhance efficacy.
`
`SECTION 2: OBJECTIVE
`
`Previously Read:
`
`The objective of th is study is to determine the safety and efficacy of
`rhuMAb HER2 .plus cyclophosphamide and doxorubicin compared with
`005
`
`PROTECTIVE ORDER MATERIAL
`Protocol: rhuMAb HER2-Genentech, Inc.
`4/P H0648g-A 1 Su mm Final
`
`GENENTECH_0000046
`
`13NOV95
`
`
`
`13 of 106
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`Celltrion v. Genentech
`IPR2017-01122
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`

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`placebo plus cyclophosphamide and doxorubicin in patients with
`HER2/neu overexpression who have not received prior cytoto.xic
`chemotherapy for metastatic breast cancer.
`
`Study endpoints are:
`
`Primacy:
`• To compare the time to disease progression in patients receiving
`rhuMAb HER2 plus cyclophosphamide and doxorubicin with those
`receiving placebo plus cyclophosphamide and doxorubicin ....
`Secondary:
`• To compare overall response rates (complete and partial
`responses) between both treatment groups
`• To compare the duration of response between both treatment
`groups in patients who have achieved a complete or partial
`response
`• To compare the quality of life of both treatment groups using the
`European Organization for Research and Treatment of Cancer
`(EORTC) quality-of-life instrument with the breast cancer module
`• To define the pharmacokinetic profile of rhuMAb HER2 when
`co-administered with cyclophosphamide and doxorubicin ....
`
`NawRedds:
`
`The objective of this study is to determine the safety and efficacy of
`rhuMAb HER2 used in addition to chemotherapy in patients with
`.
`,
`HER2/neu overexpressing metastatic breast cancer who have· not
`received prior cytotoxic chemotherapy.
`
`Study endpoints are:
`
`Primacy:
`• To compare the time to disease progression in patients receiving
`rhuMAb HER2 plus either cyclophosphamlde and doxorubicin or
`paclitaxel with those receiving placebo plus either
`cyclophosphamide and doxorubicin or paclitaxel ....
`
`PROTECTIVE ORDER MATERIAL
`Protocol: rhuMAb HER2-Genentech, Inc.
`5/P H0648g·A 1 Su mm Final
`
`006
`
`GENENTECH_0000047
`
`13NOV95
`
`·..__...
`
`. ...._,,,
`
`
`
`14 of 106
`
`Celltrion, Inc. 1046
`Celltrion v. Genentech
`IPR2017-01122
`
`

`

`Secondary:
`• To compare overall response rates (complete and partial
`responses) between both treatment arms (rhuMAb HER2 versus
`placebo)
`• To compare the duration of response between both treatment arms
`in patients who have achieved a complete or partial response
`• To compare the quality of life of both treatment arms using the
`European Organization for Research and Treatment of Cancer
`(EORTC) quality-of-life instrument with the breast cancer module
`. To define the pharmacokinetic profile of rhuMAb HEA2 when
`co-administered with either cyclophosphamide and doxorubicin or
`·
`paclitaxel....
`
`•
`
`SECTION 3: STUDY DESIGN
`
`Pmv/oustv Read:
`
`This is a Phase Ill, randomized, placebo-controlled, double-blind,
`multinational study comparing rhuMAb HER2 plus cycloph_osphamide
`and doxorubicin with placebo plus cyclophosphamide and doxorubicin.
`Approximately 450 patients with HER2/neu overexpression who have
`not received prior cytotoxic chemotherapy for metastatic breast cancer
`will be enrolled In the study. Upon signing the consent form and
`meetihg all eligibility criteria, patients will be equally randomized to one
`of two treatment groups.
`
`rhuMAb HER2 will be administered as a 4 mg/kg ... An equivalent
`amount of placebo will be administered on the same schedule ....
`
`NowRMds:
`
`This is a Phase Ill, randomized, placebo-controlled, double-blind,
`multinational study comparing rhuMAb HER2 plus either
`cyclophosphamide and doxorubicin or paclitaxel with placebo plus
`either cyclophosphamide and doxorubicin or paclitaxel. Approximately
`450 patients with HER2/neu overexpression who have not received
`cytotoxic chemotherapy for metastatic breast cancer .will be enrolled in
`the study. Upon signing the consent form and meeting all eligibility
`criteria, patients will be equally randomized to one of two treatment
`arms .
`
`007
`
`,_,,.
`
`. ..__.,
`
`PROTECTIVE ORDER MATERIAL
`Protocol: rhuMAb HER2--Genent~h. Inc.
`6/P H0648g·A 1 Summ Final
`
`GENENTECH_0000048
`13NOV95
`
`
`
`15 of 106
`
`Celltrion, Inc. 1046
`Celltrion v. Genentech
`IPR2017-01122
`
`

`

`Adt/ed:
`
`All patients will receive either rhuMAb HER2 as a 4 mg/kg ... or an
`equivalent amount of placebo on the same schedule ... . Patients who
`have not received anthracycline therapy (e.g., doxorubicin, epirubicin,
`mitoxantrone, idarubicin, or daunorubucin) in the adjuvant setting
`will receive cyclophosphamide (600 mgtm2) and doxorubicin
`(60 mg/m2) IV beginning on Day 1, then every 3 weeks on the day
`following rhuMAb HER2 administration, for a total of six cycles.
`
`If the patient received anthracycline therapy in the adjuvant setting
`and if, in the opinion of the investigator, the patient would benefit
`from paclitaxel therapy, she may receive paclitaxel (1 75 mg/m 2) over
`3 hours IV beginning on Day 1, then every 3 weeks on the day
`following administration of either rhuMAb HER2 or place"bo, for a
`total of six cycles. At the Week 17 tumor evaluation, if the patient is
`continuing to benefit from the therapy as defined below, and if there is
`TW dose-limiting toxicity defined as WHO Grade 3 or 4 neuropathy,
`paclitaxel may be continued to a maximum of 10 cycles at the same
`dose every 3 weeks on the day following administration of either
`rhuMAb HER2 or placebo until disease progression· or dose-limiting
`toxicity occurs.
`
`Criteria for continuation of paclitaxel beyond six cycles are as follows
`(see Section 7 for definitions of response criteria):
`
`• Complete Response: Patient may receive up to two more cycles of
`paclitaxel
`
`• Minor Response or Partial Response: Patient may receive
`additional cycles of paclitaxel until stabilization of best response,
`disease progression, or dose-limiting toxicity
`
`A maximum number of 10 cycles of paclitaxel will be given.
`
`•
`
`Stable Disease or Progressive Disease: Patient will not receive
`any further paclitaxel therapy
`
`PmvloUB/y Rud:
`
`One year after enrollment enrollment of the last patient, those patients
`randomized to rhuMAb HER2 who have not developed disease
`progression will be eligible to continue on that therapy in an open-label
`extension program. Those patients randomized to placebo will be
`Q Q 8
`PROTECTIVE ORDER MATERIAL
`Pn)tocol: rhuMAb HER2-Genentech, Inc.
`GENENTECH_0000049
`7/P H0648g·A1 Summ Final
`13NOV95
`
`
`
`16 of 106
`
`Celltrion, Inc. 1046
`Celltrion v. Genentech
`IPR2017-01122
`
`

`

`followed for disease status until progression or study termination. · All
`patients who develop disease progression will be followed for survival
`information every 2 months until termination of statistical analysis of the
`study.
`
`The primary endpoint of the study ... The complete and partial response
`rates and response duration will be determined and compared between
`the two groups ....
`
`Now Beads:
`
`One year after enrollment of the last patient, those patients randomized
`to rhuMAb HEA2 who have not developed disease progression will be
`eligible to continue on that therapy. Those patients randomized to
`placebo will be followed for disease status until progression or study
`termination. All patients who develop disease progression will be