'-./. Genentech, Inc.
`
`460 Point San Bruno Boulevard
`South San Francisco. CA 94080-4990
`(4151 225-1 000
`FAX: (4 15) 225-6000
`
`October 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 hwnanized Anti-ptssHER2 Monoclonal
`Antibody (rhuMAb HER2)
`Information Amendment: Clinical
`Serial No. 052
`
`Dear Ms. Risso:
`
`Reference is made to Genentech's Investigational New Drug Application,
`BB-IND No. 4517, recombinant h\imanized Anti-p18SHER2 Monoclonal
`Antibody (rhuMAb HER2), for treating cancer patients with tumors that
`overexpress the HER2 proto-oncogene (submitted on April 20, 1992, Serial
`No. 000).
`
`The purpose of this letter is to request a teleconference with the Agency to
`follow up an important issue initially discussed at our Pr~pivotal Trial
`meeting on December 22, 1994. Specifically, the difficulty in enrolling the
`pivotal comparative protocol H0648g, ''A Phase ill Multinational,
`Double-Blind Study Comparing Recombinant Humanized Anti-p18sHER2
`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 Breast Cancer" (submitted
`March 7, 1995/Serial No. 033).
`
`1/4517.0:W IUb ,,
`PROTECTIVE ORDER MATERIAL
`
`EXHjBIT
`Tt41Jllf'lf.IJW#I S
`::? 17 ''tr
`
`MARK RICHMAN, APA
`
`GENENTECH_0000001
`
`
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`....__...
`
`Ms. Sharon Risso
`{)ctober16,1995
`f'.age 2
`
`Background
`
`·..._.....·
`
`Protocol H0648g has a planned enrollment of 450 patients. The first patient
`enrolled on June 12, 1995, and only 11 patients have been treated to date.
`Although the reasons for lack of accrual are multifactorial in this complex
`trial, one factor appears to stand out in our discussions with oncologists:
`increasing use of doxorubicin in the adjuvant setting has made finding
`doxorubicin-naive patients presenting with first recurrence of metastatic
`disease difficult in most geographic areas. Since only patients with HER2
`overexpression are eligible for this study, 70 - 75% of patients are already
`excluded. It has become clear to us that the eligibility criteria should be
`modified with respect to patients who have seen prior anthracycline
`chemotherapy.
`
`We propose the addition of paclitaxel to a strata of patients who have
`received an anthracycline in the adjuvant setting. Although not approved
`for first-line therapy, we recognize the off-label use of paclitaxel by American
`clinical oncologists and the clinical trend in the use of taxanes as therapeutic
`agents in this fatal disease area. Since only a portion of patients receiving
`paclitaxel will have relapsed within 6 months of adjuvant therapy with
`doxorubicin, paclitaxel use in this present protocol will be outside the labeled
`indication in a significant number of patients. In effect, some patients will
`receive paclitaxel off-label while some patients will receive paclitaxel within
`the label.
`
`Proposal
`
`As per our original protocol, doxorubicin-naive patients will be treated with
`six cycles of cyclophosphamide and doxorubicin coadministered with
`rhuMAb HER2 or placebo.
`
`We propose to enroll patients who have seen prior doxorubicin. Patients
`who have been treated with doxorubicin in the adjuvant setting will receive
`paclitaxel 175 mg/m2 every three weeks coadministered with rhuMAb HER2
`or placebo. Paclitaxel will be given for six cycles and if neither disease
`progression nor dose limiting neurotoxicity has been reached, the
`investigator will be permitted to give additional cycles until either of those
`events occur.
`
`PROTECTIVE ORDER MATERIAL
`2/ 4511.(09 IUb ,.
`
`GENENTECH_0000002
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`. ..__..
`
`Ms. Sharon Risso
`October 16, 1995
`Page3
`
`As per the original protocol, the primary endpoint for this study remains the
`same: time to disease progression. The objective will be to demonstrate a 50%
`increase in time to progression in the group receiving chemotherapy (AC or
`paclitaxel) plus rhuMAb HER2 as compared to the group receiving
`chemotherapy alone.
`
`In terms of the analysis of the study, we propose the following:
`
`• patients will be randomized to rhuMAb HER2 or placebo
`• the randomization will be stratified by prior exposure to doxorubicin
`(yes/no)" and by type of metastatic disease (visceral/superficial)
`- patients who received doxorubicin in adjuvant setting will receive
`paclitaxel alone
`- patients who never received doxorubicin will receive a combination
`of doxorubicin and cydophosphamide (AC) as per the original
`protocol
`
`' - -.·
`
`The ·primary analysis will be based on the pooled data: all patients receiving
`rhuMAb HER2 versus all patients receiving placebo. Subgroup analysis will
`be of an exploratory nature only.
`
`The sample size of 450 patients remains unchanged and will reflect the
`following assumptions (unchanged):
`
`- 50% increase in time to disease progression
`- time to progression on chemotherapy only is eight months
`- the primary analysis is based on the pooled data
`- follow-up ti.me one year
`- loss to follow-up 20%
`- two-tail test Logra:nk test
`- level of significance p < .05, power 90%
`
`Because of the sample size (450 patients), we acknowledge that an increase in
`progression must be seen in l?oth strata (AC or paclitaxel); however, within
`none of the strata will a statistical significance of 0.05 be achieved due to the
`lack of power in subgroup analysis.
`
`We propose that patients enrolled to the current study will contribute to the
`total sample size (as part of the "no prior doxorubicin" strata) and will be
`included in the final analysis.
`
`·-··
`
`PROTECTIVE ORDER MATERIAL
`S/'517~ tub 1>
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`GENENTECH_0000003
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`·..._
`
`Ms. Sharon Risso
`October 16, 1995
`Page4
`
`Summary
`
`We would like to discuss with the Agency the following issues:
`
`• Does the Agency agree with the proposal to use paclitaxel off-label
`in the pivotal comparator trial H0648g?
`
`• Does the Agency agree with the proposed changes of the analysis
`plan for H0648g?
`
`• Does the Agency agree that the patients currently enrolled in
`H0648g will be included as part of the sample size and will be
`included the final analysis?
`
`._..·
`
`We would like to discuss our proposal with the Agency as soon as possible.
`Therefore, we would like to request a teleconference within the next week. If
`scheduling will not a permit a teleconference within the next week we ask
`that the Agency identify a day and time that would be convenient to discuss
`our proposal. Karl G. Trass of my office will be in contact with you to follow
`up on this request.
`
`If you have any questions or comments concerning this submission, please
`contact Karl G. Trass, Senior Associate, Regulatory Affairs, of my staff at
`(415) 225--5892.
`
`acFarlane, Ph.D.
`Vice President
`Regulatory Affairs
`
`·-·
`
`PROTECTIVE ORDER MATERIAL
`•/4517'°'9... ,,
`
`GENENTECH_0000004
`
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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 OD, the Freedom of Information Act (5 U.S.C. §552[bJI4] &
`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
`
`GENENTECH_0000005
`
`
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`L
`
`DEPARTMENT OF HEAL TH AND .HUMAN SERVICES
`PUBLIC HEAL TH SERVICE
`FOOD AND DRUG ADMINISTRATION
`INVESTIGATIONAL NEW DRUG APPLICATION (IND)
`(TITLE 21, CODE OF FEDERAL REGULATIONS (CFR) Patt S12)
`
`1 NAMEOFSPONSOR
`Genentech, Inc.
`3 ADDRESS (Number. SlrNt City, Sta/9 and z.p Code)
`460 Point San Bruno Boulevard
`South San Francisco, California 94080-4990
`
`Fam~~,..,. 091().()014.
`EJpafal DeJe: ""'*1""1r 81, 1992.
`s.. ()1.6 SlaJmlnt al RMr9a
`NOTE: No ct\,Q nwt be ttipped ordricel
`~be!Jll'"'an N>bhll
`lrMalgdc11 ls n elllGt (21 CFR 312.40),
`2 DATE OF SUBMISSION
`October 16, 1995
`4' TELEPHONE NUMBER
`(1nt:lut» MM Code)
`
`(415) 225-1557
`
`5 NAME(S) OF DRUG (lncWe all aVllilabltl ll&t1W: Trade, Generic, Chernlc.i Code)
`Recombirumt Humanized Anti·p18SHDl Monoclonal Antibody (rhuMAbHER2)
`
`S IND NUMBER (If pmlousfy 8$$/gMd)
`BB-IND4517
`
`7 INDICATION(S) (Cover.d by this Wbm/$slon)
`Treatment of Cancer Patients with Tumors that Overexpress the HER2 Prot<H>nc:ogene
`
`8 PHASE($) OF CLINICAL INVESTIGATION TO BE CONDUCTED 0PHASE 1 0 PHASE2 • ftiA.SE3 0 OTHER
`
`(SpecllyJ
`9 LIST NUMBERS OF All INVESTIGATIONAL NEW DRUG APPt.ICATlONS (21 CFR Part 312), NEW DRUG OR ANTIBIOTIC APPLICATIONS
`(21 CFR Part 314), DRUG MASTER ALES (21 CFR 314.420), AND PRODUCT LICENSE APPLICATIONS (21CFRPert601) REFERRED TO IN THIS
`APPLICATION.
`
`I
`
`'- 10 IND submissions should be consecutlYely numbered. TM lnltJaJ IND should be numbered
`•&Jtfltl Number: 000. • The next submission (e.g., amendment, f'BPOl'f, or correspondence)
`should be numbenKI "Serial Number: 001. • Subsequent submissions should be numbered
`consecutively in the order Jn which they are submitted.
`
`SERIAL NUMBER;
`...Q._! 1
`
`11 THIS SUBMISSION CONTAINS THE FOLLOWING: (Chec:K all 11lat apply)
`C INmAL INVESTIGATIONAL NEW DRUG APPLICATION (IND)
`
`PROTOCOL AMENDMENT($):
`C NEW PROTOCOL
`C CHANGE IN PROTOCOL
`C NEW INVESTIGATOR
`
`INFORMATION AMENDMENT($):
`C CHEMISTRY/MICROBIOLOGY
`C PHARMACOLOGY/TOXICOLOGY
`•CLINICAL
`
`C RESPONSE TO CLINICAL HOLD
`
`IND SAFETY REPORT(S):
`0 INITIAL WRITTEN REPORT
`C FOLLOW-UP TO A WRITTEN REPORT
`
`C RESPONSE TO FDA REQU~ST FOR INFORMATION
`
`O ANNUAL REPORT
`
`C GENERAL CORRESPONDENCE
`
`D REQUEST FOR REINSTATEMENT OF IND THAT IS WITHDRAWN,
`INACTIVATED, TERMINATED OR DISCONTINUED
`
`COTHER
`
`{SpedfyJ
`
`CHECK ONLY IF APPUCABlE
`
`JUSTIACATION STATEMENT MUST BE SUBMITTED WITH APPLICATION FOR ANY CHECKED BELOW. REFER TO THE CITED CFR SECTION FOR
`FURTHER INFORMATION.
`
`C TREATMENT IND 21 CFR 312.35(b) C TREATMENT PROTOCOL 21CFR312.35(a) C CHARGE REQUEST/NOTIFICATION 21 CFR 312.7(d)
`
`CDR/OBINDIOGD RECEIPT STAMP
`
`FOR FDA USE ONLY
`DOR RECEIPT STAMP
`
`IND NUMBER ASSIGNED
`
`,
`
`' -
`
`DIVISION ASSIGNMENT
`
`PROTECTIVE ORDER MATERIAL
`
`FORM FDA 1571 (6 92)
`
`PREVIOUS EDITION OBSOLETE
`
`GENENTECH_0000006
`
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`CONTENTS OF APPLICATION
`This application contains the following items: (check all that apply)
`
`181 1. Fonn FDA 1571
`[21CF_R312.23(s)(1)]
`O 2. ,Table of contents {21CFR312.23(a)(2}]
`O 3. lntroclucto,Y statement {21CFR312.23(a}(3}]
`0 4. General lnvestlgational plan {21 CFR 312.23(a)(3)]
`0 5. Investigator's brochure [21 CFR 312.23(a)(5)]
`6. Protocol(s) [21CFR312.23(a)(6)]
`0 a Study protocol(s) [21 CFR 312.23(a)(6)]
`0 b. Investigator data {21 CFR 312.23(a)(6}(lll)(b)J or completed Form(s) FDA 1572
`De. Facilities data [21CFR312.23(a)(6)(iii)(b)] or completed Form(s) FDA 1572
`0 d. Institutional Review Board data [21CFR312.23(a)(6)(/0)(b)] or completed Form(s) FDA 1572
`0 7. Chemistry, manufacturing, and control data [21 CFR 312.23(a)(7)J
`0 Environmental assessment or claim for exclusion [21 CFR 312.23(a)(7)(iv)(e)]
`0 8. Pharmacology and toxicology data (21 CFR 312.23(a)(8)]
`0 9. Previous human experience [21CFR312.23(a)(9)]
`010. Additional information {21CFR312.23(a)(10)]
`13 IS ANY PART OF THE CLINICAL STUDY TO BE CONDUCTED BY A CONTRACT RESEARCH ORGANIZATION? a YES a NO
`a YES a NO
`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,
`IDENTIACATION OF THE CLINICAL STUDY, AND A LISTINO OF THE OBLIGATIONS TRANSFERRED.
`
`_,
`
`14 NAME AND TITLE OF THE'PEASON RESPONSIBLE FOR MONITORING THE CONDUCT AND PROGRESS OF THE CLINICAL INVESTIGATIONS
`Tom Twaddell, M.D.
`Associate Director
`
`15 NAME(S} AND TITLE(S} OF THE PERSON($) RESPONSIBLE FOR REVIEW AND EVALUATION OF INFORMATION RELEVANT TO THE SAFETY
`OFTHEORUG
`Barry Sherman, m.D., Vic:e President, Medical Affairs
`Timothy G. Terrell, DVM, Ph.D., Director, Pathobiology and Toxicology
`
`I agree not to begin cllnlcal Investigations until 30 days after FDA'• receipt of the IND unless I receive
`I also agree not to begl.n or continue cllnlcal
`earner 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 complies with the requirements aet forth In 21 CFR Part 5S wlll be responsible for
`the Initial and continuing review and approval of each of the studies In the proposed clinical Investigation.
`I
`agree to conduct the Investigation In accordance with all other appllcable regulatory requirements.
`
`16 NAME OF SPONSOR OR SPONSOR'S AUTHORIZED
`
`REPRESENTATIVE
`M. David MacFarlane, Ph.D.
`Vice President, Regulatory Affairs
`18 ADDRESS (Nlxnber, Street City, Statea/YJZip Cod6)
`
`~:z:;:PO R OR SPONSOR'S AUTHORIZED
`VE
`
`_.
`',
`•
`
`/
`
`19 TELEPHONE NUMBER
`(lncfude AIM Code)
`
`(415) 225-1557
`
`-
`
`20 DATE
`
`460 Point San Bruno Boulevard
`South San Francisco, California 94080-4990
`
`(WARNING: A wlllfully fal1e mtement la a cffmlMI often-. U.S.C. Title 18, Sec.1001.)
`
`
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