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`Patent Docket Pl256Rl
`.
`.
`THE UNITED STATES PA~~.~~~RADEMARK OFFICE
`
`In re Application of
`
`Group Art Unit: 1642
`
`Susan D. Hellman et al. (as amended)
`
`Examiner: J. Nichole (Hunt)
`
`Serial No.: 09/208,649
`
`Filed: December 10, 1998
`
`For:
`
`TREATMENT WITH ANTI-ErbB2
`ANTIBODIES
`
`DECLARATION UNDER 37 CFR §1.131
`
`Assistant Commissioner of Patents
`Washington, D.C. 20231
`
`RECEIVED
`AUG 3 O 2000
`
`Sir:
`
`.. OFFICE OF PETITIONS
`I, Susan D. Hellmann, M.D., M.P.H., do hereby declare and say as follows:
`
`1. I am an inventor of the subject matter of the above-identified patent application. I am the sole
`inventor of method claims l· 13 and 24-27 of the above application. All work described hereinafter was
`performed by me or on my behalf in the United States of America.
`
`0
`
`1996, I conceived of and first began to reduce to P.ractice a method of
`2. Prior to December 12,
`treating a human patient with a disorder characterized by overexpression ofErbB2 receptor comprising
`administering a combination of an inti-ErbB2 antibody and a taxoid (in the absence of an anthracycline
`derivative) in an amount effective to extend the time to di~ase progression (TTP) in the patient.
`
`3. Evidence of the conception and reduction to practice of the claimed invention is set forth in
`the exhibits attached to this declaration (with dates and irrelevant information obscured).
`
`4. Exhibit A attached represents copies of selected slides from a presentation I gave to
`Genentech's Product Development Committee (PDC). The presentation w~s prior to December 12, 1996.
`At the presentation, I discussed revisions to the rhuMAb HER2 clinical plan. (rhuMAb HER2 is.the
`:recombinant humanized anti-HER2/ErbB2 antibody (HERCEPTIN®) disclosed in the Example of the
`above application.) One revision to the H0648 clinical trial I had conceived of, and presented at that
`
`1
`
`EXHIBIT
`3
`
`Oesmonc!-HeTimann
`
`3/23/2018 CAR.
`
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`._., - --.:
`
`.. 9
`
`time, was to treat metastatic breast cancer in human patients with a combination of an anti-ErbB2
`antibody (rhuMAb HER2) and a taxoid (paclitaxel), in the absence of an anthracycline derivative. The
`patients to be treated in the H0648 pivotal trial were "HER2 positive", i.e. had a disorder characterized
`by overexpression of ErbB2 receptor. Copies of the minutes o~ this PDC presentation are attached as
`ExhibitB.
`
`5. Exhibit C is a copy of the minutes from a further PDC presentation at which I co-presented
`prior to December 12, 1996. As noted in the Q &A section of those minutes, by that time I had conceived
`that the combination of the anti-ErbB2 antibody and the taxoid (paclitaxel) would extend the TTP in
`patients treated with this combination.
`
`6. Thus, before December 12, 1996, I had conceived of the invention of treating a human patient
`with a disorder characterized by overexpression of ErbB2 receptor, comprising administering a
`combination of an anti-ErbB2 antibody and a taxoid (in the absence of an anthracycline derivative) in
`an amount effective to extend the TTP in the human patient. Further, on a date preceding December
`12, 1996, reduction to practice of.the invention was initiated under my direction via the enrollment of · .
`human patients in the H0648 clinical trial, with the enrolled patients being treated with the combination
`of rhuMAb HER2 and paclitaxel, in the absence of an anthracycline derivative. The work to establish
`that the therapy extended TTP was conducted continuously thereafter, up until filing on December 12,
`1997 the provisional application on which the present application is based.
`
`I declare further that all statements made herein of my own knowledge are true and that all
`statements made on information and be.lief are believed to be true; and further that these statements
`were made with the knowledge that willful false statements and the like so made are punishable by fine
`or imprisonment or both, under Section 1001 of Title 18 of the United States Code and that willful false
`
`Date:
`
`8'12.-3 ( Oo
`
`2
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`..-;
`
`::r:
`0
`~
`~
`~ .....
`0
`""d .....
`$:\)
`.....
`~ <
`..... ........
`0
`IV .
`,_. IV
`
`•
`.~
`
`; '
`
`PDC·
`
`SUE ·HELLMANN
`
`·. rhuMAb HER2 CLINl.CAL
`PLAN REVISION ·
`
`EXHIBIT A
`
`,. ...
`
`-
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`Therapy in Breast Ca~cer
`
`Initial Diagnosis
`
`Radiology±
`Surgical Therapy
`
`Adjuvant Ch~mother~py ~--
`
`Second-Line Metastatic
`Chemotherapy
`
`First-Line Metast~·
`Chemotherapy
`
`-
`
`Local
`Disease
`
`No Apparent
`Disease
`
`Relapse
`
`Metastatic
`Disease
`
`r-- Pivotal Trial - L
`
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`rhuMAbHER2
`REGISTRATIONAL PROGRAM
`
`r---~··-··-
`
`.
`.
`H0648: 450 patient pivotal trial: first line ·
`.
`....-·----.
`- -.------ -···----··-·- ·--···-··- ··-
`. metastatic {iiiet~)· t~~~~py-raiiaomized·;-·blinded AB
`+ chemQtlierapy .
`...
`. ..
`. ... __ _
`·-.... _ .......... .._ ... ---·- -
`
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`-SITE
`RECRUITMENT I AC.CRUAL
`UPDATE
`
`.
`
`.
`
`• H0648: 44% of the 138 sites initiated
`11/450 patients entered
`
`i
`'
`
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`.GOAL·S ·OF CLINICAL PLAN
`'REVISION
`
`/
`
`/ /
`·.J-1:. Increase study accrual
`. (f'Broad~n eligibility criteria
`lYincrease interest of investigators
`/
`.
`~. Mor~ rapid patient entry/PLA filing
`/
`..
`-
`.
`__ __ ......
`..
`WII •. Broaden pQtent~al label claim
`
`.
`
`..
`
`.
`
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`FACTORS WHICH ARE NOT
`SUBJECT TO REVISION:
`
`.. .......... _, __ '""
`
`'-..'...
`
`. ...
`
`.
`
`.
`
`.
`
`l.~5% of breast canCer is HER2 positive
`.
`//
`\ -"11. Weekly intravenous dosing. of .antibody
`. ~ .
`.
`~-III. Co11:1peting protocols: autologous BMT
`
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`c ·LINICAL PRACTICE:
`BREAST CANCER
`
`\ .....
`
`• I. Increasi~~- use of adjuvant ch~~c;>~.her_~~
`(especially for HER2 positive given worse
`pro@o~~) .
`·
`---·
`
`- ·- ···-··· ......
`
`II. Increasing use Of i!dJyvant Adriamyc.in therapy
`/
`v1i1. Intrc;»c;lµ~tio_n._ !!!!d. in,~re~sing u1;10 of Taxol for
`· metastatic br.east . can~er (Taxotere advisory
`committee 10/17/95) ·
`
`.
`
`... -·····
`
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`STUDY H0648:
`POSSIBLE REVISIONS.
`
`Y. Allow prior Adriamycin in the adjuvant setting
`/
`l!Al. Remov~ study _ b~iitdin~
`
`..
`
`•
`
`:::c:
`0
`{/)
`1-"0
`
`~
`~ -0
`
`1-"0 -
`°8 <
`P>
`-
`- 2. N.
`oo N
`
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`STUDY H0648:
`OPTIONS TO ENABLE PRIOR
`----·
`. ......... _ ...... -... --....... .
`ANTHRACYCLINES
`
`.
`
`···-
`
`-·-·- ·
`
`.
`
`. .
`
`·-·
`
`-.....
`
`. . ...
`
`·-··--....__
`
`• vii. Taxol +/- rhuMAb HER2
`
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`.
`
`.
`
`.... .
`
`. .................
`
`I
`
`.
`
`..._ __ -··--··· -··-- ·-··-·----···-···--
`
`MAJOR ISSUES: TAXOL
`... ---.....
`p~gs: . .
`.
`.
`~lows use with a taxane, a class of drugs likely .
`to be i~porta~t in breast cancer therapy in t~e
`. next decade ·
`.
`·
`J Saine sample size unless there is statistical
`interaction
`CONS:
`• Not the la~eled indication (second line
`metastatic unless relapse < 6 months following
`· adjuvant)
`u1nconclusive preclinical results ·
`.
`• Expensive combination therapy
`
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`·
`
`·
`
`FEEDBACK REQUESTED FROM
`THE FOLLOWING GROUPS:
`~ Clipj~al: world-Wide feasibility /impact on
`
`a<;cruai'·--- · ... ---·-·----....
`,,./
`L/ / II. Biostatistics~ issues regarding sample size/
`assessment of interaction/possible bias by
`removing blinding
`/
`\....YllI •. Preclinical/PK: use.. of rhuMAb HER2 with
`Taxol
`·
`·'.·
`..... _·--·· ·---·---·-·· ·-- ·--.. -·-- ·- --·-- .. ·-·.--
`_/ .... __ ----·-· ··-· ,:_
`v·IV. Regulatory: strategy for FDA
`,
`teleconference/impact on PLA filing
`lA. Marketing: current clinical p:i-actice/imp~ct 9n
`label/pric_ing sensitivity
`
`·--..
`
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`. i J.·A
`
`RECO.MMENDATION .TO PDC
`, · \Studv H0648): .
`(...,.j,( ;erfilit Tax:ol therapy for patients previously
`
`'·---/Jreated with Adriamycin
`~
`v / II. Remove· ~tudy ·blinding if needed ~~ meet
`timelines and if approved by the .FDA
`~ .....
`.
`
`,,.....
`
`-
`
`IVi ¥.M t~l~~()nforenCe to discuss GNE plan for ·
`amendment
`--··- - ...
`
`•
`
`}
`
`.
`' . ,
`
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`Genentech, Inc.
`
`I N T E R 0 F F I C E
`
`M E M O· R A N D U M
`
`· r .
`
`TO: Sue Hellmann
`'I'O:
`JIM GREEN
`TO: Thomas Twaddeli
`TO: Remote Addressee
`
`CC: Maureen Collins
`CC: Kimberley Burke
`
`Date:
`From:
`
`Edith Matsuyarna
`MATSUYAMA.EDITH
`Tel No:
`xl944
`Doc No:
`0'09086
`.
`.
`HELLMANN.SUE )
`GREEN.JAMES )
`TWADDELL.TOM )
`MINUTESCC@GENE .COM@WINS
`
`COLLINS . MAUREEN
`BURKE . KIMBERLEY
`
`Subject:
`
`. Anti-HER2 - . PDC minutes & Recommendations
`
`PDC minutes
`
`PDC Attending: K.Hitchner, T.Love, J.McLaughlin, E.Patzer, B.Sherman,
`B.Young, B.Matlock
`PDC Absent: D.Brewer, A.Levinson
`Invited Attendee: E.Matsuyama
`•••**************•******~**************************••~·· · ···· · ····
`CONFIDENTIAL
`CONFIDENTIAL
`CONFIDENTIAL
`CONFIDENTIAL
`*• * ****************************•*********************~· · ··········
`Anti-HER2 - Brief update on possibility of revised clinical strategy
`Presenter: Sue Hellmann
`Team:
`Jim Green, Tom Twaddell
`
`PDC recommendation:
`
`The PDC agrees with the team's recommendations to address enrol·lment
`and accrual in the Phase III trial. The FD~ teleconference should
`occur and the team should return to PDC on
`with their
`revised development plan and its impact on the timeline .
`
`EXHIBIT B
`
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`_$2$DOS4: [MATS'CJ'YAM>..OA) MAT009
`
`.LrSt l
`
`v
`
`Page 2
`
`SuMMARY:
`
`The team has been reviewing all aspects of the phase III trials to find
`ways to accelerate enrollment. They have concluded that studies H0649
`and H0650 (antibody alone treatment) do not need any changes to the
`protocol since they are doable and accruable.
`
`Prot~col H0648 is the 450 patient pivotal trial for first-line
`metastatic patients. Currently, 44\ of the 138 sites have been .
`initiated and ll of 450 patients enrolled. Should this protocol be
`changed?
`
`The goals of the c linical plan revision are to increase study accrual
`by broadening' the eligibility criteria and i~crease the_ interest of
`investigators. This will result in more rapid pati~t accrual (and
`ultimately the PLA filing) and potentially broaden the label claim.
`
`Possible revisions to protocol H0648 are:
`l. Allow patient s with prior Adriamycin treatment in the adjuvant
`setting into the trial.
`this would be a major change in
`Note:
`2. Remove study blinding.
`the protocol and the FDA is expecting us to do a blinded study.
`However, there is the question of whether we need to ' have a
`blinded study. The Taxol studies were not blinded.
`
`There are two possible patient groups with prior antbracycline
`treatment that could be added to the H0648 protocol:
`l. Taxol treated patients +/- rhuMAb HER2
`
`The team recommends the following changes to protocol H0648 to PDC:
`l. Permit Taxol therapy for patients previously treated with
`Adriamycin
`( the team feels that this change will have the
`highest likelihood of success and it should be the only change).
`2. Remove study blinding if needed to meet the timelines and if this
`is approved by the FDA.
`·
`·
`
`4.
`
`FDA teleconference to discuss GNE's plan for the protocol
`amendment.
`
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`.-~
`
`. -·
`
`_$2$DUS4:{MATSoYAMA.OA)MAT009
`
`.Ll:S;1
`
`Page 3
`
`DETAILS.:
`
`Sue Hellmann wishes "to give credit to the project team for their help
`with this presentation.
`
`Anti-HER2 therapy is targeted for breast cancer patients who have
`metastatic disease· and a~e undergoing first-line chemotherapy.
`
`The team has been. reviewing all aspects of the phase III trials to find
`ways to accelerate enrollment. They have concluded that studies H0649
`and H0650 (antibody alone treatment) do not need any changes to the
`protocol since they are doable and accruable. Currently, H0649 has 42%
`of the 50 sites initiated and 26 of 200 pati~nts have been enrolled.
`
`Protocol H0648 is the 450 patient pivotal trial for first-line
`metastatic patients. The patients are randomized in a double-blind
`antibody +/- chemotherapy trial. Currently, 44% of the 138 sites have
`been initiated and 11 of 450 patients enrolled. Should this protocol
`be changed?
`
`The goals of the clinical plan revision are to increase study accrual
`by broadening the eligibility criteria and increase the interest of
`investigators. This will result in more rapid patient accrual (and
`ultimately the PLA filing) and potentially broaden the label c~aim.
`
`The factors which cannot be changed are:
`-25% of breast cancer is HER2 positive ·
`-Antibody is dosed weekly, IV
`-Other ~ompeting breast cancer protocols such as autologous bone
`marrow transplant
`·
`·
`
`The clinical . practice of treating breast cancer is changing and
`evolving. There is increased use of adjuvant chemotherapy especially
`for HER2 positive patients given the worse prognosis. Adriamycin
`adjuvant therapy is increasing and approximate+y 50% of p~tients in
`first-line chemotberapy are treated with this. Due to its · toxicity,
`prior adriamycin treatment is an exclusion criteria in protocol H0648.
`Al-so, the introduction of Taxol has resulted in an increased use of
`this therapy ·in t.he treatment of metastatic breast cancer.
`
`Possible revisions to protocol H0648 are:
`l. Allow patients with prior Adriamycin treatment in the adjuvant
`setting into the trial.
`·
`this would be a major change in
`2. Remove study blinding.
`Note:
`the protocol and the . FDA is expectipg us to do a blinded study.
`'However, there is the question of whether we need to have a
`blinded study. The Taxol studies were not blinded.
`
`·There are two possible patient gr~ups with prior anthracycline
`treatment that could be added to the H064B protocol:
`1. Taxol treat.ed patients +I- rhuMAb HER2
`
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`...
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`\J • I'
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`Page 4
`
`The major issues with the addition of prior Taxol treatment are:
`Pros:
`-rt allows the rhuMAb HER2 to be used with a taxane which is a
`c·lass of drugs that are likely to be important in breast cancer
`therapy in the next decade.
`-The sample size (450 patients) is unchanged assuming that there is
`no interaction of rhuMAb HER2 with Taxol.
`Cons:
`-Preclinical ·results with Taxol were inconclusive.
`-Taxol is a very expensive drug and in combination with rhuMAb
`HER2, treatment could be very expensive.
`
`The following has been requested from the following groups:
`-Clinical : world-wide feasibility/impact on accrual for the addition
`of Taxol
`· ~BiostatYstics: analysis of the issues regarding the sample size and
`possible interactions of the rhuMAb HER2 with the cytotoxic agent;
`possible bias by rembving blinding
`-Preclinical/PK: use of rhuMAb HER2 with Taxol.
`-Regulatory:
`a strategy for the FDA teleconference to oe scneduied
`soon (tentative date is l0fl7).
`Impact of p~otocol changes to the
`filing of the PLA.
`·
`-Marketing:
`an assessment of the cµrrent clinical practice and the
`impact of protocol changes on label/pricing sensitivity.
`The team reco~ends the following ·changes to protocol H0648 to PDC :
`1. Permit Taxol therapy for patients previously treated with
`Adriarnycin
`(the team feels that this change will have the
`highest likelihood of success and it should be the only change).
`2. Remove study blinding if needed to ·meet the timelines and if this
`is approved by the FDA.
`
`4. FDA teleconference to discuss GNE's plan for the protocol
`amendment.
`
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`-~~~$DOS~: [MATSUYAMA.OA)MATOOe: 1'.:IS;.l
`
`Page 1
`
`Genent·ech, In(:;.
`
`I N T E R 0 F F I C E
`
`M E M 0 'R A N 0 U M
`
`Date:
`From:
`
`Tel No:
`DOC· No:
`
`1 06:0lpm PST
`tdith Matsuyama
`MATSUYAMA.EDITH
`xl944-
`009270
`
`TO: See Below
`
`Subject:
`
`,Anti-HE~2 Poe recommendations &. minutes
`
`)?DC Min11tes
`
`PDC/Ops Attending: D.Brewer, K.Hitchner, A,.Levinson, T.Love,
`J.McLaughlin, £.Patzer, B.Young, L.Lavigne
`PDC Absent:
`B.Sherman
`.
`.
`Invited Attendee: . E.Matsuyama
`********•*********************************************•***********
`CONFIDENTIAL
`CONFIDENTIAL
`CONFIDENTIAL
`CONFIDENTIAL
`
`Anti-HER2 Project Action Plan
`Presenters: Mauri Okamoto-Kearney, Sue Hellmann, Hank Fuchs
`Team:
`Jim Green, Tom TWaddell, Theresa .Musser, Mark Sliwkowski, Julie
`Badillo
`Reviewers: Todd Rich, Robert Rosen ( Art Devault, Roxanne Bales, Bob
`Cohen, Dave Stump
`
`EXHIBIT C
`
`HOSPIRA EX. 1011 Vol. 2
`Page 137
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`...
`
`·~$~$Dt1~4: [MAT~t1Y.1'MA. OA] MATOO e
`
`. LIS 11
`
`·.·
`
`Pa9e 2
`
`POC RECOMMENDATION:
`
`The team's pri.niary goal should be to complete enrollment in the pivotal
`study according to·tbe original LRP timeline. Measures to be taken and
`parameters to be evaluated should be chosen .to predict if we will
`achieve that goa1.
`.
`.
`_The POC approves t he team's recommendations and action plan to address
`the enrollment issues in the pivotal study. The team should focus it's
`~fforts on· impl~menting the· Taxol revision and operational fixes. The .
`team should repor t back immediately to the PDC if FDA or other feedback
`.causes a change to the strategy ..
`
`The PDC approves the team's recommended evaluation plan. The PDC would
`like the team to clar1fy, in a simple communication, . what parameters
`. .
`.
`.
`will be evaluated to measure progress between now and the end of
`.
`
`The PDC approves the action items and the use .of resources currently in
`the
`budget for developing a parallel strategy.
`
`with
`The team should report back to PDC in the first week Of
`the pivotal study update and the registration plan, includin9 the
`pai:-allel strategy if appropi:-ia·te.
`·
`
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`SUMMARY:
`
`The action plan to increase enrollment into the Phase III pivotal trial
`is to maintain the focus on front-line metastatic breast cancer
`patients. The protocol will be amende~ to allow Taxol use in patients
`who have been previously treated with doxorubicin in the adj uvant
`setting. More sites and investigator committment. will be needed to
`achieve this goal.
`·
`
`The registrationa.l strategy for rhuMAb HER2 will include· the pivotal
`.
`trial with Adriamycin and Cytoxan in first line metastatic therapy .
`.
`The refractor-y trial studying rhuMAb HER2 alone in second or third line
`therapy will al~o be included:
`·
`
`The . gains for the pivotal trial with the proposed amendment are:
`-Increased number (2-fold) of eligible patients .
`-Better reflection of current standards of therapy (high risk
`patients are more likely to receive Adriamycin in the 'adjuvant
`setting and Taxol first- line. Prior use of adjuvant Adriamycin as
`exclusionary was a big issue with investigator's.)
`-Increased enthusiasm of investigator's for the trial
`-The endpoint/study question and the sample size has remained
`. unchanged.
`·
`
`The preclinical data for combined rhuMAb HER2 and
`taxol administration in tumor bearing nude mice. ~ho~ that:
`
`-Inconsistent results have been obtained with two different
`pr.eclinical mode·ls. These result;s are likely due to intrinsic
`differences between the two models themselves. At this point ·it is
`
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`difficult to predict which model will correlate with the proposed
`clinical program.
`
`-From drug disposition studies, there is no system that gives a
`negative interaction of rhuMAb HER2 with cyto~oxic chemotherapy.
`
`-~t is reasonable to assume that rhuMAb HER2 will mediate its
`biological effects regardless of the presence or the type of
`cytotoxic chemotherapy.
`
`-Based on pre-clinical data alone •. the expected· clinical outcome for
`the administration of rhuMAb HER2 with taxol is less certain than
`co~administratibn with cisplat~num or doxorubicin. Because our
`experience with H0648g to date indicates ' that enrollment is a
`problem, we must weigh the
`inconsistency of the scientific data
`versus the need to e·xpedi~ntly enroll the trial .
`. ·
`The action plan for increasing the accrual rate for the Phase III
`program was presented. The main areas for improvement in patient
`accrual are more eligible patients, more sites, building investigator
`committrnent, improvement of the role of ac~ivists/advocates, and
`management of the project teams bett~r. Additional costs will be
`incurred, however. it is not expected to .exceed S~ million:
`
`In . con~lusion:
`-The Taxol revision is expected to provide an enrollment. boost for
`the' pivotal trial. The impact on the project timeline is uncertain
`at this time.
`-Initial FDA feedback on the Taxol modification is positive.
`-The operational and strategic changes are being aggressively
`implemented to meet the oroject timeline.
`-By the end of
`the .team will have:·
`-Determined the -~deauacv or the revisions to H0648 to deliver on the
`project goal of
`approval.
`-If these revisions are deemed inadequate, an alternate strategy will
`be proposed to PDC.
`Initiation of this supplemental strategy in
`will allow for approval in !
`
`The project team recommendations are:
`-Poe approval of the action plan to maintain focus on the current
`pivotal trial with the Taxol revision and other operational fixes.
`-PDC to approve the evaluation plan and next steps targeted for
`
`-PDC to approve resources and action items for the parallel strategy
`such as the formation of a planning group reporting to the project
`team. One clinical 'scientist will be needed to support these .
`efforts. The parallel strategy plan will be presented to ' the PDC
`with an evaluation of the registrational p-lan in
`
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`~$~$DU~4:[MATS~AMA.OA]MATOO~.LI~;1
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`. Pag~ 5
`
`DETAILS:
`
`Mauri Okamoto-Kearney began the presentation by. outlining the
`objectives of today's presentation which are to confirm the project
`direction, inform the PDC of the action pl~n. and review the
`expectations for the dates and deliverables.
`
`Tne action plan to ·increase enrollment into the Phase III pivotal trial
`is to maintain t he focus on front -line metastatic breast cancer
`patients. The protocol will be amended to allow Taxol use in patient·s
`who have been previous.ly treated with doxorubicin in the adjuvant
`setting. More sites and investigator committment will be needed to
`achieve this goal.
`
`Sue Hellmann presented the strategic direction for the project.
`
`The registrational strategy for rhuMAb HER2 will include the pivotal
`trial with Adriarnycin and Cytoxan in first line metastatic therapy.
`The refractory trial studying rhuMAb HER2 alone in second or third line
`therapy will also be included.
`
`rhe proposed amendment to the pivotal trial will be to expand the
`eligibility crite ria to allow prior adjuvant Adriamycin. Patients who
`have received adjuvant Adriamycin will receive Taxol chemotherapy.
`Randomization to prior chemotherapy for rhuMAb HER2 versus no antibody
`will remain unchanged.
`
`The gains for the pivotal trial with the proposed amendment are:
`-Increased number (2-fold) of eligible patients
`-Better reflect ion of current standards of therapy (high risk
`patients are more likely to receive Adriamycin in the adjuvant
`setting and Taxol first-line.
`.Prior use of adjuvant Adriamycin· as
`exclusionary was a big issue with· investigator's:)
`-Increased enthusiasm of investigator's for the trial
`-The endpoint/study question and the sample size has remained
`unchanged.
`
`The addition of Taxol therapy to the protocol is an effort to exploit
`the preclinical biology. There are three proposed mechanisms of action
`for rhuMAb 0HER2:
`-Antibody-dependent cellular cytotoxicity
`-Down regulation of receptor signaling pathways
`-Interference of damaged DNA repair induced by chemotherapy.
`Taxol will help to address the first two possible mechanisms of
`action of the antibody. · There is conflicting data on whether or ~ot
`rhuMAb HER2 adds to the cytotoxicity of Taxol. However, there is
`consistent aata that rhuMAb HER2 does not antagonize the Taxol
`effect.
`
`Taxol plus Cisplatin ~s .a new control arm was assessed. This treatment
`is not widely accepeed as first-line therapy for breast cancer . There
`are significa~t conerns from clinicians regarding the safety of these
`therapies. Thus. the addition of this new arm would not .help accrua l .
`
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`~;2$D0~4:(KATSOYAMA.OA]MAT00~.LIS;l
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`Page 6
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`;. PDC
`The recommendation from the team has not changed ·from the
`presentation. That is. patients with prior-doxorubicin treatment with
`Taxol chemotherapy should be included in the piv?tal trial.
`
`The action items for the paraJ.J.el. strategy .......... , .... .,:
`-Provide feedback to the project team on an intermittent ongo~ng
`basis
`- Provide a plan to PDC by
`of the . current registrational plan.
`
`tog~ther with an update
`
`Mar°k Sliwkowski reviewed the pr.eclinical data for rhuMAb HER2 in
`combination with chemotherapeutic agents.
`
`rhuMAb HER2 combined .with Pt and doxorubicin have increased cytotoxic
`effects. Precli~ically. studies with rhuMAb HER2 combined with Taxol
`have resulted in controversial results.
`
`In multiple experiments. rhuMAb HER2 in combination with taxol .have
`shown dramatic results at Memorial Sloan Kettering. Equivocal results
`have been pbtained using a different model System a~ UCLA.
`
`In summary, the preclinical data for combined rhuMAb HER2. and
`ta~ol administra~ion in tumor bearing nude mice show that:
`
`-Inconsis'tent results have been obtained with two different
`preclinical models. These results are likely d~e to intrinsic
`
`:
`
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`\ .
`v
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`Page 7
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`differences between the two models themselves. At this point it is
`difficult to predict which model will correlate with the proposed
`clinical program. :
`.
`
`-From drug disposition s"tudies, .there is no. system that gives a
`negative intera~ti?n of rhuMAb HER2 with cytotoxic chemotherapy ..
`
`-It is reasonabfe to assume that rhuMAb HER2 will mediate its ·
`biological effects regardless of the presence or the ty~e of
`cytotoxic chemotherapy.
`·
`
`-Based on pre-clinical data alone •. the expected clinical outcome for
`the administration of rhuMAb HER2 with taxol is less certain than
`cd-administ·rat.ion with cisplatinurn or doxorubicin. Because our
`experience with H0648g to da.te indicates that enrollment :ls a ·
`problem, we must weigh the
`inconsistency of the scientific data
`versus the need to expedientiy enroll the trial.
`·
`
`· - -- - - -- - - - - ·- ·--· ..
`
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`Mauri Okamoto-Kearney
`conclusions:
`-The Taxol revision
`the pivotal trial.
`at this time.
`
`concluded the presentation witn tne following
`
`is expected to provide an enrollment boost for
`The impact on· the project timeline is uncertaln
`
`The project team recommend.at ions are:
`-PDC approval of the action plan to maintain focus on the current
`.Pivotal trial with the Taxol revision and othei; operational fixes.
`
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`~$~$D~S4:(MATSOYAMA.OA)MAT009~.LIS1l
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`Page 9
`
`Q&A:
`
`A:
`
`Q: The sample size has remained unchanged for the Phase III pivotal
`trial. Do you expect to se~ any differences?
`. .
`(Hellmann) Time to progression will likely be equivalent in the 2
`arms. We've made the assumption that the effect of anti-HER2 will
`not be affected with the presence of the chemotherapeutic agerit.
`Attempts have been made to balance the trial by center.
`
`Q:
`
`·A:
`
`Is there any possibility that
`the Phase III pivotal trial)?
`claim?
`(Hellmann) The FDA will look
`new drugs for breast cancer.
`pivotal and supporting trials
`want to approve.
`
`the FDA would subset the data (from
`What would that do to the labeling
`
`at subsets. The FDA wants to approve
`If we have positive data in the
`for the compound, then the FDA will
`
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`.. ... ,
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`_$2$DUS4:[MATSO'YAMA.OA]MAT00
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`.LIS;l
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`·pa9e 10
`
`Discussion with Reviewer.s:
`
`In ~he antibody alone ·trial we
`I support the Taxol amendment.
`Stump:
`saw a response which was very compelling.
`
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`Distribution:
`
`Please use the SH (SHow message) option
`to view the addressees
`
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