'.-:. .
`
`a . ..
`
`Patent Docket Pl256Rl
`
`In re Application of
`
`Group Art Unit: 1642
`
`Susan D. Hellman (as amended)
`
`Examiner: J. Hunt
`
`Serial No.: 091208,649
`
`Filed: December I 0, 1998
`
`For: TREATMENT WITH ANTI-ErbB2
`ANTIBODIES
`
`DECLARATION UNDER 37 CFR §1.131
`
`Assistant Commissioner of Patents
`Washington, D.C. 20231
`
`Sir:
`
`I, Susan D. Desmond-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 1-13 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.
`
`2.
`
`Prior to December 12, 1996, I conceived of and reduced to practice a method of treating a
`
`hwnan patient with a disorder characterized by overexpression ofErbB2 receptor, or with
`metastatic breast cancer, comprising administering a combination of an anti-ErbB2 antibody
`and a taxoid, in the absence of an anthracycline derivative, to the patient in an amount
`effective to extend the time to disease progression (TIP) in the patient.
`
`EXHIBIT
`4
`
`Oosmond-Hellmann
`
`3/23/2018 CA R.
`
`HOSPIRA EX. 1011 Vol. 2
`Page 237
`
`
`
`1 of 76
`
`Celltrion, Inc. 1042
`Celltrion v. Genentech
`IPR2017-01122
`
`

`

`. .,;,· : .
`
`' 3.
`
`Evidence of the reduction to practice of the claimed invention is set forth in the exhibits
`
`attached to this declaration with dates obscured. The patient's initials in Exhibit B are also
`
`redacted to ensure confidentiality of the identity of the patient.
`
`4.
`
`Attached as Exhibit A is the H0648g Protocol which was amended prior to December 12,
`
`l 996 to include a treatment regimen which involved combining an anti-Erb82 antibody and
`
`a taxoid in the absence of an anthracycline derivative.
`
`5.
`
`As noted in Sections 3 and 4 of the H0648g Protocol, this was a Phase III study of
`
`chemotherapy alone or in combination with recombinant hum~ized anti-HER2 monoclonal
`
`antibody (rhuMAb HER2) in women with HER2 overexpression who had not received prior
`
`cytotoxic chemotherapy for metastatic breast cancer.
`
`6.
`
`Section 5.3.1 of the H0648g Protocol details the administration and dosage ofrhuMAb
`
`HER2. On Day 0, a 4 mg/kg loading dose ofrhuMAb HER2 was administered IV over a 90-
`
`minute period. Be~n.ning on Day 7, patients received weekly administration of2 mg/kg
`
`rhuMAb HER2 IV over a 90-minute period. If the first dose was well tolerated, subsequent
`
`infusions ofrhuMAb HER2 were given in 30 minutes. Section 5.3.2 of the protocol explains
`
`that patients further received one of two chemotherapy regimens for a minimum of six
`
`cycles: a) cyclophosphamide and doxorubicin or epirubicin, if patients had not received
`
`anthracycline therapy in the adjuvant setting, orb) paclitaxel, if patients had received any
`
`anthracycline therapy in the adjuvant setting. The initial dose of rhuMAb HER2 preceded
`
`the first cycl~ of either chemotherapy regimen by 24 hours. As noted in subsection b. of
`
`Section 5.3.2, paclitaxel was given at a dose of 175 mg/m2 over 3 hours by IV infusion.
`
`Section 5.5 explains that concomitant chemotherapy other than protocol-specified
`
`chemotherapy was not allowed during the study period. Section 8.1.1 of the H0648g
`
`Protocol states that the primary endpoints of the study were TIP and safety profile of
`
`rhuMAb HER2. The dosages ofrhuMAb HER2 and paclitaxel administered extended TTP
`
`in patients treated with the combination. It is clear from these sections of the protocol, that
`
`2
`
`HOSPIRA EX. I 0 I I Vol. 2
`Page 238
`
`
`
`2 of 76
`
`Celltrion, Inc. 1042
`Celltrion v. Genentech
`IPR2017-01122
`
`

`

`.,'. ,., .
`
`patients were being treated with a combination of an anti-ErbB2 antibody (rhuMAb HER2)
`
`and a taxoid (paclitaxel), in the absenceofananthracyclinederivative, in an amount effective
`
`to extend TIP in the patients.
`
`7.
`
`Case report forms (CRFs) detailing administration of rhuMAb HER2 to a patient followed
`
`by administration of paclitaxel to that patient the following day, according to Sections 5.3. l
`
`and 5.3.2(b) of the H0648 Protocol, are attached as Exhibit B. The infusions described in
`
`Exhibit Band subsequent infusions of the combination of rhuMAb HER2 and paclitaxel for
`
`the total course of therapy were administered to the patient prior to December 12, 1996.
`
`8.
`
`Thus, it is clear that the method I conceived of for treating a human patient with a disorder
`
`characterized by overexpression of ErbB2 receptor, or with metastatic breast cancer,
`
`comprising administering a combinativn of an anti-ErbB2 antibody and a taxoid, in the
`
`absence of an anthracycline derivative, to the patient in an amount effective to extend the
`
`TIP in the patient was reduced to practice before December 12, 1996.
`
`I declare further that all statements made herein of my own knowledge are true and that all
`
`statements made on information and belief 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 l 001 of Title 18 of the United States Code and that
`
`willful false statements may jeopardize the validity of the application or any patent issued thereon.
`
`Date:
`
`~~-~
`~ :-Hellmann, M.D., M.P.H.
`
`3
`
`\
`
`HOSPIRA EX. 1011 Vol. 2
`Page 239
`
`
`
`3 of 76
`
`Celltrion, Inc. 1042
`Celltrion v. Genentech
`IPR2017-01122
`
`

`

`,
`
`TITLE:
`
`:D m
`()
`rn
`~ ~ <
`C> g m
`~ g
`0
`
`PROTOCOL
`
`CHEMOTHERAPY AND ANTIBODY
`RESPONSE EVALUATION (CARE):
`A PHASE Ill, MULTINATIONAL,
`RANDOMIZED STUDY OF RECOMBINANT
`HUMANIZED ANTl·p18SHER2 MONOCLONAL
`ANTIBODY (rhuMAb HER2) COMBINED
`WITH CHEMOTHERAPY IN PATIENTS WITH
`HER2 OVEREXPRESSION WHO HAVE NOT
`RECEIVED CYTOTOXIC CHEMOTHERAPY
`FOR METASTATIC BREAST CANCER
`
`PROTOCOL NUMBER:
`
`H0648g
`
`STU.DY DRUG:
`
`Recombinant Humanized Anti-p18sHER2
`Monoclonal Antibody (rhuMAb HEA2)
`
`IND:
`
`BB-IND 4517
`
`MEDICAL MONITOR:
`
`Steven Shak, M.D.
`\
`
`Genentech, Inc.
`460 Point San Bruno Boulevard
`South San Francisco, CA 94080-4990 U.S.A.
`
`SPONSOR:
`
`DATE FINAL:
`
`AMENDED:
`
`C ONFIDENTIAL
`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 may be used only for evaluating or conducting clinical
`investigations; any other proposed use requires written consent from Genentech, lnc.
`E.X\-\\Brr A
`
`Protocol: rhuMAb HER2-Genenteeh, Inc.
`P H0648g·A3 Cvr Final
`
`HOSPIRA EX. 1011 Vol. 2
`Page 240
`
`
`
`4 of 76
`
`Celltrion, Inc. 1042
`Celltrion v. Genentech
`IPR2017-01122
`
`

`

`TABLE OF CONTENTS
`
`SYNOPSIS....................... .... ....... . ....................
`1.
`INTRODUCTION . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
`1.1
`HER2 and Cancer . . . • . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
`1.2 Clinical Studies of rhuMAbHER2.......................
`1.3 Study Rationale . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
`2. OBJECTIVES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
`2.1
`Primary Objectives . . . . . . . . . . . . .. . . . . . . . . . . . . .. . . . . . . .
`2.2 Secondary Objectives ................ : . . . . . . . . . . . . . . . .
`3. STUDY DESIGN . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
`4. STUDY POPULATION . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
`4.1
`Eligibility Criteria . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
`4.2 Exclusion Criteria . . . • . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
`5. STUDY MEDICATION . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
`5.1
`Fonnulatiori . . ... ·. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
`5.2 Storage Requirements . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
`5.3 Administration and Dosage . . . . . . . . . . . . . . . . . . . . . . . . . . . .
`5.4 Guidelines for Dose Modification . . . . . . . . . . . . . . . . . . . . . . .
`5.5 ConcomitanVExcluded Therapy . ................. · . . . . . .
`PATIENT MONITORING . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
`6.1
`Preadmission Evaluations . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
`6.2 Study Evaluations . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
`6.3 Post-Treatment Follow-Up .... . ... ... ...... .... .... ....
`7. PROGRESSION AND RESPONSE CRITERIA . . . . . . . . . . . . . . . . .
`7.1 Response Ev~luation Committ~ . . . . . . . . . . . . . . . . . . . . . . .
`7 .2 Response Criteria . . . . . .. . . . . .. .. . . .. . . . . .. .. . . . . . . .. .
`8. STATISTICAL CONSIDERATIONS . . . . . . . . . . . . . . . . . . . . . . . . . . .
`8.1 Response Variables (Endpoints} . . . . . . . . . . . . . . . . . . . . . . .
`8.2 Statistical Analysis . . ............ ; ............... : . . . .
`8.3 Randomization . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
`8.4 Data Safety Monitoring Board and Interim Analysis . . . . . . .
`8.5 Sample Size and Power . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
`
`6.
`
`~
`1
`2
`2
`4
`6
`7
`7
`7
`8
`9
`9
`1 O
`11
`11
`11
`12
`14
`14
`15
`15
`16
`19
`19
`19
`20
`21
`21
`21
`25
`25
`27
`
`Protocol: rhuMAb HER2-Genentech, Inc.
`ii/P H0648g-A3 Cvr Final
`
`HOSPIRA EX. 1011 Vol. 2
`Page 241
`
`
`
`5 of 76
`
`Celltrion, Inc. 1042
`Celltrion v. Genentech
`IPR2017-01122
`
`

`

`~
`27
`32
`32
`32
`
`32
`32
`33
`33
`34
`34
`34
`35
`
`36
`36
`· 37
`
`TABLE OF CONTENTS (cont'd)
`
`9. ADVERSE EVENT REPORTING . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
`10. DISCONTINUATION . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
`10.1 Patient Discontinuation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
`10.2 Study Discontinuation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
`
`INSTITUTIONAL REVIEW BOARD/ETHICS COMMITIEE . . . . . .
`11 .
`INFORMED CONSENT REQUIREMENTS . . . . . . . . . . . . . . . . . . . .
`12.
`13. STUDY MONITORING REQUIREMENTS . . . . . . . . . . . . . .. . . .. . .
`14. CASE REPORT FORMS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
`15. STUDY MEDICATION ACCOUNTABILITY. ........ . .......... .
`16. REPORTING REQUIREMENTS . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
`16.1 Study Initiation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
`16.2 Study Completion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
`
`17. DISCLOSURE OF DATA . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
`18. RETENTION OF RECORDS .. ..... .. ... . .......... . . .. . . . .. .
`REFERENCES . . . . . . . . . . . . . . . . . • . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
`Appendix A: Study Flowchart
`Appendix B: Determination of HEA2 Overexpression
`Appendix C: Evaluation of Performance Status
`(Karnofsky Scale)
`Appendix D: Guidelines for Dose Modification
`Appendix E: Directions for Shipment of Laboratory
`Specimens to SciCor, Inc. (for sites in
`the United States, Canada, and Europe)
`Appendix F: Directions for Shipment of Laboratory Specimens
`to Douglass Laboratories (for sites in Australia
`and New Zealand)
`Appendix G: Directions for Obtaining, Storing, and
`Shipping Blood Samples
`Appendix H: EORTC Quality-of-Life Questionnaire
`Supplemental Questionnaire
`Appendix I:
`
`Protocol: rhuMAb HER2-Genentech, Inc.
`iii/P H064Bg·A3 Cvr Final
`
`HOSPIRA EX. 1011 Vol. 2
`Page 242
`
`
`
`6 of 76
`
`Celltrion, Inc. 1042
`Celltrion v. Genentech
`IPR2017-01122
`
`

`

`,
`
`SYNOPSIS
`This protocol describes a Phase Ill, randomized, controlled, multinational study
`in patients with HER2 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-HER2
`monoclonal antibody (rhuMAb HER2) used in addition to chemotherapy.
`Pati~nts will be treated with either paclitaxel .or an anthracycline-containing
`regimen (e.g., doxorubicin or epirubicin) as prescribed by their physician.
`
`Approximately 450 patients will be enrolled in the study and randomized to one
`of two treatment arms: 1) the active arm, which consists of rhuMAb HER2 in
`combination with cytotoxic chemotherapy (the chemotherapy regimen must be
`determined prior to randomization), or 2) the control arm, which consists of
`cytotoxic chemotherapy alone (no study drug). All patients randomized to the
`active arm of the study will receive rhuMAb HEA2 as a 4 mg/kg intravenous (IV)
`loading dose on Day O and then weekly at a dose of 2 mg/kg IV throughout the
`course of the study. Patients who are randomized to the control arm (cytotoxic
`chemotherapy alone, without rhuMAb HER2) will be evaluated and treated
`similarly to patients randomized to active treatment. Tumor evaluations will
`occur at prescribed intervals during the study to assess disease progression.
`Patients will remain on study until disease progression is documented by an
`independent Response Evaluation Committee.
`
`After the compl~tion of cytotoxic chemotherapy, those patients assigned to
`rhuMAb HEA2 will continue to receive weekly rhuMAb HEA2 infusions. Patients
`from the control group will be eligible to receive rhuMAb HER2 in an open-label
`study (H0659g) following documented progression of their disease. All patients
`who develop disease progression and do not enroll in the subsequent study will
`be followed for survival information every 2 months until termination of statistical
`analysis of the study.
`
`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 control groups. Quality of life will be
`assessed using the European Organization for Research and Treatment of
`Cancer (EORTC) quality-of-life instrumen.t with the module for breast cancer. A
`supplemental instrument will be used to explore pharmacoeconomic issues in
`the treatment groups. Time to treatment failure, including patients who either
`have progressive disease or have discontinued chemotherapy due to toxicity, will
`be a secondary, supportive analysis.
`
`Protocol: rhuMAb HER2-G nentech, Inc.
`1/P H0648g-A3 P Fmal
`
`HOSPIRA EX. 1011 Vol. 2
`Page 243
`
`
`
`7 of 76
`
`Celltrion, Inc. 1042
`Celltrion v. Genentech
`IPR2017-01122
`
`

`

`1.
`1.1
`
`INTRODUCTION
`HER2 AND CANCER
`Cancer of the breast Is the most common malignancy occurring In
`women. On average, women experience a 1 in 9 chance of developing
`breast cancer during their lives. In the United States alone, there are
`approximately 185,000 new cases of breast cancer each year. Despite
`advances in early detection and surgical and adjuvant therapy, nearly
`50,000 women will develop metastatic disease each year.
`Conventional, cytotoxic chemotherapy plays an important role in the
`management of patients with breast cancer. Reduction in tumor size
`can be achieved with chemotherapy. However, such treatment with
`chemotherapy causes patients to experience numerous side effects
`such as nausea, vomiting, and hair loss because of the non·specific
`way that such agents act on living cells. Despite such potent therapy,
`little impact on disease progression, overall survival, and patient quality
`of life has been achieved. Breast cancer remains the most common
`cause of non-preventable cancer death in women. New treatments
`specifically directed at the cancer in such a way as to delay disease
`progression while avoiding systemic toxicity would represent a
`significant advance in the care of patients.
`
`Numerous efforts over the past few years have attempted to define the
`biologic factors governing tumor development, growth, and metastasis.
`Growth factors and their receptors are known to play critical roles in
`development, cell growth, and differentiation (1). Such receptors span
`the membrane of the cell. The extracellular domain binds to specific
`growth factors. while the intracellular domain transmits the growth
`signal. Expression of abnonnal quantities of human epidermal growth
`factor receptor 2 (HER2) Is observed in approximately 25% of tumors
`taken from women with breast cancer, suggesting that the
`o.verexpression of this growth factor receptor may contribute to
`malignant transformation and tumorigenesis (2,3,4). In most cases,
`overexpression of the HEA2 protein, also called p1a5HER2, results from
`gene amplification.
`
`Overexpression of HER2 has been correlated with poor clinical
`outcome in patients with breast cancer. In an initial evaluation of
`103 patients with breast cancer, those having more than three axillary
`lymph nodes were more likely to overexpress HEA2 than patients with
`
`Protocol: rhuMAb HER2--Genentech, Inc.
`21P H0648g·A3 P Final
`
`HOSPIRA EX. 1011 Vol. 2
`Page 244
`
`
`
`8 of 76
`
`Celltrion, Inc. 1042
`Celltrion v. Genentech
`IPR2017-01122
`
`

`

`,
`
`t
`
`less than three (2). In a subsequent evaluation of 86 node-positive
`patients with breast cancer. there was a significant correlation between
`the extent of gene amplification, early relapse, and short survival. The
`median period of disease-flree survival is approximately 5-fold shorter
`in patients with more than f.ive copies of the HEA2 gene than in
`patients without gene amplification. This correlation was present even
`after correcting for nodal status and other prognostic factors in
`multivariate analyses. These findings were extended in
`187 node-positive patients and indicated that gene amplification,
`increased amounts of mRNA (determined by Northern blotting), and
`protein expression (determined immunohistochemically) were also
`correlated with shortened survival time (3).
`
`Several lines of evidence support a direct role for p185HER2
`overexpression in the pathogenesis and poor clinical course of human
`tumors (5). When the mutated gene is transfected into mouse
`fibroblast cells (NIH-3T3) it causes transformation, and the resulting
`cells are tumorigenic in the nude mouse (6, 7). Additionally, transgenic
`mice that overexpress the neu gene (the rodent homolog of the human
`HER2 gene) develop breast cancer (8). Finally, specific antibodies to
`the extracellular domain of the human HER2 gene product inhibit the
`growth of experimental tumors that overexpress the gene (9-12).
`These data suggest a direct role for HER2 in both malignant
`transformation and enhanced tumorigenicity. Therefore, a strategy to
`antagonize the abnormal function of overexpressed HER2 was
`developed to improve the course of patients with breast cancer.
`
`Murine monoclonal antibodies (muMAbs) were produced against the
`extracellular domain of the HER2 receptor. One such antibody, called
`405, was found to inhibit the proliferation of human tumor cells
`overexpressing HER2. Unfortunately, chronic administration of
`muMAbs in humans is limited by immune responses to the non-human
`protein. Therefore, regions of the murine antibody that determine
`anti-HER2 binding specificity were inserted into the framework of a
`generic human antibo.dy (13). The resulting antibody, rhuMAb HER2,
`binds specifically to the HER2 protein. The antibody is highly
`homologous to native human immunoglobulin and is therefore referred
`to as humanized. An additional property of rhuMAb HER2 is that it
`induces antibody-dependent cellular cytotoxicity (ADCC) against tumor
`
`Protocol: rhuMAb HER2-Genentech, Inc.
`3/P H0648g-A3 P Final
`
`HOSPIRA EX. 1011 Vol. 2
`Page 245
`
`
`
`9 of 76
`
`Celltrion, Inc. 1042
`Celltrion v. Genentech
`IPR2017-01122
`
`

`

`cell lines in the presence of human peripheral blood mononuclear cells
`(PBMCs).
`
`To increase the therapeutic potential of rhuMAb HER2 therapy, clinical
`strategies that combine the antibody with the agents used in
`conventional chemotherapy have been employed. Combining
`rhuMAb HER2 and cisplatin in the treatment of tumors that overexpress
`HER2 is supported by the results from several independent
`experimental investigations (14-17). There is evidence that HER2
`antibodies interfere with DNA repair mechanisms of cells
`overexpressing p105HER2 (15). rhuMAb HER2 has also been
`evaluated in combination with several other chemotherapeutic drugs,
`including doxorubicin, thiotepa, etoposide, 5·fluorouracil (18), and
`paclitaxel (19). In most cases, the effect of the antibody and the
`cytotoxic agent is at least additive.
`
`Thus, there are at least three mechanisms by which rhuMAb HER2
`could alter the progression .of breast cancer. First, the antibody can
`antagonize the function of the growth-signaling properties of the HER2
`system. Second, the antibody may signal immune cells to attack and
`kill the tumor target. Third, the antibody may augment
`chemotherapy-induced cytotoxicity.
`
`1.2
`
`CLINICAL STUDIES OF rhuMAb HER2
`Three Phase I and two Phase II studies of rhuMAb HER2 are complete.
`In the first Phase I trial (H0407g), 16 patients with HEA2-overexpressing
`tumors received a single dose (ranging from 10 to 500 mg) of
`rhuMAb HER2 administered intravenously (IV). Two patients
`developed chills during the infusion; fever developed in 4 patients (1 in
`each of the dose groups).
`
`·In the second Phase I trial (H0452g), 17 patients were .treated with
`eight weekly doses of IV rhuMAb HER2 (ranging from 10 to 509 mg).
`Adverse events reported were not unexpected given the study
`population, and no clinically significant severe adverse events were
`attributed to rhuMAb HER2.
`
`In the third Phase I trial (H0453g), 15 patients were treated with nine
`weekly doses of rhuMAb HEA2 (ranging from 10 to 500 mg) and three
`
`Protocol: rhuMAb HER2-Genentech, Inc:.
`4/P H0648g-A3 P Fmal
`
`HOSPIRA EX. 1011Vol.2
`Page 246
`
`
`
`10 of 76
`
`Celltrion, Inc. 1042
`Celltrion v. Genentech
`IPR2017-01122
`
`

`

`,
`
`doses of cisplatin (100 mg/m2) administered IV every 4 weeks. Two
`patients discontinued because of adverse events, 1 because of
`Grade 3 renal toxicity and Grade 4 thrombocytopenia, and 1 because
`of Grade 3 renal toxicity. As would be expected in a population
`receiving cisplatin, episodes of nausea and vomiting occurred
`frequently. Hearing loss was reported by 1 o patients and required
`discontinuation of cisplatin in 1 patient. There was no clear relationship
`between rhuMAb HER2 and the incidence of any of these adverse
`events. Administration of cisplatin did not affect the pharmacokinetics
`of rhuMAb HER2.
`
`Although the small number of patients and the lack of randomization
`preclude any statement being made about a possible dose effect in
`tumor responses, 4 of 6 patients in the 250-mg and 500-mg dose
`groups had a partial response (defined as a 50% reduction in tumor
`burden). One patient In the 250-mg dose group had supraclavicular
`nodes and multiple pulmonary metastases pretreatment, a partial
`response at Day 70, and was disease-free following a second 10-week
`course of 250 mg of rhuMAb HER2 plus cisplatin. She remains
`disease-free and well as of March 1996, and has had no additional
`therapy in the past 3 years. No responses were seen in the lower dose
`groups.
`
`In the first Phase II trial. of rhuMAb HEA2 (H0551 g), 46 patients with
`metastatic breast cancer overexpressing HER2 were treated with a
`250-mg IV loading dose followed by 100 mg IV weekly for 1 O weeks.
`Twenty-one patients with responses or stable disease at Day 77
`en.tered the maintenance program; 1 patient remains to date.
`rhuMAb HER2 was well tolerated in this study. No deaths were
`attributed to study drug. The median time to disease progression was
`2.8 months. Of the 43 eva11uable patients, 5 (12%) had a complete or
`partial response, 16 (37%) had a minor response or stable disease,
`and the remaining 22 (51%} had progressive disease. The duration of
`the'five responses (one complete, four partial} ranged from 1 month to
`28 months (for the complete responder). The complete responder is a
`51-year-old patient whose tumor is estrogen- and progesterone
`receptor-negative and who had four cycles of neoadjuvant doxorubicin
`prior to a left modified mastectomy for a poorly differentiated
`carcinoma. Biopsy-proven chest wall disease recurred within 2 months
`
`Protocol: rhuMAb HER2-Genentech, ln.c.
`5/P H0648g-A3 P Final
`
`HOSPIRA EX. 1011 Vol. 2
`Page 247
`
`
`
`11 of 76
`
`Celltrion, Inc. 1042
`Celltrion v. Genentech
`IPR2017-01122
`
`

`

`,
`
`of cessation of doxorubicin. muMAb HER2 was initiated and a partial
`response was seen by Day 77. A complete response was confirmed
`by negative biopsies 2 months later. The patient is continuing on
`weekly muMAb HER2 and has remained free of disease for nearly
`34 months.
`
`In the second Phase II trial {H0552g), 39 patients were treated with a
`250-mg IV loading dose of rhuMAb HER2, followed by 100 mg IV
`weekly for 8 weeks. Clsplatin was given at a dose of 75 mg/m2 every
`4 weeks, 24 hours after rhuMAb HER2 administration. Nineteen
`patients with responses or stable disease entered the maintenance
`program; as of February 1996, all patients have discontinued
`treatment. No deaths were attributed to rhuMAb HEA2 treatment. For
`the 36 evaluable patients, 9 (25%) had a partial response, 9 {25%) had
`a minor response or stable disease, and the remaining 18 patients
`{50%) had progressive disease. The median time to disease
`progression was 3.6 months. The duration of response ranged from
`1.6 to 18 months (median=S.7 months). With one quarter of the
`patients having a partial response, this study showed an encouraging
`overall tumor response to rhuMAb HER2 plus cisplatin in refractory
`patients with HEA2-overexpressing metastatic breast cancer.
`
`rhuMAb HER2 was administered safely, and there were few or no
`changes in vital signs. Adverse events and laboratory abnormalities were
`not unusual for this patient population. Three patients had an elevated
`serum creatinine > 2.2 mg/dL Two patients had fever ( > 38°C) during or
`after infusion. The observed toxicity did not appear to be greater than
`that expected with cisplatin therapy (20), and the observed response rate
`was higher than that expected with cisplatin treatment alone in this
`population. However, the lack of a control group precludes any definitive
`conclusion about the response rates seen in this study.
`
`No antibodies to muMAb HER2 were detected in any of the five clinical
`studies.
`
`1.3
`
`STUDY RATIONALE
`Given the important role that HER2 plays in the pathogenesis and
`progression of breast cancer, it is vital to test the hypothesis that
`rhuMAb HEA2 treatment is a valuable addition to standard
`
`Protocol; rhuMAb HER2-Genentech, Inc.
`6/P H0648g-A3 P Final
`
`HOSPIRA EX. I 011 Vol. 2
`Page 248
`
`
`
`12 of 76
`
`Celltrion, Inc. 1042
`Celltrion v. Genentech
`IPR2017-01122
`
`

`

`r
`
`chemotherapy. While it is desirable in clinical trials to avoid introduction
`of bias through the use of placebo, such a strategy has proved difficult
`to implement during some cancer clinical trials due to the limited life
`expectancy and requirements for venous infusions in patients with
`metastatic disease. In the present study, patients randomized to a
`control group will undergo concomitant therapy, tumor evaluation, and
`general health surveillance· similar to patients assigned to the active
`therapy group. Importantly, the occurrence of the primary endpoint,
`disease progression, will be assessed by a Response Evaluation
`Commit.tee composed of radiologists and oncologists, who will be
`blinded to study treatment and uninvolved with the daily and routine
`care of patients in the study. In this manner, the trial will effectively
`compare the effect of rhuMAb HER2 administration on disease
`progression.
`
`OBJECTIVE
`The goal of this study is to determine the efficacy and safety of
`rhuMAb HER2 used in addition to chemotherapy in patients whose
`metastatic breast cancer overexpresses HEA2 and who have not
`received cytoto~ic chemotherapy.
`
`PRIMARY OBJECTIVES
`The primary objectives of the study are:
`To compare the time to disease progression (as determined by the
`Response Evaluation Committee) in patients receiving
`rhuMAb HER2 plus cytotoxic chemotherapy with those receiving
`chemotherapy alone
`
`• To further characterize the safety profile of rhuMAb HEA2
`
`SECONDARY OBJECTIVES
`The secondary objectives of the study are:
`.
`• To compare overall response rates (complete and partial
`responses) between both treatment arms (rhuMAb HER2 vs.
`control)
`.
`To compare the duration of response between both treatment arms
`in patients who have achieved a complete or partial response
`
`•
`
`2.
`
`2.1
`
`2.2
`
`Protocol: rhuMAb HER2-Genentech, Inc.
`7/P H0648g·A3 P Final
`
`HOSPIRA EX. 1011 Vol. 2
`Page 249
`
`
`
`13 of 76
`
`Celltrion, Inc. 1042
`Celltrion v. Genentech
`IPR2017-01122
`
`

`

`,
`
`3.
`
`• 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 assess the pharmacokinetics of rhuMAb HER2 when
`co-administered with chemotherapy
`
`• To determine 1-year survival estimates
`• To compare time to treatment failure (e.g., discontinuing due to
`toxicity without progression)
`
`STUDY PESIGN
`This is a Phase Ill, randomized, controlled, multinational study of
`chemotherapy alone or in combination with rhuMAb HER2.
`Approximately 450 patients with HEA2 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 wfll be equally randomized to one of two
`treatment arms: 1) the active arm, which consists of rhuMAb HER2 in
`combination with cytotoxic chemotherapy (the chemotherapy regimen
`must be determined prior to randomization), or 2) the control arm,
`which consists of cytotoxic chemotherapy alone (no study drug). All
`patients in the study will be required to follow similar study procedures.
`
`All patients randomized to tlhe rhuMAb HER2 arm will receive treatment
`as a 4 mg/kg IV loading dose on Day 0 (the first day of rhuMAb HER2
`infusion, or the day of randomization for patients in the control group),
`then weekly at a dose of 2 mg/kg IV throughout the course of the study.
`The initial dose of rhuMAb HER2 will precede either chemotherapy
`regimen by 24 riours. Subsequent doses of rhuMAb HER2 may be
`given immediately before chemotherapy (on the same day) if the initial
`dose of rhuMAb HER2 was well tolerated. All patients, regardless of
`the original randomization, will be monitored during each study visit by
`a clinical assessment, a symptom-directed physical examination (if
`appropriate), and laboratory tests (see Appendix A, Study Flowchart).
`Routine tumor evaluations will be conducted for all patients at
`prescribed intervals during the study. All adverse events will be
`recorded.
`
`After the completion of cytotoxic chemotherapy, those patients
`assigned to receive rhuMAb HER2 will continue weekly rhuMAb HER2
`
`Protocol: rhuMAb HER2-Genentech, Inc.
`8/P H0648g·A3 P Final
`
`HOSPIRA EX. 1011 Vol. 2
`Page 250
`
`
`
`14 of 76
`
`Celltrion, Inc. 1042
`Celltrion v. Genentech
`IPR2017-01122
`
`

`

`r
`
`infusions until disease progression is confirmed by radiographic or
`other objective criteria or until study termination. Patients from the
`control group will be eligible to receive rhuMAb HER2 in an open-label
`study (H0659g) following documented progression of their disease,
`confirmed by an independent Response Evaluation Committee (see
`Section 7.1).
`
`All patients who develop disease progression and do not enroll in the
`subsequent study will be followed for survival information every
`2 months until termination of statistical analysis of the study.
`
`The primary endpoint of the study will be time to disease progression
`as determined by the Response Evaluation Committee. The complete
`and partial response rates and response duration will be determined
`and compared between the groups. Quality of life will be assessed
`using the EORTC quality-of-life instrument with the breast cancer
`module. A supplemental instrument will be used to explore
`pharmacoeconomic issues in the treatment groups.
`
`STUDY POPULATION
`The study population will consist of women with HER2 overexpression
`who have not received pri