Site Initiation Meeting – May 23, 2013

Montreal General Hospital, McGill CRP

Nadine Ezer Clinical Trial Monitor Roche

2

JACOB Study(BO25114)

A double-blind, placebo-controlled, randomized, multicenter Phase III Study evaluating the efficacy and safety of pertuzumab in combination with trastuzumab and chemotherapy in patients with HER2-positive metastatic gastroesophageal junction and gastric cancer

3

The global statusStudy Timelines & Status

Final Protocol(27 Sep)

1st Investigator

meeting(Mar)

1st Site activation(Mar/Apr)

780 subjects recruited

FPI(Apr

2013)

LPI(May 2016)

Final Primary Analysis(Jun 2017)

2012 2014 - 2015 2016 2018 - 202220172013

LSLO

CompletedUpcomingStudy MilestonesData Point

1st Interim Safety Analysis(Oct 2013)

2nd Interim Safety Analysis(Feb 2014)

1st HA/IRB approval

(Dec)

Interim Analysis

70% OS event(Sep 2016)

4

OUR 2013 SMT (GDT) Goal for the JACOB Study

Enrollment of 110 patients of the total 780 patients required

by 31 December 2013

5

Other Teams Supporting the Study

IXRS

Central Laboratory

Central HER2 Testing

Overview of Gastric/GEJ cancer

7

Increasing incidence of adenocarcinoma of gastric cardia/GEJ• Multifactorial etiology (obesity, gastroesophageal reflux, diets high in

salted/smoked foods, FH, H. pylori, tobacco and alcohol use)• 65% diagnosed with regional/distant disease3

• Median survival < 1 year – better treatments are needed!

4th most common cancer diagnosis (1,000,000 new cases each year) 1

3rd leading cause of cancer death in males globally (700,000 deaths) 2

>70% of new cases and deaths occur in developing countries 2 –

Gastric/GEJ Adenocarcinoma

6. cardia (including gastroesophageal junction)

1. GLOBOCAN 20082. Jemal et al., CA CANCER J CLIN 2011;61:69–903. Howlader SEER data 2001-7

10

The incidence of gastric cancer is highest in Asia

Parkin DM, et al. CA Cancer J Clin 2005; 55:74–108.

Age-standardised incidence(per 100,000)

Incidence Mortality

60 50 40 30 20 10 10 20 30 40 50 60

Eastern AsiaCentral and Eastern Europe

Less developed regionsWorld

South AmericaMore developed regions

Central AmericaSouthern Europe

South-Eastern AsiaCaribbeanPolynesia

Melanesia

Northern Europe

Australia/New ZealandSouth-Central Asia

Middle AfricaEastern Africa

Northern AmericaWestern Africa

Micronesia

Western Europe

Southern AfricaNorthern Africa

Western Asia

0

Male Female

11

Gastric cancer clinical presentation/RX

Abdominal pain, weight loss, obstruction, GI bleed

Limited disease (resectable without distant mets)

• Surgical resection of primary tumor and LN with perioperative chemotherapy and XRT

Locally advanced (unresectable)/metastatic

• Chemotherapy – differs by geographic region, - usual regimens: ECF, EOF, ECX, TC

• Biologic therapy (eg. Trastuzumab, Met inhibiting agents)

• Palliative surgery (e.g. bypass)

• Palliative radiotherapy

12

HER2 positive cancer

Breast cancer 20% HER2 positive• Trastuzumab with chemotherapy improves OS in adjuvant and metastatic settings

Gastric cancer 20% HER2 positive • Trastuzumab with chemotherapy improves OS in metastatic settings (ToGA)

HER2 positive rates may be slightly lower in Asian populations (19 vs. 15%)

Different guidelines for interpreting HER2+ in gastric vs. breast cancer• Breast cancer methods result in underscoring of HER2 in gastric ca

New HER2 targeted therapies• Lapatinib: oral TKI of HER1 and HER2 approved for met breast ca

• TYTAN trial in second line HER2+ (by FISH) GC lapatinib did not prolong OS• LOGiC trial in first line HER2+ GC

• Pertuzumab: IV monoclonal antibody targets HER2• T-DM1: IV antibody drug conjugate targets HER2

Bang et al Lancet 2010 / Hofmann et al Histopath 2008 / Ruschoff et al Mod Path 2012

13

ToGA trial designPhase III, randomized, open-label, international, multicenter study

Locally Advanced (inoperable) vs. Metastatic GC vs. GEJMeasurable vs. Non-measurableECOG PS 0-1 vs. 2Capecitabine vs. 5-FU

Primary endpoint OS

a Chosen at investigator’s discretion 1 Bang et al; Abstract 4556, ASCO 2009

GEJ, gastroesophageal junctionBang Lancet 2010

5-FU or capecitabine a + cisplatin

(n=290)

RHER2-positiveadvanced GC

(n=584)5-FU or capecitabine a

+ cisplatin + trastuzumab(n=294)

3807 patients screened

810 HER2-positive

(22.1%)(IHC 3+ or FISH +)

Stratification factors

14

ToGA (BO18255)

The results of the ToGA study (Herceptin®/trastuzumab plus fluoropyrimidine-cisplatin chemotherapy) established a new standard of care for treatment of HER2 positive AGC*: Adding trastuzumab to chemotherapy prolongs survival

Median OS duration improved from 11.1 to 13.8 months in the full analysis population

Median OS duration improved from 11.8 to 16.0 months in the high HER2 overexpressing population (tumors that are IHC3+ or IHC2+/ISH+)

* AGC = Advanced Gastric Cancer Defined as Inoperable, locally advanced or metastatic gastric/GEJ adenocarcinoma

15

No.at riskF/X + C + H

F/X + C

13.8

K-M Plot of Overall Survival in ToGA Study(full analysis population)

H, Herceptin / Bang YJ., et al., Lancet 2010; 376: 687-697

Time (Months)

Even

t

1.0

0.8

0.6

0.2

0

0.4

0

294

290

36

0

0

20

43

24

10

147

117

32

4

0

4

246

223

16

71

47

24

21

14

28

12

6

2

277

266

6

209

185

8

173

143

12

113

90

14

90

64

18

56

32

22

30

16

26

13

7

30

6

5

34

1

0

HR = 0.7495% CI (0.60, 0.91)p value = 0.0046

OS13.8

Events167182 11.1

F/X + C + HF/X + C

11.1

Median

16

No.at riskFC + H

FC

K-M Plot of Overall Survival in ToGA Study(High HER2 overexpressors = IHC3+ or IHC2+/FISH+)

H, Herceptin / Bang YJ., et al., Lancet 2010; 376: 687-697

Time (Months)

Even

t

1.0

0.8

0.6

0.2

0

0.4

0

228

218

36

0

0

20

39

20

10

122

96

32

4

0

4

196

170

16

65

39

24

20

11

28

11

3

2

218

198

6

170

141

8

142

112

12

100

75

14

84

53

18

51

28

22

28

13

26

12

4

30

5

3

34

1

0

HR = 0.6595% CI (0.51, 0.83)

OS16.0

Events120136 11.8

FC + HFC

Median

16.0

11.8

17

Evidence that pertuzumab + trastuzumab are more active than either agent alone

Pertuzumab has a different mechanism of action and a different binding site on the HER2 receptor than trastuzumab

Additive activity in pre-clinical animal models• Breast cancer• Gastric cancer

Activity seen in phase II/III studies in HER2 positive BC• BO17929 (phase II – 2nd line MBC)• NEOSPHERE (phase II – EBC)• CLEOPATRA (phase III – 1st line MBC)

18

Pertuzumab (Perjeta)

An IgG1 (k) humanized monoclonal antibody

Produced in CHO (Chinese Hamster Ovary) cell cultures

Targets the HER2 receptor extra-cellular domain (sub-domain II)

Adams CW et al. Cancer Immunol Immunother 2006

19

Pertuzumab and trastuzumabbind different epitopes on HER2

• Inhibits ligand-independent HER2 signalling• Prevents HER2 ECD shedding• Activates ADCC

• Inhibits ligand-dependent HER2 signalling• Inhibits HER2 hetero-dimerization • Activates ADCC• Non-competitive with trastuzumab

due to different binding domain on HER2 receptorHubbard SR Cancer Cell 2005; Molina MA et al. Cancer Res 2001;Junttila TT et al. Cancer Cell 2009; Scheuer W et al. Cancer Res 2009;Franklin MC et al. Cancer Cell 2004; Agus DB et al. Cancer Cell 2002

pertuzumab

trastuzumab dimerization domain

Trastuzumab-HER2 complex Pertuzumab-HER2 complex

20

Patients treated with pertuzumab and trastuzumab until progression of disease or unmanageable toxicityIf docetaxel discontinued, treatment with pertuzumab and trastuzumab may continue

CLEOPATRA: Study Design: Registration Trial for Pertuzumab in Metastatic Breast Cancer

Pivotal CLEOPATRA trial: Multicenter, randomized, double-blind, placebo-controlled, Phase III study in patients with HER2+ metastatic breast cancer (mBC)

Placebo + trastuzumab (q3w)

Docetaxel (q3w)Minimum of 6 cycles

(n=406)

(n=402)

1:1‡ Docetaxel (q3w) Minimum of 6 cycles

Pertuzumab + trastuzumab (q3w)

20

q3w = every 3 weeks. * HER2 overexpression was defined as IHC 3+ or FISH amplification ratio ≥2.0. IHC 3+ is defined as uniform, intense membrane staining in >10% of tumor cells. † Patients with prior adjuvant or neoadjuvant therapy were required to have a disease-free interval of ≥12 months to be eligible for enrollment in the trial. ‡ Randomization was stratified by prior treatment status (de novo or prior adjuvant/neoadjuvant therapy) and geographic region (Europe, South America, and Asia).

Patients with HER2+,* locally recurrent, unresectable, or mBC previously untreated with a biologic or chemotherapy for metastatic disease† (n=808)

21

CLEOPATRA: Primary Endpoint1

Prog

ress

ion-

free

sur

viva

l (%

) 100

80

60

20

0

Time (Months)

40

Patients at riskPertuzumab+T+D

Placebo+T+D

Progression-Free Survival (PFS): A hazard ratio (HR) of 0.62 describes 38% reduction in risk of disease progression or death

* Stratified by prior treatment status and geographic region.Source: 1. PERJETA™ (pertuzumab) full prescribing information. Genentech, Inc., June 2012.

0

402

406

40

0

0

20

83

42

10

267

209

35

0

0

5

345

311

15

139

93

25

32

17

30

10

7

Pertuzumab +trastuzumab + docetaxel

Placebo + trastuzumab + docetaxel

HR = 0.62*95% CI (0.51, 0.75)p value = <0.0001

18.5

12.4

22

CLEOPATRA: Confirmatory interim analysis of overall survival (OS IA2)

Ove

rall

surv

ival

(%)

100

80

60

20

0

Time (Months)

40

Patients at riskPtz + T + D

Pla + T + D

D, docetaxel; OS, overall survival; Pla, placebo; Ptz, pertuzumab; T, trastuzumabS Swain, San Antonio Breast Cancer Symposium (SABCS), 2012 (Abstract #P5-18-26)

Pertuzumab + T + D: 113 events;median not reached

Placebo + T + D: 154 events; median 37.6 months

0

402

406

55

0

0

20

317

285

10

371

350

35

84

67

5

387

383

15

342

324

25

230

198

30

143

128

HR = 0.6695% CI (0.52−0.84)p value = 0.0008

40

33

22

45

9

4

50

0

0

Stopping boundary for concluding statistical significance at this interim analysis was p≤0.0138

Median follow-up: 30.0 months, n=267 OS events

23

CLEOPATRA: Adverse events (all grades)≥25% incidence or ≥5% difference between arms

Adverse event, n (%) Placebo + trastuzumab + docetaxel (n=397)

Pertuzumab + trastuzumab + docetaxel (n=407)

Diarrhea 184 (46.3) 272 (66.8)Alopecia 240 (60.5) 248 (60.9)Neutropenia 197 (49.6) 215 (52.8)Nausea 165 (41.6) 172 (42.3)Fatigue 146 (36.8) 153 (37.6)Rash 96 (24.2) 137 (33.7)Decreased appetite 105 (26.4) 119 (29.2)Mucosal inflammation 79 (19.9) 113 (27.8)Asthenia 120 (30.2) 106 (26.0)Peripheral edema 119 (30.0) 94 (23.1)Constipation 99 (24.9) 61 (15.0)Febrile neutropenia 30 (7.6) 56 (13.8)Dry skin 17 (4.3) 43 (10.6)

24

Perjeta/Pertuzumab 1st Line MBCApprovals as of 16 May 2013

Country Approval

United States 08 Jun 2012

Switzerland 14 Aug 2012

Mexico 26 Sep 2012

Macau 03 Dec 2012

Uruguay 26 Dec 2012

Kosovo 20 Jan 2013

Georgia 21 Jan 2013

Aruba 31 Jan 2013

Kuwait 6 Feb 2013

Country Approval

Israel 12 Feb 2013

European Union 4 Mar 2013

Iceland Mar 2013

Canada 14 Apr 2013

Russia 16 Apr 2013

Argentina 25 Apr 2013

Norway Apr 2013

Luxemburg Apr 2013

Australia 5 May 2013

25

Rationale for a Phase III study of pertuzumab in HER2-positive gastric cancer

Preclinical data show that pertuzumab increased the activity of trastuzumab in HER2-positive gastric cancer xenograft models

HER2-positive gastric/GEJ cancer (ToGA): clinical evidence that HER2-targeted therapy extends survival

In HER2-positive mBC: CLEOPATRA study confirmed improved efficacy of combined HER2-directed therapy with docetaxel

Large safety database showing good tolerability across multiple indications , includes data with capecitabine and platinum

Plan → Phase III trial in advanced gastric/GEJ cancer.

• But what dose Pertuzumab in aGC ?

26

JOSHUA BP27836: Phase IIa study rationale

Determine pertuzumab dose in HER2 positive advanced GEJ/gastric cancer

Achieve PK clinical target for minimum pertuzumab concentration of 20 g/ml in >90% of patients

• Same clinical target concentration as in HER2-positive breast cancer

Move to Phase III with dose modeled from Phase IIa data

27

JOSHUA: Study design, Phase IIa trial

Estimate minimum (trough) serum pertuzumab concentration to identify a steady state of ≥20 g/ml in 90% of patientsSafety and tolerability

HER2-positiveinoperable locally

advanced or recurrent and/or metastatic GEJ/GC

(IHC3+ or IHC2+ and FISH+; ECOG PS 0 or 1)

Primary objectives:

Arm APertuzumab 840 mg,

then 420 mg + X + cisplatin x6 q3w

+ trastuzumabn=15

ECOG PS, Eastern Cooperative Oncology Group performance status; FISH, fluorescence in situ hybridisation; GC, gastric cancer; GEJ, gastroesophageal junction; IHC, immunohistochemistry; PD, progressive disease; pK, pharmacokinetics; X, capecitabine

Arm BPertuzumab 840 mg

+ X + cisplatin x6 q3w + trastuzumab

n=15

Dose selection for Phase III

study based on PK modelling

The JACOB Study (BO25114):

Rationale of Study Design and Protocol Overview

29

The JACOB Study (BO25114) Design

Randomization (1:1)

n = 780 (approximately

390 pertreatment arm)

Follo

w-U

p #

Study Treatment ~ 6 treatment cycles

(21 day cycle)

Study Treatment* HER2 targeted therapy

continues until PD or unacceptable toxicity

• HER2-positive Metastatic gastric/GEJ adenocarcinoma• IHC 3+ or IHC 2+/ISH+ (central testing required)• ECOG PS 0 or 1

Key EligibilityCriteria: * After Cycle 6, continuation of chemotherapy

is at physician’s discretion

Primary Endpoint

OS(Events = 502)

Secondary Endpoints

PFS, ORR, DoR,CBR, Safety,

PK, QOL

Treatment Arm A

Treatment Arm B

Capecitabine or 5FU + Cisplatin

Capecitabine or 5FU + Cisplatin

Trastuzumab + Pertuzumab 840 mg IV Q3W

Trastuzumab + Pertuzumab placebo IV Q3W

*

*

# If patients permanently stop study treatment (HER2-directed), they continue to be followed for side effects and cardiac monitoring

• Geographic Region (Japan, N. America/W. Europe, Asia (not including Japan), Latin America/E. Europe)• Prior gastrectomy (yes/no)• HER2 IHC3+ vs. IHC2+/ISH+

Stratificationfactors:

30

JACOB: Study endpoints

PrimaryOverall survival (15.0 vs. 19.3 mos, HR 0.78)

SecondaryPFS, ORR, duration of objective response, clinical benefit rateSafetyPKQoL

ExploratoryBiomarkers • Tumor tissue: HER receptor status, ERCC1, PTEN, PI3K, MET• Blood: HER2 ECD, HER ligands, anti-therapeutic antibody

ORR, objective response rate; PFS, progression-free survival; pK, pharmacokinetics; QoL, quality of life

31

JACOB: Biomarker Analyses Overview

* Minimum of 15 slides to be sent if country or site regulations do not allow shipment of a tumor block

Patient selection(Block/partial block*)

Exploratory BM Research(Block/partial block*)

RCR(Roche clinical repository, optional)

Central confirmation of HER2 (prospectively)

• IHC• ISH

• Serum • Plasma• Whole blood

sample for DNA extraction

• c-MET• ERCC1• PTEN• PIK3CA mutations• HER2/3 mRNA• HER3 protein

Biomarker analysis and sampling strategy in JACOB

32

JACOB: Statistical assumptions

Hazard ratio 0.78

Number of patients 780

Number of events for 80% power 502

Median OS: control vs. experimental arm, months 15 vs. 19.3 (Δ=4.3)

Minimum detectable difference at 80% power 0.8372.9 months

Enrollment*, months 38

Expected availability of OS data†, months 55 ~ Q4 2017

* Assuming a 5% withdrawal rate within 55 months† Clinical cut-off from EAST plus 2 monthsOS, overall survival

33

JACOB: Interim Analyses

Safety:Monthly review of AEs first six months

Regular safety monitoring reviews (approximately every 6 months)

Two formal interim safety analyses• After 50 patients have been enrolled and followed up for at least 2 months• After 100 patients have been enrolled and followed up for at least 4 months

Efficacy:One interim analysis of OS after 351 deaths have occurred

34

JACOB: Target Study Population

Approximately 780 patients with histologically confirmed metastatic GEJ/GC who have received no prior treatment for metastatic disease• Measurable or non-measurable evaluable (RECIST 1.1)

• ECOG PS 0 or 1

• Baseline LVEF ≥ 55% (MUGA or echocardiogram)

• Life expectancy ≥ 3 months

HER2 positive (IHC3+ or IHC2+/ISH+) tumor by central laboratory testing

35

Definition of HER2 positivity in JACOB

HER2 positivity isdefined as:

IHC 3+ (regardless of ISH results)

IHC 2+ if confirmed by a positive ISH result (cut-off for ISH ratio: 2.0 HER2/CEP17)

For IHC testing, the cut-off as approved by FDA in context of ToGA will apply

35

Screening population

IHC test

IHC 0 and 1+ IHC 2+ IHC 3+

Not eligible Reflex test by ISH eligible

ISH- ISH+

Not eligible eligible

36

Tissue requirements for HER2 central assessment

Tumor blocks preferred (submission of slides should be an exception!) Cutting at central lab ensures higher quality and higher level of

standardization and saves tissue!

If blocks not available a minimum of 15 unstained and freshly cut slides can be submitted for HER2 testing and exploratory Biomarker analyses (maximum 48hrs from slicing to shipment)Biopsy or surgical specimen of either primary or recurrent/metastatic tumor are allowed for HER2 assessment • For biopsies, ideally 6 to 8 biopsies taken from different metastatic

lesions should be submitted and assessed• Fine needle aspirates CANNOT be accepted

The fixative allowed is neutral buffered formalin (10%)

37

JACOB: Exclusion criteria

Cancer-Related Exclusion Criteria1. Previous systemic cytotoxic chemotherapy for advanced (inoperable or metastatic) disease

2. History of exposure to the following cumulative doses of anthracyclines:a) Epirubicin > 720 mg/m2

b) Doxorubicin or liposomal doxorubicin > 360 mg/m2

c) Mitoxantrone > 120 mg/m2 and idarubicin > 90 mg/m2

d) Other (e.g., other anthracycline greater than the equivalent of 360 mg/m2 of doxorubicin)e) If more than one anthracycline has been used, then the cumulative dose must not exceed the equivalent of 360 mg/m2 of

doxorubicin

3. Evidence of disease progression documented within 6 months after completion of prior neoadjuvant and/or adjuvant cytotoxic chemotherapy or radiotherapy for gastric/GEJ adenocarcinoma

4. Previous treatment with any HER2-directed therapy, at any time, for any duration

5. Previous exposure to any investigational treatment within 30 days before the first dose of study treatment

6. Radiotherapy within 30 days before the first dose of study treatment (within 2 weeks if given as palliation to peripheral bone metastases, if recovered from all toxicities)

7. History or evidence of brain metastasis

8. Clinically significant active GI bleeding (Grade ≥ 2 according to CTCAE v4.03)

9. Residual toxicity resulting from previous therapy, e.g., hematologic, cardiovascular, or neurologic toxicity that is Grade ≥ 2 (according to CTCAE v4.03). Alopecia is permitted

10. Other malignancy (in addition to GC) occurring within 5 years before enrollment, except for carcinoma in situ of the uterine cervix or squamous or basal cell carcinoma of the skin that has been previously treated with curative intent

1. Previous systemic cytotoxic chemotherapy for advanced (inoperable or metastatic) disease

2. History of exposure to the following cumulative doses of anthracyclines:a) Epirubicin > 720 mg/m2

b) Doxorubicin or liposomal doxorubicin > 360 mg/m2

c) Mitoxantrone > 120 mg/m2 and idarubicin > 90 mg/m2

d) Other (e.g., other anthracycline greater than the equivalent of 360 mg/m2 of doxorubicin)

e) If more than one anthracycline has been used, then the cumulative dose must not exceed the equivalent of 360 mg/m2 of doxorubicin

3. Evidence of disease progression documented within 6 months after completion of prior neoadjuvant and/or adjuvant cytotoxic chemotherapy or radiotherapy for gastric/GEJ adenocarcinoma

4. Previous treatment with any HER2-directed therapy, at any time, for any duration

38

JACOB: Exclusion criteria

Clinical Laboratory Exclusion Criteria (must be confirmed within 7 days before first dose of study treatment)11. Absolute neutrophil count (ANC) < 1.5 109/L

12. Platelet count < 75 109/L

13. Hemoglobin < 9.0 g/dL

14. Creatinine clearance < 60 mL/min/1.73 m²

15. Serum bilirubin (total) > 1.5 ULN of laboratory normal range; in case of known Gilbert’s disease a total bilirubin of 2 ULN is permitted

16. AST, ALT, and alkaline phosphatase (ALP) parameters:a) In patients with no liver and no bone metastases

i. AST or ALT > 1.5 × ULN, and ALP > 2.5 × ULNii. AST or ALT > 2.5 × ULN

b) In patients with liver metastases and no bone metastasesi. AST or ALT > 5 × ULN, and ALP > 2.5 × ULN

c) In patients with liver metastases and bone metastasesi. AST or ALT > 5 × ULN, and ALP > 10 × ULN

d) In patients with bone metastases and no liver metastasesi. AST or ALT > 1.5 × ULN, and ALP > 10 × ULN

17. Serum albumin < 25 g/L

18. Serum pregnancy test positive in a female patient of childbearing potential

39

JACOB: Exclusion criteria

General Exclusion Criteria

19. Documented history of congestive heart failure of any New York Heart Association (NYHA) criteria

20. Angina pectoris requiring treatment

21. Myocardial infarction within the past 6 months before the first dose of study treatment

22. Clinically significant valvular heart disease or uncontrollable high-risk cardiac arrhythmia, i.e., atrial tachycardia with a heart rate > 100/min at rest, significant ventricular arrhythmia (ventricular tachycardia) or higher-grade AV-block (second degree AV-block Type 2 [Mobitz 2] or third degree AV-block)

23. History or evidence of poorly controlled arterial hypertension (systolic blood pressure > 180 mmHg or diastolic blood pressure > 100 mmHg)

24. Baseline LVEF value < 55%, assessed by echocardiogram [ECHO], MUGA scan, or cardiac MRI

40

JACOB: Exclusion criteria

25. Dyspnea at rest due to complications of advanced malignancy or other disease or requirement of supportive oxygen therapy

26. Any significant uncontrolled intercurrent systemic illness (e.g., active infection, poorly controlled diabetes mellitus)

27. Previous major surgery within 30 days before the first dose of study treatment, unless completely recovered

28. Known infection with HIV, hepatitis B virus, or hepatitis C virus that requires active treatment

29. Ongoing chronic treatment or high-dose treatment with corticosteroids. Inhaled steroids and clinically indicated short courses of oral steroids are permitted

30. Known dihydropyrimidine dehydrogenase (DPD) deficiency31. Known hypersensitivity to any component of study treatment32. Current use of antiviral drug sorivudine or its chemically related analogues, such as

brivudine33. Lactating female patient34. Any patient unwilling or unable to use adequate contraceptive measures

41

Contraception

For women of childbearing potential and male participants with partners of childbearing potential: Agreement to use one highly effective form of contraception or two effective forms of non-hormonal contraception by the patient and/or partner while on study treatment and for 6 months after stopping study treatment:

Highly effective (any one)• True abstinence• Male sterilization• Tubal ligation• Combined hormonal contraceptives

Effective (any two)• IUD/IUS• Condom with spermicidal foam/gel/film/cream/suppository• Occlusive cap (diaphragm or cervical/vault cap) with

spermicidal foam/gel/film/cream/suppository

42

Screening Assessments

Day -28 to -1• Informed consent• HER2 tumor testing• Serum sample for levels of HER2

shed extracellular domain (ECD)• Demographics and medical history • Physical exam• ECOG PS• Tumor assessments• ECG & LVEF assessments• Tumor tissue block for biomarkers• Concomitant therapy

Day -7 to -1• Randomization• Hematology, serum chemistries• Creatinine clearance • Urinalysis• Pregnancy test• Concomitant therapy

43

JACOB: Study treatment

All agents will be given on the same day in the following order(pertuzumab/placebo → trastuzumab → chemotherapy)

Chemotherapy backbone will be administered on a 3-weekly schedule

• Capecitabine 1000 mg/m2 taken orally twice daily for 14 days then7 days off q3w

OR• 5-Fluorouracil 800 mg/m2/24 hours given intravenously by continuous

infusion for 120 hours (Days 1−5) q3w

• Cisplatin 80 mg/m2 intravenously (Day 1) q3w

• Pertuzumab 840 mg or placebo q 3 weeks• Trastuzumab 8 mg/kg initial dose, followed by 6 mg/kg q3w

with

with

44

Incomplete dose:If patient receives 50-75% of dose, the remainder should be given during the same treatment cycle, preferably before day 15 (Section 4.3.1.4.1 for details)

Administration guidelines for pertuzumab and trastuzumab

Administration Time (minutes)

Observation Time (minutes)

First dose

Pertuzumab/placebo 60 60

Trastuzumab 90 60

All later doses

Pertuzumab/placebo 30 30

Trastuzumab 30 30

The JACOB Study (BO25114):

Safety Monitoring

46

Overview of Safety Monitoring

Upfront discussion of diarrhea management and anti-diarrheal medicines prescribed

C1 Day 7 safety check (by phone) ** please document in source !

AE grading using CTCAE version 4.03• Progressive disease is not an AE

47

Diarrhea management anddose reductions

Grade 2 or greater: STOP capecitabine

Supportive care with loperamide

Cannot restart until grade ≤1 and last loperamide given 24 hrs beforehand• If controlled within 2 days, can restart at 100%• If > 2 days, medical evaluation required

Table 4 in protocol

48

Diarrhea grades

CTCAE Grade(v. 4.03)

1 Increase of < 4 stools per day over baseline; mild increase in ostomy output compared to baseline

2 Increase of 4 – 6 stools per day over baseline; moderate increase in ostomy output compared to baseline

3Increase of >= 7 stools per day over baseline; incontinence; hospitalization indicated; severe increase in ostomy output compared to baseline; limiting self care ADL

4 Life-threatening consequences; urgent intervention indicated

49

Dose Modifications for pertuzumab and trastuzumab

No dose reduction permitted for toxicity, for either pertuzumab or trastuzumab

Treatment with either pertuzumab or trastuzumab (or both) may be delayed to assess or treat AEs• Dosing should be resumed as soon as appropriate after the AE has

improved (see protocol section 4.3.1.4.1)• Patients should be re-assessed at least weekly to determine if

treatment can be resumed

If trastuzumab dosing is delayed and ≥ 6 weeks have elapsed since the last dose, a re-loading dose of 8 mg/kg should be given as the next dose, then resume the 6 mg/kg Q3W dosing schedule• Pertuzumab, capecitabine, and cisplatin dosing should be

re-synchronized to the new schedule

50

If recovery has not occurred after a delay of 3 weeks (i.e., 6 weeks since previous chemotherapy doses), the patient should be permanently discontinued from fluoropyrimidine and cisplatin.

Dose Modifications for HematologicToxicity Due to FP Chemotherapy

ANC(x 109/L)

Platelets(x 109/L) Fluoropyrimidine/Cisplatin

≥ 1.5 and ≥ 75 100% of original doses, without delay

≥ 1.0 – < 1.5 and ≥ 75 75% of original doses, without delay

< 1.0 and/or ≥ 75

Delay for up to 3 weeks, then resume treatment if ANC ≥ 1.0 and platelets ≥ 75. If

ANC is ≥ 1.0 – < 1.5, administer 75% of original doses. If ANC is ≥ 1.5, administer

100% of original doses.If ANC < 1.0 or platelet count is < 75,

permanently discontinue fluoropyrimidine and cisplatin for unacceptable toxicity.

Table 2 in protocol

51

Interrupt chemotherapy Dose reduce as directed when starting next cycleDose reductions are permanent

Dose Modifications for Life-Threatening Hematologic Toxicity Occurring during FP Administration

ToxicityFluoropyrimidineand Cisplatin in

Subsequent Cycles

Grade 4 neutrophil count decrease > 5 days in duration 75% of original doses

Grade 4 platelet count decrease 50% of original doses

Grade 3 febrile neutropeniaANC < 1000/mm3 with a single temperature of > 38.3⁰C (101⁰F) or a

sustained temperature of ≥ 38⁰C (100.4⁰F) for more than 1 hour75% of original doses

Grade 4 febrile neutropeniaANC < 1000/mm3 with a single temperature of > 38.3⁰C (101⁰F) or a sustained temperature of ≥ 38⁰C (100.4⁰F) for more than 1 hour and

life-threatening consequences

50% of previous original, at investigator’s discretion

Table 3 in protocol

52

Cardiac Safety Monitoring

HER2 directed therapy has been implicated in cardiac toxicity• Pertuzumab and trastuzumab cardiac safety must be monitored

• Currently, there is no evidence for increased cardiac toxicity with pertuzumab-containing combination regimens

Regularly scheduled ECG and LVEF assessments are mandatory• Every 9 weeks while on chemotherapy treatment

• Every 12 weeks while on antibody alone treatment

• Every 6 months for 1 year after stopping study drug

• Then annually during survival follow up for up to 5 years

53

Algorithm for Asymptomaticdecline in LVEF

LVEF drop from baseline

LVEF ≥ 50% LVEF < 50%

LVEF drop≤ 20%

LVEF drop> 20%

LVEF drop< 10%

LVEF drop≥ 10%

CONTINUETreatment

CONTINUE Treatment and repeat LVEF in 3 weeks

HOLD Treatment and repeat LVEF in 3 weeks

Not Confirmed(LVEF drop < 10pts or

LVEF ≥ 50%)

LVEF drop CONFIRMED(LVEF drop ≥ 10pts and

LVEF < 50%)

RESUME Treatment STOP Treatment

Figure 3 of Protocol

54

Pertuzumab/Trastuzumab Cardiac Toxicity: Reporting AE/SAE

Observation How to Report Term to be Reported Grading

Asymptomatic decline in LVEF < 10% points from baseline or to an LVEF ≥ 50%

No additional reporting required, LVEF results to

be reported on eCRFN/A N/A

Asymptomatic decline in LVEF ≥ 10% points from baseline to an LVEF < 50% AE (eCRF)

“Ejection fraction

decreased”

NCI CTCAE for “ejection fraction

decreased”

Asymptomatic decline in LVEF requiring treatment or leading to discontinuation of pertuzumab/placebo and trastuzumab

AE (eCRF)“Ejection fraction

decreased”

NCI CTCAE for “ejection fraction

decreased”

Congestive heart failure (symptomatic LVSD) SAE (eCRF) “Congestive

heart failure”NCI CTCAE for “heart failure”

and NYHA Class

AE = adverse events; CTCAE = Common Terminology Criteria for Adverse Events; eCRF = electronic Case Report Form; LVEF = left ventricular ejection fraction; LVSD – left ventricular systolic dysfunction; N/A = not applicable; NCI = National Cancer Institute; NYHA = New York Heart Association; SAE = serious adverse event.Notes: Any symptomatic LVSD event must be reported as “congestive heart failure”.

Table 7 in protocol

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LVSD Dysfunction eCRF

If a patient has a decrease in LVEF by ≥10 percentage points from baseline to an absolute value below 50% recorded in the LVEF assessment CRF, the Principal Investigator will then complete the following CRF:

Does the subject have difficulty breathing?

If yes, select all that apply:

While climbing less than 8 stair steps

While getting dressed

At rest

While lying flat

Other

Does the subject have any clinical signs that may be due to heart failure?

If yes, select all that apply:

Bilateral ankle edema

Pulmonary rales

Weight gain

Jugular venous distention

Other

58

Tumor Assessments

Measurable or non-measurable evaluable tumor (RECIST 1.1)

Baseline assessment at screening, then after every 9 weeks until progressive disease (PD) is documented

Measurable disease should be imaged using CT or MRI – use the same method throughout the study for a given patient

Report measurements of target and non-target lesions for measurable disease (per RECIST)

Report objective response (CR/PR, SD, PD) for both measurable and non-measurable evaluable disease• If PD occurs off cycle, an unscheduled Tumor Assessment

should be performed

61

Schedule for PharmacokineticSampling for Pertuzumab and Trastuzumab

Appendix 2 in protocol

Cycle 1

Cycle2

Cycle3

Cycle4

Cycle6

Cycle8 a

Post-treatment

Monitoring Visit 1 b

(28 days post

last dose)

Post-treatment

Monitoring Visit 2 c

(60-90 days post last dose)

Predose d ● ● ● ● ● ● ● ●

Postdose e ● ● ● ●

a Sample collected when on biologic therapy alone and last chemotherapy was ≥6 weeks ago. This timepoint may not coincide with Cycle 8 for all patients

b Sample collected 28 days after last administration of study

c Sample collected 60-90 days after last administration of study treatment

d Sample can be collected up to 6 hours prior to administration of the specified drug

e Sample can be collected up to 30 minutes after end of drug infusion of specified drug

62

Table 1-2 Follow-up Assessments until Death

Post-treatment Phase Monitoring d SurvivalFollow-up

TimepointPost-treatment Monitoring

Visit 2 60-90 days after

last study treatment

24 wk (±2 wk)

Every 12 weeks a (±2 wk)

ATA ●

PK sampling ●

Cardiac monitoring: LVEF b (MUGA/ECHO/MRI),ECG including cardiac

medication (start and end dates, changes in dosing)

●

Drug-related SAEs c ● ● ●

Survival assessment d ● ● ●

Post-treatment phase anticancer therapy

Information about any subsequent (post-study treatment) anticancer

therapy will be collected, including the names of all components of treatments

and start and end dates of dosing

●

63

Recruitment Challenge: High Screen Failure Rate

It is assumed that screening ineligibility rate may be ~85%

Primarily driven by requirement for HER2 positivity • ~ 22% of patients with advanced gastric cancer are HER2+

But… it’s not impossible: ToGA trial recruited successfully with a ~80% screen failure rate

Improve overall screening rates by implementing process of pre-identifying and pre-screening patients • This will help reduce screening failure rate not related to HER2

positivity• If local pre-screening HER2 result is borderline or equivocal, please still

send for central HER2 testing

Reviewing pre-screening information will help identify why potentially eligible patients are not considered for screening

64

Synergy with MetGastric study

JACOB study accepts HER2 test result from Targos and vice versa

In those MetGastric and JACOB overlapping sites (25%), screen for MetGastric study first

Where patient screened in MetGastric study has HER2 positive status:• Obtain Informed Consent for JACOB• Investigator/study nurse registers MetGastric study patient screen

number in the JACOB’s IXRS screening module• Send results transfer form with detailed patient information to Targos

→ Tissue sample will be transferred within Targos

If site is not a JACOB/MetGastric overlapping site, a referral network is recommended

65

Role and responsibility of CRC (Cardiac Review Committee)

CRC Patients with potential cardiac events (e.g. symptomatic LVSD) per investigator assessment will be reviewed by independent external Cardiac Review Committee (CRC)• CRC provides independent blinded central determination of symptomatic

declines in LVEF and definite and probable cardiac deaths for reporting to IDMC

CRCC (Duke Clinical Research Institution) is the vendor who will: Raise queries using RAVE (10 day turnaround)Request/collect source documents via emailEnsure relevant variables are cleanPrepare event packetsRecord CRC adjudicationsCoordinate CRC adjudication meetings

66

Potential source documents to be collected

Physician progress or consultation notes

Discharge summary

ECG tracing and report

ECHO/MUGA/cardiac MRI report

Chest X-ray report

Any other documents that CRCC deems necessary for case adjudication, e.g. cardiac catheterization report

• CRCC will be responsible for document translationif in language other than English

Q&A