1. Nadine Ezer Clinical Trial Monitor  Roche
Site Initiation Meeting – May 23, 2013 Montreal General Hospital, McGill CRP
Nadine Ezer
Clinical Trial Monitor  Roche

2. 22-Apr-17
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 status Study Timelines & Status
Completed
1st Site activation (Mar/Apr)
Upcoming
780 subjects recruited
Study Milestones
Data Point
1st Investigator meeting (Mar)
FPI (Apr 2013)
LPI (May 2016)
LSLO
2012
2013
2016
2017
Final Protocol (27 Sep)
1st HA/IRB approval (Dec)
Final Primary Analysis
(Jun 2017)
Interim Analysis 70% OS event (Sep 2016)
1st Interim Safety Analysis (Oct 2013)
2nd Interim Safety Analysis (Feb 2014)

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
Central Laboratory
IXRS
Central HER2 Testing

6. Overview of Gastric/ GEJ cancer

7. Gastric/GEJ Adenocarcinoma
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 –
GLOBOCAN 2008
Jemal et al., CA CANCER J CLIN 2011;61:69–90
Howlader SEER data
6. cardia (including gastroesophageal junction)

8. Gastric or Stomach Cancer
Anatomy of the stomach
Esophagus
Diaphragm
Proximal
Lower esophagus
sphincter
Fundus
Gastric or Stomach Cancer
GE junction = cardia
Lesser curvature
Body (Corpus)
Pylorus
Distal
Antrum
Small intestine
Greater curvature
Williams, et al. Gray’s Anatomy 1995

9. Siewert classification of adenocarcinoma of the GEJ
Type II true cardia
Esophageal adenocarcinoma
Type I distal oesophagus
5 cm
1 cm
Z line
GEJ adenocarcinoma
2 cm
5 cm
Type III subcardia
Gastric adenocarcinoma
Type
Features
Topographic anatomical criteria
Type I
Adenocarcinoma of the distal oesophagus, which usually arises from an area with specialised intestinal metaplasia of the oesophagus (i.e. Barrett oesophagus) and may infiltrate the oesophago-gastric junction from above
The centre of the cancer or more than two thirds of identifiable tumour mass is located >1 cm proximal to the gastro-oesophageal junction
Type II
True carcinoma of the cardia arising immediately at the oesophagogastric junction
The centre of the cancer or the tumour mass is located in an area extending 1cm proximal to the gastro-oesophageal junction to 2cm distal to it
Type III
Subcardial gastric carcinoma that infiltrates the oesophagogastric junction and distal oesophagus from below
The centre of the cancer or more than two thirds of identifiable tumour mass is located >2cm below the gastro-oesophageal junction
GEJ = gastro-esophageal junction

10. The incidence of gastric cancer is highest in Asia
Mortality
Eastern Asia 60 50 40 30 20 10 10 20 30 40 50 60
Central and Eastern Europe
Less developed regions
World
South America
More developed regions
Central America
Southern Europe
Western Asia
South-Eastern Asia
Caribbean
Polynesia
Melanesia
Western Europe
Northern Europe
Micronesia
Australia/New Zealand
South-Central Asia
Middle Africa
Eastern Africa
Northern America
Western Africa
Southern Africa
Northern Africa
Age-standardised incidence (per 100,000)
Male
Female
Parkin DM, et al. CA Cancer J Clin 2005; 55:74–108.

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 / Hofmann et al Histopath / Ruschoff et al Mod Path 2012

13. ToGA trial design Phase III, randomized, open-label, international, multicenter study
Primary endpoint OS
5-FU or capecitabine a + cisplatin
(n=290)
3807 patients screened
810 HER2-positive (22.1%)
(IHC 3+ or FISH +)
HER2-positive advanced GC (n=584) R
5-FU or capecitabine a + cisplatin + trastuzumab
(n=294)
Stratification factors
a Chosen at investigator’s discretion 1 Bang et al; Abstract 4556, ASCO 2009
GEJ, gastroesophageal junction
Bang Lancet 2010
Locally Advanced (inoperable) vs. Metastatic
GC vs. GEJ
Measurable vs. Non-measurable
ECOG PS 0-1 vs. 2
Capecitabine vs. 5-FU 13

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. K-M Plot of Overall Survival in ToGA Study (full analysis population)
1.0
Median
Events OS
F/X + C + H
167
13.8
0.8
F/X + C
182
11.1
0.6
HR = 0.74
95% CI (0.60, 0.91)
p value =
13.8
Event
11.1
0.4
0.2 2 4 6 8 10 12 14 16 18 20 22 24 26 28 30 32 34 36
Time (Months)
No.at risk
F/X + C + H
294
277
246
209
173
147
113 90 71 56 43 30 21 13 12 6 4 1
F/X + C
290
266
223
185
143
117 90 64 47 32 24 16 14 7 6 5
H, Herceptin / Bang YJ., et al., Lancet 2010; 376:

16. K-M Plot of Overall Survival in ToGA Study (High HER2 overexpressors = IHC3+ or IHC2+/FISH+)
1.0
Median
Events OS
FC + H
120
16.0
0.8 FC
136
11.8
0.6
HR = 0.65
95% CI (0.51, 0.83)
16.0
Event
11.8
0.4
0.2 2 4 6 8 10 12 14 16 18 20 22 24 26 28 30 32 34 36
Time (Months)
No.at risk
FC + H
228
218
196
170
142
122
100 84 65 51 39 28 20 12 11 5 4 1 FC
218
198
170
141
112 96 75 53 39 28 20 13 11 4 3 3
H, Herceptin / Bang YJ., et al., Lancet 2010; 376:

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 trastuzumab bind different epitopes on HER2
Trastuzumab-HER2 complex
Pertuzumab-HER2 complex
pertuzumab
trastuzumab
dimerization domain
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 receptor
Hubbard 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

20. 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)
Patients with HER2+,* locally recurrent, unresectable, or mBC previously untreated with a biologic or chemotherapy for metastatic disease† (n=808)
Docetaxel (q3w)
Minimum of 6 cycles
Pertuzumab + trastuzumab (q3w)
(n=402)
1:1‡
Placebo + trastuzumab (q3w)
Docetaxel (q3w)
Minimum of 6 cycles
Patients treated with pertuzumab and trastuzumab until progression of disease or unmanageable toxicity
If docetaxel discontinued, treatment with pertuzumab and trastuzumab may continue
(n=406)
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). 20

21. CLEOPATRA: Primary Endpoint1
Progression-Free Survival (PFS): A hazard ratio (HR) of 0.62 describes 38% reduction in risk of disease progression or death
HR = 0.62*
95% CI (0.51, 0.75)
p value = <0.0001
100
Pertuzumab + trastuzumab + docetaxel 80 60
18.5
Progression-free survival (%) 40
12.4 20
Placebo + trastuzumab + docetaxel 5 10 15 20 25 30 35 40
Time (Months)
Patients at risk
Pertuzumab+T+D
402
345
267
139 83 32 10
Placebo+T+D
406
311
209 93 42 17 7
* Stratified by prior treatment status and geographic region.
Source: 1. PERJETA™ (pertuzumab) full prescribing information. Genentech, Inc., June 2012.

22. CLEOPATRA: Confirmatory interim analysis of overall survival (OS IA2)
Median follow-up: 30.0 months, n=267 OS events
100
Pertuzumab + T + D: 113 events; median not reached 80
HR = 0.66
95% CI (0.52−0.84)
p value = 60
Overall survival (%) 40
Placebo + T + D: 154 events; median 37.6 months 20
402
406 5
387
383 10
371
350 15
342
324 20
317
285 25
230
198 30
143
128 35 84 67 40 33 22 45 9 4 50 55
Time (Months)
Patients at risk
Ptz + T + D
Pla + T + D
Stopping boundary for concluding statistical significance at this interim analysis was p≤0.0138
D, docetaxel; OS, overall survival; Pla, placebo; Ptz, pertuzumab; T, trastuzumab
S Swain, San Antonio Breast Cancer Symposium (SABCS), 2012 (Abstract #P )

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 MBC Approvals 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
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
HER2-positive inoperable locally advanced or recurrent and/or metastatic GEJ/GC
(IHC3+ or IHC2+ and FISH+; ECOG PS 0 or 1)
Arm A Pertuzumab 840 mg, then 420 mg + X + cisplatin x6 q3w + trastuzumab
n=15
Dose selection for Phase III study based on PK modelling
Arm B Pertuzumab 840 mg + X + cisplatin x6 q3w + trastuzumab
n=15
Primary objectives:
Estimate minimum (trough) serum pertuzumab concentration to identify a steady state of ≥20 g/ml in 90% of patients
Safety and tolerability
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 27

28. The JACOB Study (BO25114): Rationale of Study Design and Protocol Overview

29. The JACOB Study (BO25114) Design
Study Treatment
~ 6 treatment cycles (21 day cycle)
Study Treatment
* HER2 targeted therapy
continues until PD or unacceptable toxicity
Randomization (1:1) n = 780
(approximately 390 per treatment arm)
Primary Endpoint OS
(Events = 502)
Secondary Endpoints
PFS, ORR, DoR,
CBR, Safety, PK, QOL
Treatment Arm A
Capecitabine or 5FU + Cisplatin *
Trastuzumab + Pertuzumab 840 mg IV Q3W
Follow-Up #
Treatment Arm B
Capecitabine or 5FU + Cisplatin *
Trastuzumab + Pertuzumab placebo IV Q3W
Key Eligibility Criteria:
HER2-positive Metastatic gastric/GEJ adenocarcinoma
IHC 3+ or IHC 2+/ISH+ (central testing required)
ECOG PS 0 or 1
* After Cycle 6, continuation of chemotherapy is at physician’s discretion
Stratification
factors:
Geographic Region (Japan, N. America/W. Europe, Asia (not including Japan), Latin America/E. Europe)
Prior gastrectomy (yes/no)
HER2 IHC3+ vs. IHC2+/ISH+
# If patients permanently stop study treatment (HER2-directed), they continue to be followed for side effects and cardiac monitoring

30. JACOB: Study endpoints
Primary
Overall survival (15.0 vs mos, HR 0.78)
Secondary
PFS, ORR, duration of objective response, clinical benefit rate
Safety PK
QoL
Exploratory
Biomarkers
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
Biomarker analysis and sampling strategy in JACOB
Patient selection
(Block/partial block*)
Exploratory BM Research (Block/partial block*)
RCR (Roche clinical repository, optional)
Central confirmation of HER2 (prospectively)
IHC
ISH
c-MET
ERCC1
PTEN
PIK3CA mutations
HER2/3 mRNA
HER3 protein
Serum
Plasma
Whole blood sample for DNA extraction
* Minimum of 15 slides to be sent if country or site regulations do not allow shipment of a tumor block

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
0.837
2.9 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 months OS, 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 is defined as:
IHC 3+ (regardless of ISH results)
IHC 2+ if confirmed by a positive ISH result (cut-off for ISH ratio: HER2/CEP17)
For IHC testing, the cut-off as approved by FDA in context of ToGA will apply
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 Criteria
Previous systemic cytotoxic chemotherapy for advanced (inoperable or metastatic) disease
History of exposure to the following cumulative doses of anthracyclines:
Epirubicin > 720 mg/m2
Doxorubicin or liposomal doxorubicin > 360 mg/m2
Mitoxantrone > 120 mg/m2 and idarubicin > 90 mg/m2
Other (e.g., other anthracycline greater than the equivalent of 360 mg/m2 of doxorubicin)
If more than one anthracycline has been used, then the cumulative dose must not exceed the equivalent of 360 mg/m2 of doxorubicin
Evidence of disease progression documented within 6 months after completion of prior neoadjuvant and/or adjuvant cytotoxic chemotherapy or radiotherapy for gastric/GEJ adenocarcinoma  
Previous treatment with any HER2-directed therapy, at any time, for any duration
Previous exposure to any investigational treatment within 30 days before the first dose of study treatment
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)
History or evidence of brain metastasis
Clinically significant active GI bleeding (Grade ≥ 2 according to CTCAE v4.03)
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
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
Previous systemic cytotoxic chemotherapy for advanced (inoperable or metastatic) disease
History of exposure to the following cumulative doses of anthracyclines:
Epirubicin > 720 mg/m2
Doxorubicin or liposomal doxorubicin > 360 mg/m2
Mitoxantrone > 120 mg/m2 and idarubicin > 90 mg/m2
Other (e.g., other anthracycline greater than the equivalent of 360 mg/m2 of doxorubicin)
If more than one anthracycline has been used, then the cumulative dose must not exceed the equivalent of 360 mg/m2 of doxorubicin
Evidence of disease progression documented within 6 months after completion of prior neoadjuvant and/or adjuvant cytotoxic chemotherapy or radiotherapy for gastric/GEJ adenocarcinoma  
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)
Absolute neutrophil count (ANC) < 1.5  109/L
Platelet count < 75  109/L
Hemoglobin < 9.0 g/dL
Creatinine clearance < 60 mL/min/1.73 m²
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
AST, ALT, and alkaline phosphatase (ALP) parameters:
In patients with no liver and no bone metastases
AST or ALT > 1.5 × ULN, and ALP > 2.5 × ULN
AST or ALT > 2.5 × ULN
In patients with liver metastases and no bone metastases
AST or ALT > 5 × ULN, and ALP > 2.5 × ULN
In patients with liver metastases and bone metastases
AST or ALT > 5 × ULN, and ALP > 10 × ULN
In patients with bone metastases and no liver metastases
AST or ALT > 1.5 × ULN, and ALP > 10 × ULN
Serum albumin < 25 g/L
Serum pregnancy test positive in a female patient of childbearing potential

39. JACOB: Exclusion criteria
General Exclusion Criteria
Documented history of congestive heart failure of any New York Heart Association (NYHA) criteria
Angina pectoris requiring treatment
Myocardial infarction within the past 6 months before the first dose of study treatment
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)
History or evidence of poorly controlled arterial hypertension (systolic blood pressure > 180 mmHg or diastolic blood pressure > 100 mmHg)
Baseline LVEF value < 55%, assessed by echocardiogram [ECHO], MUGA scan, or cardiac MRI

40. JACOB: Exclusion criteria
Dyspnea at rest due to complications of advanced malignancy or other disease or requirement of supportive oxygen therapy
Any significant uncontrolled intercurrent systemic illness (e.g., active infection, poorly controlled diabetes mellitus)
Previous major surgery within 30 days before the first dose of study treatment, unless completely recovered
Known infection with HIV, hepatitis B virus, or hepatitis C virus that requires active treatment
Ongoing chronic treatment or high-dose treatment with corticosteroids. Inhaled steroids and clinically indicated short courses of oral steroids are permitted
Known dihydropyrimidine dehydrogenase (DPD) deficiency
Known hypersensitivity to any component of study treatment
Current use of antiviral drug sorivudine or its chemically related analogues, such as brivudine
Lactating female patient
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
Pertuzumab 840 mg or placebo q 3 weeks
Trastuzumab 8 mg/kg initial dose, followed by 6 mg/kg q3w
with
Capecitabine 1000 mg/m2 taken orally twice daily for 14 days then 7 days off q3w OR
5-Fluorouracil 800 mg/m2/24 hours given intravenously by continuous infusion for 120 hours (Days 1−5) q3w
with
Cisplatin 80 mg/m2 intravenously (Day 1) q3w

44. Administration guidelines for pertuzumab and trastuzumab
Administration Time (minutes)
Observation Time (minutes)
First dose
Pertuzumab/placebo 60
Trastuzumab 90
All later doses 30
Incomplete dose:
If patient receives 50-75% of dose, the remainder should be given during the same treatment cycle, preferably before day 15 (Section for details)

45. 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 and dose reductions
Table 4 in protocol
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

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 3
Increase 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 )
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. Dose Modifications for Hematologic Toxicity Due to FP Chemotherapy
Table 2 in protocol
ANC (x 109/L)
Platelets (x 109/L)
Fluoropyrimidine/Cisplatin
≥ 1.5
and
≥ 75
100% of original doses, without delay
≥ 1.0 – < 1.5
75% of original doses, without delay
< 1.0
and/or
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.
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.

51. Dose Modifications for Life-Threatening Hematologic Toxicity Occurring during FP Administration
Table 3 in protocol
Toxicity
Fluoropyrimidine and 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 neutropenia
ANC < 1000/mm3 with a single temperature of > 38.3⁰C (101⁰F) or a sustained temperature of ≥ 38⁰C (100.4⁰F) for more than 1 hour
Grade 4 febrile neutropenia
ANC < 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
Interrupt chemotherapy
Dose reduce as directed when starting next cycle
Dose reductions are permanent

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 Asymptomatic decline in LVEF
Figure 3 of Protocol
LVEF drop from baseline
LVEF ≥ 50%
LVEF < 50%
LVEF drop ≤ 20%
LVEF drop > 20%
LVEF drop < 10%
LVEF drop ≥ 10%
CONTINUE
Treatment
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

54. Pertuzumab/Trastuzumab Cardiac Toxicity: Reporting AE/SAE
Table 7 in protocol
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 eCRF
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
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”.

55. 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

56. Pertuzumab/Trastuzumab Cardiac Toxicity: Reporting AE/SAE
Table 7 in protocol
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 eCRF
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
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”.

57. Algorithm for Asymptomatic decline in LVEF
Figure 3 of Protocol
LVEF drop from baseline
LVEF ≥ 50%
LVEF < 50%
LVEF drop ≤ 20%
LVEF drop > 20%
LVEF drop < 10%
LVEF drop ≥ 10%
CONTINUE
Treatment
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

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

59. Schedule of Assessment • Until Post-treatment Monitoring Visit 1 (1)
Screening/
Baseline
Cycle
Post-treatment
Monitoring
Visit 1 b
(28 days post last dose) 1 2 3 4 5 6 7 8 9+
Day
-28 to -1
-7 to -1 22
(± 7) 43 64 85
106
127
148
169+
(± 7) a
Informed consent ●
Randomization c
● c
Demographic data
Medical history
Physical examination
● d
Height
Weight
Vital signs e
ECOG PS
Hematology f
Biochemistry f
Creatinine clearance g
● h
Urinalysis
As clinically indicated
Pregnancy test i
● i
HER2 status (central testing) j
● j
Tumor assessment k
● k
PK sampling l
● l

60. Schedule of Assessment • Until Post-treatment Monitoring Visit 1 (2)
Screening/
Baseline
Cycle
Post-treatment
Monitoring
Visit 1 b 1 2 3 4 5 6 7 8 9+
Day
-28 to -1
-7 to -1 22
(± 7) 43 64 85
106
127
148
169+
(± 7) a
Serum for HER2/neu ECD (shed ECD) and HER ligands m ●
ECG n
● n
● n,o,p
LVEF n (MUGA/ECHO/MRI)
● n,p
Safety monitoring q
AEs and SAEs will be monitored from the time of enrollment
Concomitant therapy
● r
Capecitabine (28 doses, Days 1-15/ cycle) OR 5-FU (120-hour CIV, Days 1-5/ cycle) s
Cisplatin (Day 1/cycle) s
Pertuzumab or matching
placebo (Day 1/cycle) t
Trastuzumab (Day 1/cycle) t
Patient-reported outcomes u
Antitherapeutic antibodies
● v
Tumor tissue block for mandatory biomarker analyses (FFPE) w
Serum for RCR (optional)
● x
● y
Plasma for RCR (optional)
Whole blood for RCR DNA (6 mL) (optional)

61. Schedule for Pharmacokinetic Sampling for Pertuzumab and Trastuzumab
Appendix 2 in protocol
Cycle 1
Cycle 2
Cycle 3
Cycle 4
Cycle 6
Cycle 8 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 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
Survival Follow-up
Timepoint
Post-treatment Monitoring Visit 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)
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
Ensure relevant variables are clean
Prepare event packets
Record CRC adjudications
Coordinate 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 translation if in language other than English

67. Q
& A