appendix i protocol amendment summary
appendix b schedule of assessments

d. The assessment (except for vital sign that needs to be obtained prior to the infusion) does not need to be repeated if it was done within 3 days prior to the first dose  
e. Height required at screening only. Vital signs: screening, day 1 of each cycle prior to the start of study drug dosing, days 2 and 3 prior to etoposide administration during Cycles 1 through 6 and treatment termination.
f. Hematology includes complete blood count (CBC) with differential, hemoglobin (Hgb), and platelet count. The results need to be reviewed by the investigator prior to each study drug and EP administration. Hematology on Day 1 of each cycle can be performed up to 3 days prior to Day 1 dosing.  
g. Full chemistry includes sodium, potassium, chloride, bicarbonate, blood urea nitrogen
(BUN), creatinine, glucose, ALT, AST, alkaline phosphatase, total bilirubin, direct bilirubin, lactate dehydrogenase (LDH), total protein, albumin, calcium, phosphate, and magnesium. Chemistry on Day 1 of each cycle can be performed up to 3 days prior to Day 1 dosing.  
h. Plasma samples will be obtained for OMP-59R5 pharmacokinetic analysis at pre-dose and 5 minutes (±2 minutes) after the end of OMP-59R5 infusion on Day 1 of Cycle 1 and Cycle 3, and on Days 3 (pre-dose) and 8 of Cycles 1 and 3, as well as at treatment termination. On days when OMP-59R5 and etoposide and/or cisplatin are given together, the plasma sample should be obtained 5 minutes (±2 minutes) after the completion of the infusion of OMP59R5, but prior to EP administration.  
k. Hair follicle mRNA expression: Predose hair samples (6 hairs) will be collected at screening and on Day 8 of Cycle 2 only for gene expression analysis of Notch pathway–related gene expression as described in Section 11.0. Instructions for the collection, handling, storage, and shipment of these samples are provided in the Study Reference Binder.  
l. Only on Day 1 of Cycle 1 prior to OMP-59R5 infusion. m. FFPE tumor specimens obtained will be collected. Notch3 expression levels will be assessed in FFPE tumor specimens, either archived or fresh core needle biopsied at study entry (two FFPE cores preferred whenever possible). FFPE samples must be obtained during screening. Notch3 levels will be measured by immunohistochemistry and/or a quantitative PCR gene expression assay. Notch 2 and other Notch-related genes and proteins may also be measured. In addition, DNA testing may be performed on the FFPE tumor specimens for subjects who sign the optional FFPE Informed Consent for DNA testing. Instructions for the collection, handling, storage, and shipment of these samples are provided in the Study Reference Binder.  
n. Optional tumor biopsy will be done at screening, on Day 8 of Cycle 2, and at the time of progression if feasible. The site can call the Sponsor's medical monitor to discuss an alternative timepoint if it is not feasible to collect the optional tumor biopsy on Day 8 (±2) of Cycle 2.  
o. Contrast CT of chest, abdomen and pelvis, and brain MRI/CT with contrast will be performed every 6 weeks (±5 days) after initial study drug dosing (prior to the start of Cycle 3 and every 6 weeks±5 days thereafter). MRI can be used in lieu of contrast-enhanced CT for subjects who are allergic to contrast. The same methodology should be used throughout the study to follow the same lesion.  
p. Subjects who have not demonstrated disease progression will have contrast CT of chest and abdomen (or MRI for subjects who are allergic to contrast), MRI/CT of brain conducted every 6 weeks (± 5 days) after initial study drug dosing until disease progression or initiation of new anti-cancer therapy. The same methodology should be used throughout the study.
d. The assessment does not need to be repeated if it was done within 7 days prior to the first dose e. Height required at screening only. Vital signs *and weight*: screening, day 1 of each cycle prior to the start of study drug dosing, days 2 and 3 prior to etoposide administration during Cycles 1 through 6 and treatment termination.  
f. Hematology includes complete blood count (CBC) with differential, hemoglobin (Hgb), and platelet count. The results need to be reviewed by the investigator prior to each study drug and EP administration. Hematology on Day 1 of each cycle *starting from Cycle 2* can be performed up to 3 days prior to Day 1 dosing.  
g. Full chemistry includes sodium, potassium, chloride, bicarbonate, blood urea nitrogen
(BUN), creatinine, glucose, ALT, AST, alkaline phosphatase, total bilirubin, direct bilirubin, lactate dehydrogenase (LDH), total protein, albumin, calcium, phosphate, and magnesium.
Chemistry on Day 1 of each cycle *starting from Cycle 2* can be performed up to 3 days prior to Day 1 dosing.  
h. Plasma samples will be obtained for OMP-59R5 pharmacokinetic analysis at pre-dose and 5 minutes (±2 minutes) after the end of OMP-59R5 infusion *and prior to the EP administration* on Day 1 of Cycle 1 and Cycle 3, and on Days 3 (pre-dose) and 8 of Cycles 1 and 3, as well as at treatment termination. On days when OMP-59R5 and etoposide and/or cisplatin are given together, the plasma sample should be obtained 5 minutes (±2 minutes) after the completion of the infusion of OMP-59R5, but prior to EP administration.  
k. Hair follicle mRNA expression: Predose hair samples (6 hairs) will be collected at Day 1 of Cycle 1 (pre-dose) and on Day 8 of Cycle 2 only for gene expression analysis of Notch pathway-related gene expression as described in Section 11.0. Instructions for the collection, handling, storage, and shipment of these samples are provided in the Study Reference Binder.  
l. Only on Day 1 of Cycle 1 prior to OMP-59R5 infusion from subjects who have signed separate pharmacogenomics Informed Consent Form.
m. FFPE tumor specimens obtained will be collected. Notch3 expression levels will be assessed in FFPE tumor specimens, either archived or fresh core needle biopsied at study entry (two FFPE cores preferred whenever possible). FFPE samples must be obtained during screening. Notch3 levels will be measured by immunohistochemistry and/or a quantitative PCR gene expression assay. Notch 2 and other Notch-related genes and proteins may also be measured. In addition, DNA testing may be performed on the FFPE tumor specimens for subjects who sign the optional FFPE Informed Consent for DNA testing. Instructions for the collection, handling, storage, and shipment of these samples are provided in the Study Reference Binder.  
n. Optional tumor biopsy will be done at screening, on Day 8 of Cycle 2, and at the time of treatment termination, if feasible. The site can call the Sponsor's medical monitor to discuss an alternative timepoint if it is not feasible to collect the optional tumor biopsy on Day 8 (±2)
of Cycle 2.  
o. Contrast CT of chest, abdomen and pelvis, and brain MRI/CT with contrast will be performed at screening. Contrast CT of chest, abdomen and pelvis will be performed every 6 weeks (±5 days) after initial study drug dosing (prior to the start of Cycle 3 and every 6 weeks±5 days thereafter). MRI can be used in lieu of contrast-enhanced CT for subjects who are allergic to contrast. The same methodology should be used throughout the study to follow the same lesion.  
p. Subjects who have not demonstrated disease progression will have contrast CT of chest, pelvis and abdomen (or MRI for subjects who are allergic to contrast), conducted every 6 weeks (± 5 days) after initial study drug dosing until disease progression or initiation of new anti-cancer therapy. The same methodology should be used throughout the study.  
Protocol 59R5-003, Amendment 6 Page 192 of 235 2016 CONFIDENTIAL
APPENDIX C SCHEDULE OF ASSESSMENTS FOR SUBJECTS IN PHASE 2
appendix i protocol amendment summary
previously read

d. The assessment (except for vital sign that needs to be obtained prior to the infusion) does not need to be repeated if it was done within 3 days prior to the first dose.  
e. Height required at screening only. Vital signs: screening, day 1 of each cycle prior to the start of the treatment, days 2 and 3 prior to etoposide administration from Cycles 1 thru 6, and treatment termination.  
f. Hematology includes complete blood count (CBC) with differential, hemoglobin (Hgb), and platelet count. The results need to be reviewed by the investigator prior to each study drug administration. Hematology on day 1 of each cycle can be performed up to 3 days prior to Day 1 dosing.  
g. Full chemistry includes sodium, potassium, chloride, bicarbonate, blood urea nitrogen
(BUN), creatinine, glucose, ALT, AST, alkaline phosphatase, total bilirubin, direct bilirubin, lactate dehydrogenase (LDH), total protein, albumin, calcium, phosphate, and magnesium. Chemistry on Day 1 of each cycle can be performed up to 3 days prior to Day 1 dosing.  
j. Only on Day 1 of Cycle 1 prior to OMP-59R5 infusion. m. Optional tumor biopsy will be done at screening, on Day 8 of Cycle 2, and at the time of progression if feasible. The site can call the Sponsor's medical monitor to discuss an alternative timepoint if it is not feasible to collect the optional tumor biopsy on Day 8 (±2) of Cycle 2.  
n. Contrast CT of chest, abdomen and pelvis, and MRI of brain will be performed every 6 week s ± 5 days) after initial study drug dosing (prior to the start of Cycle 3 and every two cycles thereafter). MRI can be used in lieu of contrast-enhanced CT for subjects who are allergic to contrast. The same methodology should be used throughout the study to follow the same lesion.  
o. Subjects who have not demonstrated disease progression will have contrast CT of chest, abdomen and pelvis (or MRI for subjects who are allergic to contrast), and MRI/CT of brain conducted every 6 weeks (±5 days) after initial study drug dosing until disease progression or initiation of new anti-cancer therapy. The same methodology should be used throughout the study.
d. The assessment does not need to be repeated if it was done within 7 days prior to the first dose.  
e. Height required at screening only. Vital signs *and weight*: screening, day 1 of each cycle prior to the start of the treatment, days 2 and 3 prior to etoposide administration from Cycles 1 thru 6, and treatment termination.  
f. Hematology includes complete blood count (CBC) with differential, hemoglobin (Hgb), and platelet count. The results need to be reviewed by the investigator prior to each study drug administration. Hematology on day 1 of each cycle *starting from Cycle 2* can be performed up to 3 days prior to Day 1 dosing.  
g. Full chemistry includes sodium, potassium, chloride, bicarbonate, blood urea nitrogen
(BUN), creatinine, glucose, ALT, AST, alkaline phosphatase, total bilirubin, direct bilirubin, lactate dehydrogenase (LDH), total protein, albumin, calcium, phosphate, and magnesium. Chemistry on Day 1 of each cycle *starting from Cycle 2* can be performed up to 3 days prior to Day 1 dosing.  
j. Only on Day 1 of Cycle 1 prior to OMP-59R5 infusion *from subjects who have signed* separate pharmacogenomics Informed Consent Form.  
m. Optional tumor biopsy will be done at screening, on Day 8 of Cycle 2, and at the time of treatment termination, if feasible. The site can call the Sponsor's medical monitor to discuss an alternative timepoint if it is not feasible to collect the optional tumor biopsy on Day 8 (±2) of Cycle 2.  
n*. Contrast CT of chest, abdomen and pelvis, and MRI of brain will be performed at screening.*
Contrast CT of chest, abdomen and pelvis will be performed every 6 week s ± 5 days) after initial study drug dosing (prior to the start of Cycle 3 and every two cycles thereafter). MRI can be used in lieu of contrast-enhanced CT for subjects who are allergic to contrast. The same methodology should be used throughout the study to follow the same lesion.  
o. Subjects who have not demonstrated disease progression will have contrast CT of chest, abdomen and pelvis (or MRI for subjects who are allergic to contrast), conducted every 6 weeks (±5 days) after initial study drug dosing until disease progression or initiation of new anti-cancer therapy. The same methodology should be used throughout the study.
appendix i protocol amendment summary
deleted

Hair Follicles: Six hairs will be plucked from your head for additional marker testing if you are participating in the first portion of the study
appendix i protocol amendment summary
previously read

Tumor assessments: An examination of your tumor(s) by CT (computerized tomography test, like an x-ray that produces a picture of your body including tumors using radiation), or MRI
(magnetic resonance imaging - use of a magnetic field to produce an image of your body including tumors) or bone scan (an X-ray to look at your bone). Your study doctor will determine which type of test (either CT or MRI) is best to assess your cancer. A bone scan will also be done to find out if tumors have spread to your bones. This is part of your routine cancer care.  
Tumor assessments: An examination of your tumor(s) by CT (computerized tomography test, like an x-ray that produces a picture of your body including tumors using radiation), or MRI (magnetic resonance imaging - use of a magnetic field to produce an image of your body including tumors) and bone scan (an X-ray to look at your bone). Your study doctor will determine which type of test (either CT or MRI) is best to assess your cancer. A bone scan will also be done to find out if tumors have spread to your bones. This is part of your routine cancer care.
appendix i protocol amendment summary
cycle 1 day 1 previously

This is the first day of study treatment (Cycle 1 Day 1).You will receive study drug, etoposide, and cisplatin on this day. You will have the following procedures done during this visit: - Physical Examination and weight before dosing (if this was done more than 3 days ago) - Electrocardiogram (ECG) before dosing (if this was done more than 3 days ago) - Urine Sample Collection before dosing (if this was done more than 3 days ago)
- Blood Sample Collection before dosing - about 1 tablespoon of blood for your health condition (if this was done more than 3 days ago)
- Additional Blood Sample Collection before dosing - about 2 tablespoons of blood to assess the level of certain markers and proteins that might be against OMP-59R5
- If you are participating in the first portion of the study, you will also have 1 teaspoon of blood taken before starting study drug dosing tocheck the level of OMP59R5 in the blood
- Your blood pressure, temperature, heart rate, rate of breathing, and weight will be measured - You will be asked about any changes in your health status after taking your initial dose of the study drug, etoposide, and cisplatin.  
This is the first day of study treatment (Cycle 1 Day 1).You will receive study drug, etoposide, and cisplatin on this day. You will have the following procedures done during this visit:
appendix i protocol amendment summary
19(67721/1('58

()  
- Physical Examination before dosing (if this was done more than 7 days ago) - Electrocardiogram (ECG) before dosing (if this was done more than 7 days ago) - Urine Sample Collection before dosing (if this was done more than 7 days ago)
- Blood Sample Collection before dosing - about 1 tablespoon of blood for your health condition (if this was done more than 7 days ago)
- *Weight before dosing* - *Hair follicles: Six hairs will be plucked from your head for additional marker testing if you* are participating in the first portion of the study
- Additional Blood Sample Collection before dosing - about 2 tablespoons of blood to assess the level of certain markers and proteins that might be against OMP-59R5
- If you are participating in the first portion of the study, you will also have 1 teaspoon of blood taken before starting study drug dosing tocheck the level of OMP59R5 in the blood
- Your blood pressure, temperature, heart rate, rate of breathing, and weight will be measured - You will be asked about any changes in your health status after taking your initial dose of the study drug, etoposide, and cisplatin.
appendix i protocol amendment summary
treatment termination previously read

Optional Tumor Biopsy: If your tumor has grown or spread, an optional tumor biopsy will be done only if you agree.  
Optional Tumor Biopsy: An optional tumor biopsy will be done only if you agree.
appendix i protocol amendment summary
pregnancy previously read

… If either you or your partner becomes pregnant during the study or within 30 days after the last dose of study drug or etoposide or cisplatin whichever is discontinued last, you and/or your partner will be followed through the first well-baby visit or longer if any abnormality is present.
…If either you or your partner becomes pregnant during the study or within 30 days after the last dose of study drug or etoposide or cisplatin whichever is discontinued last, you and/or your partner will be followed through *outcome of the birth*.
appendix i protocol amendment summary
amendment 2 19 august 2013

The following changes were made to the protocol. Italics in the text indicate new text.
appendix i protocol amendment summary
rationale

The protocol has been amended to allow the dose escalation beyond 7.5 mg/kg if the MTD is not reached. Additionally, the protocol clarifies that PET/CT scan can be used in lieu of bone scan to follow bone lesions throughout the study. Day 2 and Day 3 blood draws for hematology have been eliminated as they are not part of standard of care. Blood sample for hematology was added to Day 8 of Cycles 1 through 3 only when blood samples are taken for biomarkers and PK.
appendix i protocol amendment summary
summary of changes study design

Additionally, subjects who discontinue study treatment for any reason other than disease progression will be followed with tumor assessment every 6 weeks/42 days (±5 days) during Follow-up according to standard of care until documented disease progression or initiation of new anti-cancer therapy, whichever is sooner.  
Additionally, subjects who discontinue study treatment for any reason other than disease progression will be followed with tumor assessment every 6 weeks/42 days (±5 days) during Follow-up until documented disease progression or initiation of new anti-cancer therapy, whichever is sooner.
appendix i protocol amendment summary
efficacy evaluation previously read

…Subjects who discontinue study treatment for any reason other than disease progression will be followed with tumor assessment every 6 weeks/42 days (±5 days) during Follow-up according to standard of care until documented disease progression or initiation of new anti-cancer therapy, whichever is sooner.  
… Subjects who discontinue study treatment for any reason other than disease progression will be followed with tumor assessment every 6 weeks/42 days (±5 days) during Follow-up until documented disease progression or initiation of new anti-cancer therapy, whichever is sooner.
appendix i protocol amendment summary
3.4 clinical background previously read

…As of April 26, 2013, thirteen subjects have been treated in Study OMP-59R5-002: five at 2.5 mg/kg every other week in combination with gemcitabine at 1000 mg/m2 on Days 1, 8 and 15 of every 28 day cycle, four at 5 mg/kg every other week in combination with gemcitabine at 1000 mg/m2 on Days 1, 8 and 15 of every 28 day cycle, four at 5 mg/kg every other week in combination with nab-paclitaxel at 125 mg/m2 and gemcitabine at 1000 mg/m2 on Days 1, 8 and 15 of every 28 day cycle, No DLTs have been reported, and Grade 1 diarrhea was noted in one subject each treated with OMP-59R5 at 5 mg/kg with gemcitabine, and with nab-paclitaxel and gemcitabine.  
…As of *August 19*, 2013, *twenty four* subjects have been treated in Study OMP-59R5-002: five and *four* at 2.5 mg/kg and *5.0 mg/kg respectively* every other week in combination with gemcitabine at 1000 mg/m2 on Days 1, 8 and 15 of every 28 day cycle, four, *six and four* at 5 mg/kg, *7.5 mg/kg and 10 mg/kg respectively* every other week in combination with nabpaclitaxel at 125 mg/m2 and gemcitabine at 1000 mg/m2 on Days 1, 8 and 15 of every 28 day cycle. No DLTs have been reported, and *the most common reported OMP-59R5 treatmentrelated event is diarrhea, fatigue and nausea that are mostly grade 1 or 2, managed with* supportive care. One Grade 3 diarrhea was noted in one of four subjects treated with 10 mg/kg OMP-59R5 with Nab-P+Gem, lasted less than 48 hours and resolved to Grade 1 diarrhea after concurrent use of lomotil.
appendix i protocol amendment summary
5.3 dose escalation plan previously

The starting dose of OMP-59R5 is 5 mg/kg on Day 1 of each 21-day cycle. The subsequent dose level will be 7.5 mg/kg on Day 1 of each 21-day cycle. Dose escalation will proceed if no DLT is observed in a cohort of 3 subjects after discussion and agreement between the participating Investigators and Sponsor's Medical Monitor.  
… The starting dose of OMP-59R5 is 5 mg/kg on Day 1 of each 21-day cycle. The subsequent dose level will be *increased in 2.5 mg/kg increments (i.e., 7.5 mg/kg, 10 mg/kg, etc) until the MTD is* reached. Dose escalation will *only* proceed if no DLT is observed in a cohort of *at least* 3 subjects after discussion and agreement between the participating Investigators and Sponsor's Medical Monitor.
appendix i protocol amendment summary
5.4.1 follow-up previously read

Subjects who discontinue study treatment for any reason other than disease progression will be followed with tumor assessment every 6 weeks/42 days (±5 days) during follow-up according to standard of care until documented disease progression or initiation of new anti-cancer therapy, whichever is sooner.  
Subjects who discontinue study treatment for any reason other than disease progression will be followed with tumor assessment every 6 weeks/42 days (±5 days) during follow-up until documented disease progression or initiation of new anti-cancer therapy, whichever is sooner.
appendix i protocol amendment summary
5.5.2 follow-up previously read

Subjects who discontinue study treatment for any reason other than disease progression will be followed with tumor assessment every 6 weeks/42 days (±5 days) during Follow-up according to standard of care until documented disease progression or initiation of new anti-cancer therapy, whichever is sooner.  
Subjects who discontinue study treatment for any reason other than disease progression will be followed with tumor assessment every 6 weeks/42 days (±5 days) during Follow-up until documented disease progression or initiation of new anti-cancer therapy, whichever is sooner.
appendix i protocol amendment summary
6.2 exclusion criteria

Previously Read: 6. A history of malignancy with the exception of:  
a. Adequately treated basal cell carcinoma, squamous cell carcinoma of the skin, or in situ cervical cancer b. Adequately treated stage I cancer from which the subject is currently in remission, or
6. A history of malignancy with the exception of:  
a. Adequately treated basal cell carcinoma, squamous cell carcinoma of the skin, or in situ cervical cancer b. Superficial bladder cancer
appendix i protocol amendment summary
7.5 anti-emetics anti-diarrhea and hematopoietic

Antiemetic therapy and anti-diarrheal may be administered at the discretion of the Investigator.  
Antiemetic therapy and anti-diarrheal *medications* may be administered at the discretion of the Investigator.
appendix i protocol amendment summary
9.0 efficacy assessments previously read

Subjects who discontinue study treatment for any reason other than disease progression will be followed with tumor assessment every 6 weeks/42 days (±5 days) during Follow-up according to standard of care until documented disease progression or initiation of new anti-cancer therapy, whichever is sooner.  
Subjects who discontinue study treatment for any reason other than disease progression will be followed with tumor assessment every 6 weeks/42 days (±5 days) during Follow-up until documented disease progression or initiation of new anti-cancer therapy, whichever is sooner.
appendix i protocol amendment summary
11.1 screening

Previously Read:
- Radiographic evaluation: CT with contrast, or MRI of the chest, abdomen, pelvis, and brain, and bone scan performed as outlined by the RECIST criteria 1.1 (see APPENDIX E). Note:
The same method (CT or MRI) must be used consistently throughout the study to follow the same anatomical location.  
- Radiographic evaluation: CT with contrast, or MRI of the chest, abdomen, pelvis, and brain, and bone scan performed as outlined by the RECIST criteria 1.1 (see APPENDIX E). Note: PET/CT can be used in lieu of bone scan to identify and follow up bone lesions. The same method (CT or MRI, bone scan or PET/CT for bone lesions) must be used consistently throughout the study to follow the same anatomical location.
appendix i protocol amendment summary
11.2.1.2 cycle 1 day 2

The following assessments will be completed prior to etoposide infusion: Deleted:
- Hematology Administration of etoposide: Previously Read: Hematology results must be reviewed by the investigator prior to etoposide dosing. Now Reads:
- *Etoposide dosing will be given.*
11.2.1.3 Cycle 1 Day 3 The following assessments will be completed prior to etoposide infusion: Deleted:
- Hematology Added:
- *Adverse event reporting* Administration of etoposide:
appendix i protocol amendment summary
previously read

Hematology results must be reviewed by the investigator prior to etoposide dosing. Now Reads:
- *Etoposide dosing will be given.*
11.2.1.4 Cycle 1 Day 8 Added:
- Hematology 11.2.2.1 Day 1 (± 1 day) of Cycles 2-6  
- Tumor assessment with CT (with contrast), or MRI scan of chest, abdomen, and pelvis will be done every 6 weeks+5 days after Day 1 of Cycle 1 (Day 1 of Cycle 3 and every 6 weeks+5 days thereafter). The same method should be used throughout the study to follow the same anatomical location. Bone scan will be completed every other tumor assessment (Day 1 of Cycle 5 and every 12 weeks/+5 days).  
Tumor assessment with CT (with contrast), or MRI scan of chest, abdomen, and pelvis will be done every 6 weeks+5 days after Day 1 of Cycle 1 (Day 1 of Cycle 3 and every 6 weeks+5 days thereafter). The same method should be used throughout the study to follow the same anatomical location. *If bone scan is used to follow bone lesions, b*one scan will be completed every other tumor assessment (Day 1 of Cycle 5 and every 12 weeks/+5 days). *If PET/CT is* used to follow bone lesions, PET/CT will be done at the same schedule as the assessments for other lesions (every 6 weeks +5 days thereafter).
appendix i protocol amendment summary
added

- *Adverse event recording*  
- Tumor assessment with CT (with contrast), or MRI scan of chest, abdomen, and pelvis will be done every 6 weeks+5 days after Day 1 of Cycle 1 (Day 1 of Cycle 3 and every 6 weeks+5 days thereafter). The same method should be used throughout the study to follow the same anatomical location. *If bone scan is used to follow bone lesions,* bone scan will be completed every other tumor assessment (Day 1 of Cycle 5 and every 12 weeks/+5 days). If PET/CT is used to follow bone lesions, PET/CT will be done at the same schedule as the assessments for other lesions (every 6 weeks +5 days thereafter).
appendix i protocol amendment summary
11.2.2.2 day 2 of cycles

The following assessments will be completed prior to etoposide infusion: Deleted:
- Hematology Added:
- *Adverse event recording* Administration of etoposide: Deleted:
- Adverse event recording
appendix i protocol amendment summary
previously read

Hematology results must be reviewed by the investigator prior to etoposide dosing.  
Now Reads:
- *Etoposide dosing will be given.*
,19(67,*$7,21$/1(:'58* ()
appendix i protocol amendment summary
11.2.2.3 day 3 of cycles

The following assessments will be completed prior to etoposide infusion:
Deleted:
- Hematology Added:
- *Adverse event recording* Administration of etoposide: Deleted:
- Adverse event recording Previously Read: Hematology results must be reviewed by the investigator prior to etoposide dosing. Now Reads:
- *Etoposide dosing* will be given.  
11.2.2.4. Day 8 of Cycles 2 and 3 Only The following assessments will be completed prior to etoposide infusion: Deleted:
- Hematology Added:
- *Adverse event reporting* Administration of etoposide: Previously Read: Hematology results must be reviewed by the investigator prior to etoposide dosing.  
,19(67,*$7,21$/1(:'58* ()
Now Reads:
- *Etoposide dosing will be given.*
Deleted:
- Adverse event reporting Day 3 of Cycles 2-6 The following assessments will be completed prior to etoposide infusion: Deleted:
- Hematology Added:
- *Adverse event reporting* Administration of etoposide: Previously Read: Hematology results must be reviewed by the investigator prior to etoposide dosing. Now Reads:
- *Etoposide dosing will be given.*
Deleted:
- Adverse event reporting 11.2.2.4 Day 8 of Cycles 2 and 3 Only Added:
- Hematology 11.2.4.1 Day 1 (*± 1 day***) of Cycle 7 and every cycle thereafter**
appendix i protocol amendment summary
previously read

…
- Tumor assessment with CT (with contrast), or MRI scan of chest, abdomen, pelvis, will be done every 6 weeks+5 days after Day 1 of Cycle 1 (Day 1 of Cycle 7 and every 6 weeks+5 days thereafter). The same method should be used throughout the study to follow the same anatomical location. Bone scan will be completed every other tumor assessment (Day 1 of Cycle 9, and every 12 weeks/+5 days thereafter).  
- Tumor assessment with CT (with contrast), or MRI scan of chest, abdomen, pelvis, will be done every 6 weeks+5 days after Day 1 of Cycle 1 (Day 1 of Cycle 7 and every 6 weeks+5 days thereafter). The same method should be used throughout the study to follow the same anatomical location. If bone scan is used to follow bone lesions, bone scan will be completed every other tumor assessment (Day 1 of Cycle 9, and every 12 weeks/+5 days thereafter). If PET/CT is used to follow bone lesions, PET/CT will be done at the same schedule as the assessments for other lesions (every 6 weeks +5 days thereafter).
appendix i protocol amendment summary
11.4 follow up previously read

Additionally, subjects who discontinue study treatment for any reason other than disease progression will be followed with tumor assessment every 6 weeks/42 days (±5 days) and bone scan every 12 weeks (+/- 5 days) during the Follow-up Period according to standard of care until documented disease progression or initiation of new anti-cancer therapy, whichever is sooner.  
… Additionally, subjects who discontinue study treatment for any reason other than disease progression will be followed with tumor assessment every 6 weeks/42 days (±5 days) and bone scan every 12 weeks (+/- 5 days) during the Follow-up Period until documented disease progression or initiation of new anti-cancer therapy, whichever is sooner.
appendix i protocol amendment summary
13.1 power and sample size

The Phase 1b portion of the trial is a 3+3 dose escalation design. Table 6 shows the probability of declaring a dose as the MTD for a variety of underlying toxicity rates. For example there is an 83 percent probability to declare a dose with an incidence of dose limiting toxicity of 50 percent as the MTD. This compares with a probability of 29 percent for a dose with an incidence of dose limiting toxicity of 20 percent.
appendix i protocol amendment summary
table 6 power to declare

The Phase 1b portion of the trial is a 3+3 dose escalation design. Table 6 shows the probability of declaring a dose as *exceeding* the MTD for a variety of underlying toxicity rates. For example there is an 83 percent probability to declare a dose with an incidence of dose limiting toxicity of 50 percent as *exceeding* the MTD. This compares with a probability of 29 percent for a dose with an incidence of dose limiting toxicity of 20 percent. Table 6: Power to Declare a Dose as *Exceeding* **the MTD for Various Incidence Rates**
()  
| APPENDIX B:   |
|---------------|  
SCHEDULE OF ASSESSMENTS FOR SUBJECTS IN PHASE 1B  
  
  
NOTES TO APPENDIX B: (Cont'd) *Previously Read:* q. Bone scan will be done at screening and every other tumor assessment (every 12 weeks ±5 days) until disease progression or initiation or new anti-cancer therapy.  
,19(67,*$7,21$/1(:'58* Previously Read:
Protocol 59R5-003, Amendment 6 CONFIDENTIAL
Page 208 of 235 22 April 201 6  
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,19(67,*$7,21$/1(:'58* If bone scan is used to follow bone lesions, bone scan will be done at screening and every other tumor assessment (every 12 weeks ±5 days) until disease progression or initiation or new anti-cancer therapy. If PET/CT is used to follow bone lesions, PET/CT will be completed at the same schedule as the assessments for other lesions (every 6 weeks ±5 days). The same method (bone scan or *PET/CT) should be used throughout the study to follow bone lesions.*
SCHEDULE OF ASSESSMENTS FOR SUBJECTS IN PHASE 2 APPENDIX C  
  
Now Reads: q.  
  
Protocol 59R5-003, Amendment 6 CONFIDENTIAL
Page 209 of 235 22 April 201 6  
()
initiation or new anti-cancer therapy.  
Now Reads: p. *If bone scan is used to follow bone lesions, b*one scan will be done at screening and every other tumor assessment (every 12 weeks ±5 days) until disease progression or initiation or new anti-cancer therapy. If PET/CT is used to follow bone lesions, PET/CT will be completed at the same schedule as the assessments for other lesions (every 6 weeks ±5 days) The same method (bone scan or *PET/CT) should be used throughout the study to follow bone lesions.*
,19(67,*$7,21$/1(:'58* NOTES TO APPENDIX C: (Cont'd) *Previously Read:* p. Bone scan will be done at screening and every other tumor assessment (every 12 weeks ±5 days) until disease progression or
22 April 201 6 CONFIDENTIAL
Page 210 of 235 Protocol 59R5-003, Amendment 6
appendix f sample informed consent
procedures

The first portion of the study will include approximately 16 patients at about 5 centers in the United States and Europe. The second portion of the study will include approximately 80 patients at about 35 centers in the United States and Europe.  
The first portion of the study will include approximately 16 patients at about 7 centers in the United States. The second portion of the study will include approximately 80 patients at about 35 centers in the United States and Europe.
appendix f sample informed consent
previously read

Tumor assessments: An examination of your tumor(s) by CT (computerized tomography test, like an x-ray that produces a picture of your body including tumors using radiation), or MRI (magnetic resonance imaging - use of a magnetic field to produce an image of your body including tumors) and bone scan (an X-ray to look at your bone). Your study doctor will determine which type of test (either CT or MRI) is best to assess your cancer. A bone scan will also be done to find out if tumors have spread to your bones. This is part of your routine cancer care.  
Tumor assessments: An examination of your tumor(s) by CT (computerized tomography test, like an x-ray that produces a picture of your body including tumors using radiation), or MRI
(magnetic resonance imaging - use of a magnetic field to produce an image of your body including tumors) *or PET/CT (positron emission tomography- measures metabolic activity* within the body. When combined with CT, PET/CT will determine abnormal metabolic activity at a specific anatomic location) or bone scan (an X-ray to look at your bone). Your study doctor will determine which type of test (CT or MRI, *or PET/CT or bone scan*) is best to assess your cancer. This is part of your routine cancer care.
appendix f sample informed consent
treatment phase previously read

If you are found to be eligible to participate, you will be enrolled in the study. If you are in the first portion of the study, you will be assigned to a pre-determined dose level of OMP-59R5. The initial dose levels of OMP-59R5 that will be tested in this study are 5mg/kg and 7.5 mg/kg (if the lower doses are tolerable) administered through the vein. You will be given the following drugs every 21 days: OMP-59R5 on Day1, etoposide 100 mg/m2 on Days 1, 2, and 3, and cisplatin 80 mg/m2 on Day 1.  
… If your disease is at least stable or have responded to therapy at the end of cycle 6 and you doctor think it is appropriate, you will also receive radiation to your brain to help prevent tumors recurring around 8 weeks after the last administration of chemotherapy.  
If you are found to be eligible to participate, you will be enrolled in the study. If you are in the first portion of the study, you will be assigned to a pre-determined dose level of OMP-59R5. The dose levels of OMP-59R5 that will be tested in this study are 5 mg/kg, 7.5 mg/kg *and at 2.5 mg/kg per increment* (if the lower doses are tolerable) administered through the vein. You will be given the following drugs every 21 days: OMP-59R5 on Day1, etoposide 100 mg/m2 on Days 1, 2, and 3, and cisplatin 80 mg/m2 on Day 1. If your disease is at least stable or have responded to therapy at the end of cycle 6 and you doctor think it is appropriate, you will also receive radiation to your brain to help prevent tumors recurring *within* 8 weeks after the last administration of chemotherapy.
appendix f sample informed consent
cycle 1 day 2 deleted

- About 1 tablespoon of blood sample will be taken to review your health condition.  
- About 1 tablespoon of blood sample will be taken to review your health condition.
appendix f sample informed consent
cycle 1 day 8 previously

- About 2 tablespoons of blood sample will be taken to check the level of certain markers and the level of OMP-59R5 in the blood  
- About 3 tablespoons of blood sample will be taken to check the level of certain markers, the level of OMP-59R5 in the blood *and your health status*
appendix f sample informed consent
cycle 2 day 2 previously

- About 3 tablespoons of blood will be taken to review your health condition and to assess the level of certain markers.
- About 2 tablespoons of blood will be taken to assess the level of certain markers.
appendix f sample informed consent
cycle 2 day 3 previously

- About 1 tablespoon of blood will be taken to review your health condition. You will be asked about changes in your medical status or any new health issues and any medications you are taking since the previous study visit.
- You will be asked about changes in your medical status or any new health issues and any medications you are taking since the previous study visit.  
Previously Read:
- About 2 tablespoons of blood will be taken to check the level of certain markers.  
- About 3 tablespoons of blood will be taken to check the level of certain markers and your health status.
appendix f sample informed consent
cycle 3 day 1 previously

Tumor assessment: A CT scan or MRI will be done approximately every 6 weeks after your initial study drug dosing (Day 1 of Cycle 3 and every 6 weeks thereafter). A bone scan will be done at every other tumor assessment (approximately every 12 weeks after initial study drug dosing).  
Tumor assessment: A CT scan or MRI *or PET/CT* will be done approximately every 6 weeks after your initial study drug dosing (Day 1 of Cycle 3 and every 6 weeks thereafter). *If a bone* scan is used, bone scan will be done at every other tumor assessment (approximately every 12 weeks after initial study drug dosing).
appendix f sample informed consent
cycle 3 day 2 previously

- About 3 tablespoons of blood will be taken to review your health condition and to assess the level of certain markers.
- About 2 tablespoons of blood will be taken to assess the level of certain markers.
appendix f sample informed consent
cycle 3 day 3 deleted

- About 1 tablespoon of blood will be taken to review your health condition.  
Cycle 3 Day 8 Previously Read:
- About 2 tablespoon of blood to check the level of certain markers.  
- About 3 tablespoon of blood to check the level of certain markers *and your health status*.
appendix f sample informed consent
cycles 4-6 day 1 previously

- Tumor assessment: A CT scan or MRI will be done approximately every 6 weeks after your initial study drug dosing. A bone scan will be done at every other tumor assessment (approximately every 12 weeks after initial study drug dosing).
- Tumor assessment: A CT scan or MRI *or PET/CT* will be done approximately every 6 weeks after your initial study drug dosing. A bone scan will be done at every other tumor assessment (approximately every 12 weeks after initial study drug dosing) if a bone scan is used.
appendix f sample informed consent
cycles 4-6 day 2 deleted

- About 1 tablespoon of blood will be taken to review your health condition.
appendix f sample informed consent
end of cycle 6 previously

- At the end of cycle 6, if your disease is at least stable or have responded to therapy, you will receive radiation to your brain to help prevent tumors before continuing with study drug treatment.
- At the end of cycle 6, if your disease is at least stable or have responded to therapy, you doctor may decide that you will receive radiation to your brain to help prevent tumors before continuing with study drug treatment.
appendix f sample informed consent
cycle 7 and beyond previously

- Tumor assessment: A CT scan or MRI will be done approximately every 6 weeks after your initial study drug dosing. A bone scan will be done at every other tumor assessment (approximately every 12 weeks after initial study drug dosing).
- Tumor assessment: A CT scan or MRI *or PET/CT* will be done approximately every 6 weeks after your initial study drug dosing. *If a bone scan is used, b*one scan will be done at every other tumor assessment (approximately every 12 weeks after initial study drug dosing).
appendix f sample informed consent
treatment termination previously read

- Tumor assessment: either by CT or MRI, and bone scan, if these procedures were not done within the last 4 weeks and if the last tumor assessment did not show that your tumor has grown or spread
- Tumor assessment: either by CT or MRI *or PET/CT, or* bone scan, if these procedures were not done within the last 4 weeks and if the last tumor assessment did not show that your tumor has grown or spread
appendix f sample informed consent
possible risks and discomforts omp-59r5

OMP-59R5 is being testing in small number of patients who have cancer; diarrhea is the most common side effect and all three patients who were treated at 5 mg/kg every other week had mild diarrhea. You will be given some medications to take home to treat diarrhea. Other comment side effects reported are: fatigue-tiredness (30%), nausea (22%), decreased appetite (15%), increased liver function (ALT) (11%), dehydration (11%), low potassium level (11%), vomiting (11%), low blood counts that might make you feel tired or easy to bruise (11%).  
,19(67,*$7,21$/1(:'58* ()  
OMP-59R5 is being testing in small number of patients who have cancer; diarrhea is the most common side effect *in the first in man study* and all three patients who were treated at 5 mg/kg every other week had mild diarrhea. You will be given some medications to take home to treat diarrhea. Other comment side effects reported are: fatigue-tiredness (30%), nausea (22%), decreased appetite (15%), increased liver function (ALT) (11%), dehydration (11%), low potassium level (11%), vomiting (11%), low blood counts that might make you feel tired or easy to bruise (11%).
appendix f sample informed consent
amendment 3 23 october 2013

The following changes were made to the protocol. Italics in the text indicate new text.
appendix f sample informed consent
rationale

The protocol has been amended to refer the details on study drug (OMP-59R5/Placebo) preparation and administration in the Pharmacy Manual, to collect additional blood sample for PK and/or anti-OMP-59R5 antibody analysis at other protocol-specified times as clinically indicated such as when significant toxicities develop, to modify inclusion criterion 5c to allow medical judgment of adequate hepatic function when the lab values are outside of the corresponding cutoff. Sample Informed Consent template has been updated to reflect the changes on infusion duration, possible additional blood samples for PK and/or anti-OMP-59R5 antibody analysis when significant toxicities develop, incidences of infusion reactions in 71 patients treated with OMP-59R5 and the management of the infusion reaction. Additionally, Table 7 has been updated to reflect the probability of 4 or more subjects developing DLTs in a total of 10 subjects in the expansion to be more in line with  33% incidence of DLTs in a standard 3+3 dose escalation study.
appendix f sample informed consent
previously read

5. Adequate organ function:
a. Adequate hematologic function (absolute neutrophil count [ANC]  1,500 cells/ȝL;
hemoglobin  9 g/dL, platelets  100,000/ȝL).  
b. Adequate renal function (serum creatinine  1.5 mg/dL or calculated creatinine clearance 60 mL/min using Cockroft Gault formula). Adequate hepatic function (alanine aminotransferase [ALT]  3 x upper limit of normal [ULN], aspartate c. aminotransferase [AST]  3 x ULN); ALT and AST may be  5 x ULN if due to liver metastases but cannot be associated with concurrent elevated bilirubin >1.5xULN).  
d. Prothrombin Time (PT)/International Normalized Ration (INR) 1.5 × ULN, activated partial thromboplastin time (aPTT) 1.5 × ULN.  
5. Adequate organ function:
a. Adequate hematologic function (absolute neutrophil count [ANC]  1,500 cells/ȝL;
hemoglobin  9 g/dL, platelets  100,000/ȝL).  
b. Adequate renal function (serum creatinine  1.5 mg/dL or calculated creatinine clearance 60 mL/min using Cockroft Gault formula).  
c. Adequate hepatic function (alanine aminotransferase [ALT]  3 x upper limit of normal
[ULN], ALT may be  5 x ULN if due to liver metastases but cannot be associated with concurrent elevated bilirubin >1.5xULN unless it is approved by the Sponsor's Medical Monitor).  
d. Prothrombin Time (PT)/International Normalized Ration (INR) 1.5 × ULN, activated partial thromboplastin time (aPTT) 1.5 × ULN.
appendix f sample informed consent
test product dose and mode

OMP-59R5 is an IgG2 fully human monoclonal antibody that is directed against the Notch2/3 receptors. OMP-59R5 is supplied at a concentration of 10 mg/mL in 25mL single-use glass vial filled to 20 mL to deliver at total of 200 mg per vial. OMP-59R5 vials must be stored at 2°C– 8°C. DO NOT FREEZE. DO NOT SHAKE. OMP-59R5 must be delivered through either polyvinyl chloride (PVC) or non-PVC tubing containing a **Baxter 0.22-micron high pressure extended life filter** (part number 2H5660) which will be provided by OncoMed and should be infused over 30 minutes (+/- 5 minutes) as an IV infusion. Placebo is a formulation of 50mM Histidine, 100mM Sodium Chloride, 45mM Sucrose and 0.01% (v/v) Polysorbate-20, pH 6.0. Placebo will be administered in the same manner as OMP-59R5; i.e., withdraw the necessary amount of placebo and dilute with either half normal saline (NS) (0.45% Sodium Chloride (NaCl) or 5% Dextrose and 0.45% NaCl (D5W ½
NS)to a total volume of 250 mL and infuse over 30 minutes (+/- 5 minutes). The diluted study drug should be administered within 4 hours of preparation.  
OMP-59R5 is an IgG2 fully human monoclonal antibody that is directed against the Notch2/3 receptors. OMP-59R5 is supplied at a concentration of 10 mg/mL in 25mL single-use glass vial filled to 20 mL to deliver at total of 200 mg per vial. OMP-59R5 vials must be stored at 2°C-8°C. DO NOT FREEZE. DO NOT SHAKE. Please refer to the Pharmacy Manual for the details on OMP-59R5 preparation and administration. Placebo is a formulation of 50mM Histidine, 100mM Sodium Chloride, 45mM Sucrose and 0.01% (v/v) Polysorbate-20, pH 6.0. Placebo will be administered in the same manner as OMP-59R5. Please refer to the Pharmacy Manual for details regarding Placebo preparation and administration.
appendix f sample informed consent
immunogenicity previously read

Serum samples will be obtained for immunogenicity assessment prior to study drug administration on Day 1 of Cycle 1, every three cycles thereafter (Day 1 of Cycle 4, 7, 10, etc.) and at the time of treatment termination for all subjects enrolled in Phase 1b and Phase 2 portions. Samples that test positive will be assessed for neutralizing capability.  
Serum samples will be obtained for immunogenicity assessment prior to study drug administration on Day 1 of Cycle 1, every three cycles thereafter (Day 1 of Cycle 4, 7, 10, etc.), at other times as clinically indicated such as when significant toxicities occur and at the time of treatment termination for all subjects enrolled in Phase 1b and Phase 2 portions. Samples that test positive will be assessed for neutralizing capability.
appendix f sample informed consent
pharmacokinetic evaluation previously read

For subjects enrolled in Phase 1b portion only: Plasma samples from all subjects enrolled in Phase 1b portion will be obtained for pharmacokinetic analysis of OMP-59R5 at pre-dose and 5 minutes post infusion on Day 1 of Cycles 1 and 3, on Days 3 and 8 of Cycles 1 and 3, as well as at the time of treatment termination, as outlined in the Schedule of Assessments (APPENDIX B). Pharmacokinetic parameters (i.e. area under the curve [AUC], clearance, volume of distribution and apparent half life) of OMP-59R5 will be assessed for each evaluable subject.  
For subjects enrolled in Phase 1b portion only: Plasma samples from all subjects enrolled in Phase 1b portion will be obtained for pharmacokinetic analysis of OMP-59R5 at pre-dose and 5 minutes post infusion on Day 1 of Cycles 1 and 3, on Days 3 and 8 of Cycles 1 and 3, at other times as clinically indicated such as when significant toxicities occur as well as at the time of treatment termination, as outlined in the Schedule of Assessments (APPENDIX B). Pharmacokinetic parameters (i.e. area under the curve [AUC], clearance, volume of distribution and apparent half life) of OMP-59R5 will be assessed for each evaluable subject.
appendix f sample informed consent
3.4 clinical background previously read

No RECIST complete or partial responses have been noted on this Phase 1 study. However, six subjects have had RECIST stable disease (SD) lasting greater than 56 days (ranging from 61 days to 165 days, all of them have come off the study). OMP-59R5 is also being studied in a phase 1b/2 study in combination with nab-paclitaxel and gemcitabine in subjects with previously untreated stage IV pancreatic cancer (Study 59R5-002). The study was initially conducted in combination with gemcitabine alone and was amended to incorporate nab-paclitaxel into the chemotherapy backbone in response to the changes in standard of care in this disease population. As of August 19, 2013, twenty four subjects have been treated in Study 59R5-002: five *and four* at 2.5 mg/kg and 5.0 mg/kg respectively every other week in combination with gemcitabine at 1000 mg/m2 on Days 1, 8 and 15 of every 28 day cycle, four, six and four at 5 mg/kg, 7.5 mg/kg and 10 mg/kg respectively every other week in combination with nab-paclitaxel at 125 mg/m2 and gemcitabine at 1000 mg/m2 on Days 1, 8 and 15 of every 28 day cycle. No DLTs have been reported, and the most common reported OMP59R5 treatment-related event is diarrhea, fatigue and nausea that are mostly grade 1 or 2, managed with supportive care. One Grade 3 diarrhea was noted in one of four subjects treated with 10 mg/kg OMP-59R5 with Nab-P+Gem, lasted less than 48 hours and resolved to Grade 1 diarrhea after concurrent use of lomotil. Treatment with etoposide and cisplatin is the standard of care for subjects with untreated extended stage small cell lung cancer. The most common AE of OMP-59R5 is diarrhea, whereas cytopenia is the most common adverse event with EP administration. Therefore, the most common AEs of OMP-59R5 and EP do not overlap, providing the justification for investigating this combination in the study. Subjects enrolled in this study will receive a starting dose of 5 mg/kg of OMP-59R5 once every three weeks, which is one dose below the MTD of 7.5 mg/kg every three weeks in Study 59R5-001. Phase 1b lead-in portion of the study will provide preliminary safety and tolerability profile of this combination before the initiation of Phase 2 portion of the study. OMP-59R5 has an estimated apparent half time of 2 to 3 days at 7.5 mg/kg in Study 59R5-001, subjects will not receive PCI or WBRT within 2 weeks of study drug administration and will not receive OMP-59R5 during the radiation to alleviate any potential interaction between the study drug and the radiation. Therefore, risks and potential benefits of participation have been appropriately mitigated for this patient population. Now Reads: No RECIST complete or partial responses have been noted on this Phase 1 study. However, six subjects have had RECIST stable disease (SD) lasting greater than 56 days (ranging from 61 days to 165 days, all of them have come off the study). As of October 22, 2013, three subjects have been treated in the current study (Study 59R5-003) at 5 mg/kg dose cohort with EP; two of which have completed 6 cycles of chemotherapy and are continuing OMP-59R5 alone, and the other one is currently in Cycle 5. No significant OMP59R5 treatment-related toxicities were reported.  
OMP-59R5 is also being studied in a phase 1b/2 study in combination with nab-paclitaxel and gemcitabine in subjects with previously untreated stage IV pancreatic cancer (Study 59R5-002). The study was initially conducted in combination with gemcitabine alone and was amended to incorporate nab-paclitaxel into the chemotherapy backbone in response to the changes in standard of care in this disease population. As of *October 22,* 2013, twenty *six* subjects have been treated in Study 59R5-002: five *and four* at 2.5 mg/kg and 5.0 mg/kg respectively every other week in combination with gemcitabine at 1000 mg/m2 on Days 1, 8 and 15 of every 28 day cycle, four, six, *six and one* at 5 mg/kg, 7.5 mg/kg, 10 mg/kg *and 12.5 mg/kg* respectively every other week in combination with nab-paclitaxel at 125 mg/m2 and gemcitabine at 1000 mg/m2 on Days 1, 8 and 15 of every 28 day cycle. No DLTs have been reported, and the most common reported OMP-59R5 treatment-related event is diarrhea, fatigue and nausea that are mostly grade 1 or 2, managed with supportive care. One Grade 3 diarrhea was noted in one of *six* subjects treated with 10 mg/kg OMP-59R5 with Nab-P+Gem, lasted less than 48 hours and resolved to Grade 1 diarrhea after concurrent use of lomotil. *Three subjects have experienced grade 2* infusion-related reactions: one at 5mg/kg OMP-59R5 dose cohort with Nab-P+Gem at Cycle 4 Day 1(the baseline weight was 87kg), two at 10 mg/kg OMP-59R5 dose cohort with Nab-P+Gem at Cycle 1 Day 15 and Cycle 2 Day 1 respectively(the baseline weight was 106 kg and 84 kg respectively). Infusion reaction was also reported from two of forty two subjects treated in Study 59R5-001: one at 1.0 mg/kg weekly and the other at 5.0 mg/kg weekly dose cohorts (the baseline weight was 54.7 kg and 104 kg respectively), both occurred with the first OMP-59R5 infusion and were Grade 1 or Grade 2; Four of these five subjects have responded to use of antihistamines and/or steroids, and the subsequent doses were administered at a slower infusion rate in addition to premedication. However, one subject from the 10 mg/kg dose cohort in the ALPINE study experienced a recurrent infusion reaction even with premedication and slower infusion rate. Thus far, no infusion reactions have been reported in three subjects treated with OMP-59R5 in the PINNACLE study (59R5-003). However, in response to the incidence of infusion reactions reported at higher OMP-59R5 doses in the ALPINE study, and in heavier subjects, the details on preparation and administration of OMP-59R5 have been provided in the Pharmacy Manual.  
Protocol 59R5-003, Amendment 6 Page 222 of 235 2016 CONFIDENTIAL ()
Treatment with etoposide and cisplatin is the standard of care for subjects with untreated extended stage small cell lung cancer. The most common AE of OMP-59R5 is diarrhea, whereas cytopenia is the most common adverse event with EP administration. Therefore, the most common AEs of OMP-59R5 and EP do not overlap, providing the justification for investigating this combination in the study. Subjects enrolled in this study will receive a starting dose of 5 mg/kg of OMP-59R5 once every three weeks, which is one dose below the MTD of 7.5 mg/kg every three weeks in Study 59R5-001. Phase 1b lead-in portion of the study will provide preliminary safety and tolerability profile of this combination before the initiation of Phase 2 portion of the study. OMP-59R5 has an estimated apparent half time of 2 to 3 days at 7.5 mg/kg in Study 59R5-001, subjects will not receive PCI or WBRT within 2 weeks of study drug administration and will not receive OMP-59R5 during the radiation to alleviate any potential interaction between the study drug and the radiation. Therefore, risks and potential benefits of participation have been appropriately mitigated for this patient population.
appendix f sample informed consent
6.1 inclusion criteria previously read

…  
…
c. Adequate hepatic function (alanine aminotransferase [ALT]  3 x upper limit of normal
[ULN], aspartate aminotransferase [AST]  3 x ULN); ALT and AST may be  5 x ULN if due to liver metastases but cannot be associated with concurrent elevated bilirubin > 1.5xULN).  
c. Adequate hepatic function (alanine aminotransferase [ALT]  3 x upper limit of normal
[ULN], ALT may be  5 x ULN if due to liver metastases but cannot be associated with concurrent elevated bilirubin > 1.5xULN unless it is approved by the Sponsor's Medical Monitor).
appendix f sample informed consent
7.0 treatment of subjects previously

Study drug will be OMP-59R5 in the Phase 1b portion, and either OMP-59R5 or placebo in the Phase 2 portion. Study drug will be administered by IV infusion over 30 minutes (+/- 5 minutes) on Day 1 of every 21-day cycle. The subject should not take two consecutive doses of study drug within 18 days.  
Study drug will be OMP-59R5 in the Phase 1b portion, and either OMP-59R5 or placebo in the Phase 2 portion. Study drug will be administered by IV infusion on Day 1 of every 21-day cycle. The subject should not take two consecutive doses of study drug within 18 days.
appendix f sample informed consent
7.1.1 study drug administration previously

During Phase 1b and 2, OMP-59R5 must be delivered through tubing containing a Baxter 0.22-micron high pressure extended life filter (part number 2H5660) which will be provided by OncoMed and should be infused over 30 minutes (+/- 5 minutes) as an IV infusion. During Phase 2, Placebo will be administered in exactly the same manner as OMP-59R5; i.e., withdraw the necessary amount of placebo and dilute with either half normal saline (NS) (0.45% Sodium Chloride (NaCl) or5% Dextrose and 0.45% NaCl (D5W ½ NS) to a total volume of 250 mL and infuse over 30 minutes (+/- 5 minutes). The diluted study drug should be administered within 4 hours of preparation.  
There is no provision for intra-subject dose escalation of study drug. Weight-based doses will not be recalculated unless there is a weight change 10%.  
Please refer to the Pharmacy Manual for the details on OMP-59R5 or Placebo preparation and administration. \There is no provision for intra-subject dose escalation of study drug. Weight-based doses will not be recalculated unless there is a weight change 10%.
appendix f sample informed consent
7.1.5 study drug preparation previously

The study drug should be diluted for infusion using aseptic technique. Withdraw the necessary amount of the study drug to obtain the required dose and dilute with either half normal saline (NS) (0.45% Sodium Chloride (NaCl) or 5% Dextrose and 0.45% NaCl (D5 ½ NS), to a total volume of 250 mL. For example, if a 70-kg subject is to be dosed at 5 mg/kg, then the subject's dose would be 350 mg. Because the vials contain a concentration of 10 mg/mL, a total of 35 mL containing 350 mg should be withdrawn from the vial and diluted with either 0.45% NaCl or 5% Dextrose and 0.45% NaCl (D5W ½ NS), to a total volume of 250 mL. Any unused portion left in a vial may not be used for another subject, as the product contains no preservative (i.e., they are single-use vials). The diluted study drug solutions may be stored at room temperature (19°C–25°C) for up to 4 hours.  
Please refer to the Pharmacy Manual for details on study drug preparation. Any unused portion left in a vial may not be used for another subject, as the product contains no preservative (i.e., they are single-use vials).
appendix f sample informed consent
7.4.1 infusion reaction management previously

… For subjects whose infusion-associated events were either Grade 1 or 2, and completely resolved on the day of the infusion, the infusion may be resumed at the discretion of the Investigator at one-half of the initial rate of infusion. All subsequent infusions for that subject should then be administered at the reduced rate of infusion.  
… For subjects whose infusion-associated events were either Grade 1 or 2, and completely resolved on the day of the infusion, the infusion may be resumed at the discretion of the Investigator at *a rate that is slower than* the initial rate of infusion. Please refer to the Pharmacy Manual for details on study drug administration. All subsequent infusions for that subject should then be administered at the reduced rate of infusion. 8.5 Immunogenicity Assessments
appendix f sample informed consent
previously read

(Anti-OMP-59R5) prior to study drug administration on Day 1 of Cycle 1, every three cycles thereafter (Day 1 of Cycle 4, 7, 10, etc.) and at the time of treatment termination for all subjects enrolled in Phase 1b and Phase 2 portions. Samples that test positive will be assessed for neutralizing capability. Instructions for sample collection, handling, storage, and shipping can be found in the Study Reference Binder.  
Serum samples will be obtained for immunogenicity assessment (Anti-OMP-59R5) prior to study drug administration on Day 1 of Cycle 1, every three cycles thereafter (Day 1 of Cycle 4, 7, 10, etc.)*, at other times as clinically indicated such as when significant toxicities occur* and at the time of treatment termination for all subjects enrolled in Phase 1b and Phase 2 portions. Samples that test positive will be assessed for neutralizing capability. Instructions for sample collection, handling, storage, and shipping can be found in the Study Reference Binder.
appendix f sample informed consent
8.6 pharmacokinetic assessments previously read

For subjects enrolled in Phase 1b portion only: Plasma samples from all subjects enrolled in Phase 1b portion will be obtained for pharmacokinetic analysis of OMP-59R5 at pre-dose and 5 minutes post OMP-59R5 infusion on Day1 of Cycles 1 and 3, on Days 3 and 8 of Cycles 1 and 3, as well as at the time of treatment termination, as outlined in the Schedule of Assessments (APPENDIX B and APPENDIX C). Pharmacokinetic parameters (i.e. area under the curve [AUC], clearance, volume of distribution and apparent half life) of OMP-59R5 will be assessed for each evaluable subject. Instructions for sample collection, handling, storage, and shipping can be found in the Study Reference Binder.  
For subjects enrolled in Phase 1b portion only: Plasma samples from all subjects enrolled in Phase 1b portion will be obtained for pharmacokinetic analysis of OMP-59R5 at pre-dose and 5 minutes post OMP-59R5 infusion on Day1 of Cycles 1 and 3, on Days 3 and 8 of Cycles 1 and 3, at other times as clinically indicated such as when significant toxicities occur as well as at the time of treatment termination, as outlined in the Schedule of Assessments (APPENDIX B and APPENDIX C). Pharmacokinetic parameters (i.e. area under the curve [AUC], clearance, volume of distribution and apparent half life) of OMP-59R5 will be assessed for each evaluable subject. Instructions for sample collection, handling, storage, and shipping can be found in the Study Reference Binder. 13.1 Power and Sample Size
appendix f sample informed consent
previously read

Table 7 presents the probability that more than 3 subjects will experience a DLT in the expansion cohort of 10 subjects. The probability of seeing 3 or more subjects with a dose limiting toxicity when the true incidence is 40 percent is 83.3 percent compared with 69 percent with the 3+3 design.  
| Probability of Toxicity   | - 3/10 Not Tolerable        |
|---------------------------|--------|
| 0.05                      | 0.0115 |
| 0.10                      | 0.0702 |
| 0.15                      | 0.1798 |
| 0.20                      | 0.3222 |
| 0.25                      | 0.4744 |
| 0.30                      | 0.6172 |
| 0.35                      | 0.7384 |
| 0.40                      | 0.8327 |
| 0.45                      | 0.9004 |
| 0.50                      | 0.9453 |  
Table 7: Probability of that 3 or more Subjects will have a Dose Limiting Toxicity  
Table 7 presents the probability that more than 4 subjects will experience a DLT in the expansion cohort of 10 subjects. The probability of seeing 4 or more subjects with a dose limiting toxicity when the true incidence is 40 percent is *3.5* percent compared with 69 percent with the 3+3 design. ()  
| Probability of 4 or more DLT's in 10 Subjects   |                        |                        |                         |
|-------------------------------------------------|------------------------|------------------------|-------------------------|
| Probability of Dose                             | Given 0 DLT out of the | Given 1 DLT out of the | Given 0 or 1 DLT's out  |
| Limiting Toxicity                               | first 6 subjects       | first 6 subjects       | of the first 6 subjects |
| 0.05                                            | 0.000                  | 0.000                  | 0.000                   |
| 0.10                                            | 0.000                  | 0.001                  | 0.001                   |
| 0.15                                            | 0.000                  | 0.005                  | 0.005                   |
| 0.20                                            | 0.000                  | 0.011                  | 0.011                   |
| 0.25                                            | 0.001                  | 0.018                  | 0.019                   |
| 0.30                                            | 0.001                  | 0.025                  | 0.026                   |
| 0.35                                            | 0.001                  | 0.031                  | 0.032                   |
| 0.40                                            | 0.001                  | 0.033                  | 0.035                   |
| 0.45                                            | 0.001                  | 0.033                  | 0.034                   |
| 0.50                                            | 0.001                  | 0.029                  | 0.030                   |  
Table 7: Probability of that 4 **or more Subjects will have a Dose Limiting Toxicity**
appendix f sample informed consent
notes to appendix b previously

h. Plasma samples will be obtained for OMP-59R5 pharmacokinetic analysis at pre-dose and 5 minutes (±2 minutes) after the end of OMP-59R5 infusion and prior to the EP administration on Day 1 of Cycle 1 and Cycle 3, and on Days 3 (pre-dose) and 8 of Cycles 1 and 3, as well as at treatment termination. On days when OMP-59R5 and etoposide and/or cisplatin are given together, the plasma sample should be obtained 5 minutes (±2 minutes) after the completion of the infusion of OMP-59R5, but prior to EP administration.  
i. Serum samples will be obtained for anti-OMP-59R5 pre-dose on Day 1 of every three cycles starting from Cycle 1, and at the Treatment Termination visit.  
h. Plasma samples will be obtained for OMP-59R5 pharmacokinetic analysis at pre-dose and 5 minutes (±2 minutes) after the end of OMP-59R5 infusion and prior to the EP administration on Day 1 of Cycle 1 and Cycle 3, and on Days 3 (pre-dose) and 8 of Cycles 1 and 3, *at other* times as clinically indicated such as when significant toxicities occur, as well as at treatment termination. On days when OMP-59R5 and etoposide and/or cisplatin are given together, the plasma sample should be obtained 5 minutes (±2 minutes) after the completion of the infusion of OMP-59R5, but prior to EP administration.  
i. Serum samples will be obtained for anti-OMP-59R5 pre-dose on Day 1 of every three cycles starting from Cycle 1, *at other times as clinically indicated such as when significant* toxicities occur, and at the Treatment Termination visit.
appendix f sample informed consent
notes to appendix c previously

h. Serum samples will be obtained for anti-OMP-59R5 pre-dose on Day 1 of every third cycle starting from Cycle 1, and at the Treatment Termination visit.  
h. Serum samples will be obtained for anti-OMP-59R5 pre-dose on Day 1 of every third cycle starting from Cycle 1, *at other times as clinically indicated such as when significant* toxicities occur and at the Treatment Termination visit.
appendix f sample informed consent
appendix f sample informed consent

Your study drug (OMP59R5 or placebo) will be given through the vein for 30 minutes. Etoposide will be given through the vein for 30 to 60 minutes. Cisplatin will be given through the vein for 30 minutes to 2 hours. On days when the study drug, etoposide and cisplatin are given together, the study drug will be given first, followed by etoposide, and then cisplatin. You will receive study drug, etoposide, and cisplatin up to 6 cycles. After that, you will receive study drug only on Day 1 of each following cycle.
appendix f sample informed consent
the following procedures will take

Your study drug (OMP-59R5 or placebo) will be given through the vein for 30 minutes or longer depending on the dose you are assigned, your weight and if you have experienced any allergic reaction to study drug. Your study staff will let you know how long your treatment with study drug will be. Etoposide will be given through the vein for 30 to 60 minutes. Cisplatin will be given through the vein for 30 minutes to 2 hours. On days when the study drug, etoposide and cisplatin are given together, the study drug will be given first, followed by etoposide, and then cisplatin. You will receive study drug, etoposide, and cisplatin up to 6 cycles. After that, you will receive study drug only on Day 1 of each following cycle.
appendix f sample informed consent
the following procedures will take

Additional blood samples (approximately 1 to 2 teaspoons for each blood sample) might be taken to check the level of study drug (OMP-59R5) and/or proteins against OMP-59R5 in your body:
appendix f sample informed consent
possible risks and discomforts omp-59r5

OMP-59R5 is being testing in small number of patients who have cancer; diarrhea is the most common side effect in the first in man study and all three patients who were treated at 5 mg/kg every other week had mild diarrhea. You will be given some medications to take home to treat diarrhea. Other comment side effects reported are: fatigue-tiredness (30%), nausea (22%), decreased appetite (15%), increased liver function (ALT) (11%), dehydration (11%), low potassium level (11%), vomiting (11%), low blood counts that might make you feel tired or easy to bruise (11%). In addition, as with all antibody treatments, there is the possibility of an allergic reaction, such as fever, chills, rash, and/or hives associated with the infusion of OMP-59R5. Rarely, a severe or serious allergic reaction can occur during or following the administration of an antibody.  
OMP-59R5 is being testing in small number of patients who have cancer; diarrhea is the most common side effect in the first in man study and all three patients who were treated at 5 mg/kg every other week had mild diarrhea. You will be given some medications to take home to treat diarrhea. Other *common* side effects reported are: fatigue-tiredness (30%), nausea (22%),
decreased appetite (15%), increased liver function (ALT) (11%), dehydration (11%), low potassium level (11%), vomiting (11%), low blood counts that might make you feel tired or easy to bruise (11%). *There may be side effects that we cannot predict and in some cases they may be* serious, long-lasting, or fatal. In addition, as with all antibody treatments, there is the possibility of an allergic reaction, such as fever, chills, rash, hives, *changes in blood pressure, temperature* and heart rate associated with the infusion of OMP-59R5. Rarely, a severe or serious allergic reaction can occur during or following the administration of an antibody. As of October 22, 2013, five of 71 patients who have been given OMP-59R5 have experienced allergic reactions; all of these allergic reactions were mild or moderate. If you do have a reaction to OMP-59R5, your study doctor may need to give OMP-59R5 at a slower rate (over a longer period of time) and may give you additional medications to prevent a reaction. If after slowing the rate of infusion and giving you additional medications you continue to have the allergic reactions, you may need to stop taking OMP-59R5.  
Protocol 59R5-003, Amendment 6 Page 230 of 235 2016 CONFIDENTIAL
appendix f sample informed consent
amendment 4 17 april 2014

The following changes were made to the protocol. Italics in the text indicate new text.
appendix f sample informed consent
rationale

The protocol has been amended to add a cohort of 6 subjects to be treated with etoposide and carboplatin after the highest tolerable dose is determined with OMP-59R5 in combination with etoposide and cisplatin, the non-clinical section has been updated to include an experiment using carboplatin, to specify 15 mg/kg of OMP-59R5 as the highest dose to be tested in Phase 1b portion of the study if the MTD has not been determined after 15 mg/kg of tarextumab has been tested, in phase 2 portion of the study, the randomization will be balanced on the choice of platinum therapy (cisplatin versus carboplatin) regions (US vs Europe) and the prior use of whole brain radiation or prophylactic cranial irradiation. Choice of platinum therapy won't be changed once the subject is randomized. Additional blood samples have been added for PK and immunogenicity assessment. Inclusion criterion of Notch 3 selection has been eliminated and statistical section has been updated to include analysis on all treated subjects and Notch 3 high subjects. Subjects are required to have radiation-related adverse events recovered to be  Grade 1 in order to be eligible for the study.
appendix f sample informed consent
summary of changes

As a result, all the corresponding sections of the protocol have been updated to reflect the changes outlined above, (i.e., Synopsis, Section 2.0 List of Abbreviations, Section 3.3 Nonclinical Data, Section 3.4 Clinical Background, Section 3.5 Dose Rationale, Section 3.7 Subject Population, Section 4.1 Study Objectives, Section 5.0 Overall Study Design and Plan - Description, Section 5.1 Phase 1b Portion, Section 5.3 Dose Escalation Plan, Section 5.4 Maximum Tolerated Dose, Section 5.5 Phase 2 Portion, Section 5.5.1 Blinded Treatment Phase, Section 6.1 Inclusion Criteria, Section 6.2 Exclusion Criteria, Section 6.3 Removal of Subjects from Study Treatment, Section 6.4 Subject Identification and Replacement of Subjects, Section 7.0 Treatment of Subjects, Section 7.1.1 Study Drug Administration, Section 7.4.1 Administration, Section 7.4.2 Description, Section 7.4.3 Storage, Section 7.4.4 Packaging, Section 7.5 Dose Modifications or Delay for Treatment-Related Toxicities, Section 7.6 Anti-Emetics, Anti-diarrhea and Hematopoietic Supportive Care, Section 7.8 Treatment Compliance, Section 6.1 Inclusion Criteria, Section 8.1.4 Serious Adverse Event Reporting Procedure, Section 8.2.1 Hematology, Section 8.2.2 Serum Chemistry, Section 8.2.3 Urinalysis, Section 8.3 Vital Signs and Other Physical Findings, Section 8.4 Cardiac Studies, Section 8.5 Immunogenicity Assessments, Section 8.6 Pharmacokinetic Assessments, Section 11.0 Study Visit Schedule and Assessments, Section 11.2 Treatment Visits, Section 11.2.1.1 Cycle 1 Day 1, Section 11.2.1.2 Cycle 1 Day 2, Section 11.2.1.3 Cycle 1 Day 3, Section 11.2.2.1 Day 1 (± 1 day) of Cycles 2-6, Section 11.2.2.2 Day 2 of Cycles 2-6, Section 11.2.2.3 Day 3 of Cycles 2-6, Protocol 59R5-003, Amendment 6 Page 231 of 235 2016 CONFIDENTIAL ()
Section 11.2.2.4 Day8 of Cycles 2 and 3 Only, Section 11.2.3 After Cycle 6 of Etoposide and Cisplatin/Carboplatin with Study Drug, Section 11.2.4.1 Day 1 (± 1 day) of Cycle 7 and Every Cycle Thereafter, Section 11.2.4.2 Anytime between Day 3 thru Day 14 of Cycle 7 and Cycle 9, Section 11.2 Treatment Termination, Section 13.1.1 Phase 1b, Section 13.1.2 Sample Size Justification - Phase 2, Section 13.2 Randomization and Blinding, Section 13.4.1 Subject Populations for Analysis, Section 13.4.2 Analysis Sets, Section 13.5.1 Efficacy Endpoints, Section 13.5.3 Immunogenicity Endpoint, Section 13.5.4 Pharmacokinetic Endpoints, Section 13.5.5 Exploratory Endpoints, Section 13.6 Statistical Method, Section 13.6.1 Progression Free Survival, Section 13.6.2 Response Rate (Best Overall Response), Section 13.6.3 Duration of Response, Section 13.6.4 Overall Survival, Section 13.6.5 Landmark Survival, Section 13.7 Demographics and Baseline Characteristics, Section 13.8 Treatment Exposure, Section 13.9 Termination Criteria, Section 13.11 Data Safety Monitory Board, Section 14.0 Direct Access to Source Data/Documentation, Section 16.3 Study Monitoring, Section 16.5 Data collection, Section 17.0 References, Appendix A Study Schema, Appendix B Schedule of Assessments for Subjects in Phase 1B, Notes to Appendix B, Appendix C Schedule of Assessments for Subjects in Phase 2, Notes to Appendix C, Appendix F Sample Informed Consent, Appendix G Sample Pharmacogenomics Informed Consent for Phase 1B, and Appendix H Technical Details Supporting Calculation of Power and Type 1 Error. Additional minor changes have been made to improve clarity and consistency. Substantive new information appears in italics. This amendment represents cumulative changes to the previous amendments.
appendix f sample informed consent
amendment 5 10 september 2014

The following changes were made to the protocol. Italics in the text indicate new text.
appendix f sample informed consent
rationale

The protocol has been amended to decrease the cisplatin dose to 75 mg/m2 in the Phase 2 portion of the study. Pharmacokinetic (PK) sampling in the Phase 2 portion has been modified. The amendment also provides additional flexibility on treatment modification as clinically indicated after discussion with the Sponsor's Medical Monitor. The frequency of bone scan after treatment on study in Phase 2 has been changed to be done as clinically indicated. Subjects who have relapsed after treatment for limited disease will be excluded for Phase 2 portion of the study.  
Additionally, the amendment also modified the statistical calculation for the Phase 2 portion of the study. The timing of the first two DSMB meetings has been modified.
appendix f sample informed consent
summary of changes

As a result, all the corresponding sections in the table below have been updated to reflect the changes outlined above. Additional minor changes have been made to improve clarity and consistency. Substantive new information appears in italics. This amendment represents cumulative changes to the previous amendments.  
| Synopsis Section 2.0   | List of Abbreviations                                         |
|------------------------|---------------------------------------------------------------|
| Section 3.4            | Clinical Background                                           |
| Section 3.5            | Dose Rationale                                                |
| Section 5.0            | Overall Study Design and Plan Description                     |
| Section 5.1            | Phase 1b Portion                                              |
| Section 5.5            | Phase 2 Portion                                               |
| Section 5.5.1          | Blinded Treatment Phase                                       |
| Section 6.2            | Exclusion Criteria                                            |
| Section 6.4            | Subject Identification and Replacement of Subjects            |
| Section 7.0            | Treatment of Subjects                                         |
| Section 7.1.1          | Study Drug Administration                                     |
| Section 7.3.1          | Administration                                                |
| Section 7.5            | Dose Modifications or Delay for Treatment-Related Toxicities  |
| Section 7.6            | Anti-Emetics, Anti-diarrhea and Hematopoietic Supportive Care |
| Section 7.7            | Concomitant and Prohibited Therapy                            |
| Section 8.2.2          | Chemistry                                                     |
| Section 8.6            | Pharmacokinetic Assessments                                   |
| Section 11.1           | Screening                                                     |  
,19(67,*$7,21$/1(:'58*  
| OncoMed Pharmaceuticals, Inc.   | Tarextumab (OMP-59R5)                                                      |
|---------------------------------|----------------------------------------------------------------------------|
| Section 11.2                    | Treatment Visits                                                           |
| Section 11.2.2                  | Cycles 2-6 for Phase 1b and Cycles 2-4 for Phase 2                         |
| Section 11.2.2.1                | Day 1 (± 1 day) of Cycles 2-6 for Phase 1b and Cycles 2 -4 for Phase 2     |
| Section 11.2.2.2                | D ay 2 of Cycles 2-6 for Phase 1b and Cycles 2 -4 for Phase 2              |
| Section 11.2.2.3                | Day 3 of Cycles 2-6 for Phase 1b and Cycles 2 -4 for Phase 2               |
| Section 11.2.3                  | After Planned EP Treatment cycles                                          |
| Section 11.2.4                  | Subsequent Cycles After Completion of Planned EP Cycles                    |
| Section 11.2.4.1                | Day 1 (± 1 day) of Subsequent Cycles After Completion of Planned EP Cycles |
| Section 11.2.4.2                | Anytime between Day 3 thru Day 14 of Cycle 5 and Cycle 7                   |
| Section 11.3                    | Treatment Visits - Phase 2                                                 |
| Section 13.1.2                  | Sample Size Justification - Phase 2                                        |
| Section 13.2                    | Randomization and Blinding                                                 |
| Section 13.4.2                  | Analysis Set                                                               |
| Section 13.6.1                  | Progression Free Survival                                                  |
| Section 13.6.2                  | Response Rate (Best Overall Response)                                      |
| Section 13.6.4                  | Overall Survival                                                           |
| Section 13.9                    | Termination Criteria                                                       |
| Section 13.11                   | Data Safety Monitory Board                                                 |
| Section 13.12                   | Interim Analysis                                                           |
| Section 16.6                    | Investigational Medicinal Product Accountability                           |
| Appendix A                      | Study Schema                                                               |
| Appendix B                      | Schedule of Assessments for Subjects in Phase 1B                           |
| Notes to Appendix B  Appendix C | Schedule of Assessments for Subjects in Phase 2                            |
| Notes to Appendix C  Appendix F | Sample Informed Consent - Phase 1b                                         |
| Appendix G                      | Sample Informed Consent - Phase 2                                          |
appendix f sample informed consent
amendment 6 22 april 2016

The following changes were made to the protocol. Italics in the text indicate new text.
appendix f sample informed consent
rationale

The protocol has been amended to de-prioritize the co-primary endpoint of determining PFS benefit by adding tarextumab to EP in first-line extensive stage small cell lung cancer patients with Notch 3 expression level into secondary endpoint. In addition to assessing the treatment effect by adding tarextumab to EP in first line extensive stage small cell lung cancer patients with Notch 3 expression, the treatment effect will be also explored in subjects with Hes1, Hey2, Hey1 and Hes6 expression. The required PFS events for the different analyses have been updated and other statistical sections have been updated accordingly. Clinical background section has been updated with emerging safety information and corresponding risk section of the consent has been updated. In addition, the USAN name of tarextumab has been added throughout the protocol as appropriate.
appendix f sample informed consent
summary of changes

As a result, all the corresponding sections in the table below have been updated to reflect the changes outlined above. Additional minor changes have been made to improve clarity and consistency. Substantive new information appears in italics. This amendment represents cumulative changes to the previous amendments.  
,19(67,*$7,21$/1(:'58*  
| Synopsis Section 3.4   | Clinical Background                                |
|------------------------|----------------------------------------------------|
| Section 4.1            | Study Objectives                                   |
| Section 13.1.2         | Sample Size Justification - Phase 2                |
| Section 13.3.2         | Analysis Set                                       |
| Section 13.5           | Statistical Methods                                |
| Section 13.5.1         | Progression-Free Survival                          |
| Section 13.5.4         | Overall Survival                                   |
| Section 13.5.6         | Correlation of biomarkers with Efficacy Endpoints  |
| Section 13.11          | Analysis of PFS and OS Prior to the Final Analysis |