clinical protocol
confidential page 106 of 235

Protocol 59R5-003, Amendment 6
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,19(67,*$7,21$/1(:'58* 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.  
irs) will be collected at Day 1 of Cycle 1 (pre-dose) and on Day 8 of Cycle 2 only for gene l. Only on Day 1 of Cycle 1 prior to tarextumab 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. q. After the completion of 6 cycles of EP, subjects who do not have disease progression and have not had prophylactic cranial irradiation (PCI) or whole brain radiation (WBRT) prior to study entry and are good candidates for PCI per the Investigators should receive PCI within 8 weeks after the last dose of chemotherapy at a total dose of 25 Gy in 10 fractions. Subjects who do not receive PCI within 8 weeks after the last dose of chemotherapy can have PCI later during the study as determined by the Investigator. tarextumab administration should continue at every 21-day cycle between the completion of chemotherapy and the initiation of PCI. PCI should not be initiated within 2 weeks of study drug administration and study drug will be held during the PCI treatment period. Subjects will resume tarextumab alone 14 days after completion of PCI, until disease progression or unacceptable treatment-related NOTES TO APPENDIX B: (Cont'd) k. Hair follicle mRNA expression: Predose hair samples (6 ha toxicities or withdrawal of consent (APPENDIX A). Subjects will discontinue study treatment if there is evidence of central nervous system (CNS) metastasis.  
22 April 201 6 CONFIDENTIAL
Page 107 of 235 Protocol 59R5-003, Amendment 6  
| Tarextumab (OMP-59R5)                               | Follow-Upb                                                  | Every 3  months                                  |                               |                                                      |    |              |    |    |    |    |
|-----------------------------------------------------|-------------------------------------------------------------|--------------------------------------------------|-------------------------------|------------------------------------------------------|----|--------------|----|----|----|----|
| IND No. 106826, Serial 0037                         | Terminationa                                                |                                                  |                               |                                                      |    |              |    |    |    |    |
| Treatment                                           | X                                                           | X                                                | X                             | X                                                    | X  | X            | X  | X  | Xh |    |
| SCHEDULE OF ASSESSMENTS FOR SUBJECTS IN PHASE 2     | Cycles 1-6 (every 21 days) > Cycles 7  (every 21  days)     | Day 1(± 1  day)  (Cycles 1-3  only) Post Cycle 6 | X                             | X                                                    | X  | X            | X  | X  | X  | Xh |
| Treatment Period                                    | Day 8                                                       | X                                                |                               |                                                      |    |              |    |    |    |    |
| (± 1 day) Day 2 Day 3                               |                                                             |                                                  |                               |                                                      |    |              |    |    |    |    |
| Day 1  Day-14  to -1                                |                                                             |                                                  |                               |                                                      |    |              |    |    |    |    |
| Day - 28 to - 1                                     | X X                                                         |                                                  |                               |                                                      |    |              |    |    |    |    |
| Xd                                                  |                                                             |                                                  |                               |                                                      |    |              |    |    |    |    |
| ,19(67,*$7,21$/1(:'58*                                                     | 5.3.4.2 Protocol No. 59R5-003 - Amendment 6 - 22 April 2016 | (C1/C3/C5)                                       |                               |                                                      |    |              |    |    |    |    |
| Xd                                                  | Xd                                                          | Xd                                               | Xd                            | Xd                                                   | Xd | Xh           |    |    |    |    |
| X                                                   |                                                             |                                                  |                               |                                                      |    |              |    |    |    |    |
| APPENDIX C                                          | X                                                           | X                                                | X                             | X                                                    | X  | Chemistryg X | X  | X  | X  |    |
| Screening                                           |                                                             |                                                  |                               |                                                      |    |              |    |    |    |    |
| OncoMed Pharmaceuticals, Inc.                       | X                                                           | X                                                | Weight, vital signs,  heighte | Serum pregnancy test  (childbearing potential  only) |    |              |    |    |    |    |
| Medical and oncology  history Physical examinationc | Coagulation (PT/INR,  aPTT)                                 |                                                  |                               |                                                      |    |              |    |    |    |    |
| ECOG performance  status                            | Urinalysis (dip stick  sufficient)                          |                                                  |                               |                                                      |    |              |    |    |    |    |
| Procedure                                           | Informed Consent                                            | Electrocardiogram                                | Anti-tarextumabh              |                                                      |    |              |    |    |    |    |
| Hematologyf                                         |                                                             |                                                  |                               |                                                      |    |              |    |    |    |    |  
Protocol 59R5-003, Amendment 6 22 April 201 6  
| Tarextumab (OMP-59R5)                                                | Follow-Upb                                                  | Every 3  months           | Every 6   | weekso                    |    |
|----------------------------------------------------------------------|-------------------------------------------------------------|---------------------------|-----------|---------------------------|----|
| IND No. 106826, Serial 0037                                          | X                                                           |                           |           |                           |    |
| Treatment  Terminationa                                              |                                                             |                           |           |                           |    |
| > Cycles 7  (every 21  days)                                         | Post Cycle 6                                                |                           |           |                           |    |
| APPENDIX C SCHEDULE OF ASSESSMENTS FOR SUBJECTS IN PHASE 2 (CONT'D)  | X                                                           | X                         | Xn        | X                         | X  |
| Xl Xl                                                                |                                                             |                           |           |                           |    |
| Day 1 (± 1  day)                                                     | Xn                                                          | X                         | X         |                           |    |
| X as clinically indicated                                            |                                                             |                           |           |                           |    |
| Treatment Period                                                     | (C1/C2/C3)                                                  | (C2)                      |           |                           |    |
| m X                                                                  |                                                             |                           |           |                           |    |
| (Cycles 1-3  only)                                                   |                                                             |                           |           |                           |    |
| Day 8  Day 1  (± 1  day) Day 2 Day 3  Day-14  to -1  Day - 28 to - 1 | (C1/C3)                                                     |                           |           |                           |    |
| Xl                                                                   | Xi                                                          | X                         | X         |                           |    |
| Cycles 1-6 (every 21 days)                                           | (C1/C3/C5)                                                  |                           |           |                           |    |
| Xl                                                                   | X                                                           | X                         |           |                           |    |
| (C2/C3)                                                              |                                                             |                           |           |                           |    |
| Xi                                                                   | X                                                           | X                         |           |                           |    |
| ,19(67,*$7,21$/1(:'58*                                                                      | 5.3.4.2 Protocol No. 59R5-003 - Amendment 6 - 22 April 2016 | (C1/C3/C5)                | (C3/C5)   |                           |    |
| Xn                                                                   |                                                             |                           |           |                           |    |
| Xj                                                                   | X                                                           | X                         |           |                           |    |
| Xl                                                                   | Blood for biomarkersi Xi (C1)                               |                           |           |                           |    |
| Screening                                                            | X                                                           |                           |           |                           |    |
| OncoMed Pharmaceuticals, Inc.                                        | FFPE tissuek X  Tumor biomarker testing X                   | Optional tumor biopsy m X | X         | Concomitant medications X |    |
| Contrast CT or MRI  (chest, abdomen, and                             | pelvis), brain MRI/CT                                       | with contrastn            |           |                           |    |
| Blood for pharmacogenomics                                                                      | Survival Follow-up                                          |                           |           |                           |    |
| Procedure                                                            | Pharmacokineticsl                                           | Adverse events            |           |                           |    |
| Bone Scan                                                            |                                                             |                           |           |                           |    |  
Protocol 59R5-003, Amendment 6 22 April 201 6  
| Tarextumab (OMP-59R5)                                                 | Follow-Upb                                                  | Every 3  months            |    |    |
|-----------------------------------------------------------------------|-------------------------------------------------------------|----------------------------|----|----|
| IND No. 106826, Serial 0037                                           | X                                                           |                            |    |    |
| SCHEDULE OF ASSESSMENTS FOR SUBJECTS IN PHASE 2 (CONT'D)              | Terminationa                                                |                            |    |    |
| Treatment                                                             |                                                             |                            |    |    |
| (every 21 days)                                                       | Day 1 (± 1  day)                                            |                            |    |    |
| > Cycles 7                                                            | X                                                           |                            |    |    |
| Treatment Period                                                      | Post Cycle  6                                               | Xp                         |    |    |
| (Cycles 1-3  only)                                                    |                                                             |                            |    |    |
| Day 8  Day  2 Day 3  (± 1 day)  Day 1  Day-14  to -1  Day - 28 to - 1 |                                                             |                            |    |    |
| Cycles 1-6 (every 21 days)                                            | X  X                                                        |                            |    |    |
| ,19(67,*$7,21$/1(:'58*                                                                       | 5.3.4.2 Protocol No. 59R5-003 - Amendment 6 - 22 April 2016 | Etoposide administration X | X  | X  |
| Screening                                                             |                                                             |                            |    |    |
| APPENDIX C                                                            |                                                             |                            |    |    |
| OncoMed Pharmaceuticals, Inc.                                         | Prophylactic cranial  irradiation (PCI) p                   |                            |    |    |
| Study Drug Infusion  (tarextumab or Placebo)                          |                                                             |                            |    |    |
| Subsequent anti-cancer  therapies                                     |                                                             |                            |    |    |
| Procedure                                                             | Platinum therapy  administration                            |                            |    |    |  
Protocol 59R5-003, Amendment 6
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y drug, or etoposide or platinum therapy, whichever is discontinued last, but before the initiation of a new anticancer therapy b. All Subjects will be followed for survival and subsequent anti-cancer therapy information after the treatment termination unless a subject requests to be withdrawn from study survival follow-up. Survival follow-up and subsequent anti-cancer therapy information will be collected during telephone calls, through subjects' medical records, and/or at clinic visit every 3 months until death, loss to follow-up or study termination by the sponsor. c. Full physical examination at screening and treatment termination only. At all other times, targeted physical examination, at the Investigator's discretion. 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 (serum or plasma) 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, phosphorus, 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. Serum samples will be obtained for anti-tarextumab pre-dose on Day 1 of every other cycle starting from Cycle 1, at other times as clinically indicated such as when significant toxicities occur and at the Treatment Termination visit. i. A pre-dose sample of a total of 19 mL of blood will be drawn on Day 1 of Cycle 1 (pre-dose), on Day 2 of Cycles 2 and 3, and on Day 8 of Cycles 1-3 for subjects continuing on tarextumab to evaluate changes in plasma proteins (4 mL) (e.g., EGFR, PLGF, ENA-78, etc.), CTCs (10 mL), and Notch-related gene expression of mRNA (5 mL) as described in Section 10.0. A sample will also be obtained at the time of treatment termination, unless one has been obtained during the prior 14 days. A pre-dose sample of blood will be drawn on Day 1 of Cycle 4 and 5 to explore effects of treatment on CTCs. Instructions for the collection, handling, storage, and shipment are provided in the Study Reference Binder. j. Only on Day 1 of Cycle 1 prior to tarextumab infusion from subjects who have signed separate pharmacogenomics Informed Consent Form. k. FFPE tumor specimens obtained will be collected. Notch3*, Hes1, Hey1, Hey2, and Hes6* 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, *Hes1, Hey1, Hey2, and Hes6* levels will be measured by immunohistochemistry and/or a gene expression assays. 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.l. Plasma samples will be obtained for tarextumab pharmacokinetic analysis at on Day 1 of Cycles 1 and 3, at pre-dose and 5 minutes (±2 minutes) post tarextumab infusion; Day 3 of Cycle 1 and Cycle 3 prior to etoposide administration; Day 8 of Cycle 1 and Cycle 3 when blood sample is taken for biomarker evaluation; Day 1 of every other cycle starting from Cycle 5 prior to study drug infusion and, at other times as clinically indicated such as when significant toxicities occur as well as at the time of treatment termination. On days when tarextumab and etoposide and/or platinum therapy are given together, the plasma sample should be obtained 5 minutes (±2 minutes) after the completion of the infusion of tarextumab, but prior to EP administration.  
,19(67,*$7,21$/1(:'58* NOTES TO APPENDIX C:a. Approximately 4 weeks after the last stud Protocol 59R5-003, Amendment 6 22 April 201 6  
()
,19(67,*$7,21$/1(:'58* 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. During the study, 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. p. After the completion of 6 cycles of EP, subjects who do not have disease progression and have not had prophylactic cranial irradiation (PCI) or whole brain radiation (WBRT) prior to study entry and are good candidates for PCI per the Investigators should receive PCI within 8 weeks after the last dose of chemotherapy at a total dose of 25 Gy in 10 fractions. If subjects discontinue EP with treatment-related toxicities prior to completing 6 cycles and are good candidates for PCI per the Investigators, PCI can be initiated at the time that is determined appropriated per the Investigator. Subjects who do not receive PCI within 8 weeks after the last dose of chemotherapy can have PCI later during the study as determined by the Investigator. Study drug administration (tarextumab or Placebo) should continue at every 21-day cycle between the completion of chemotherapy and the initiation of PCI. PCI should not be initiated within 2 weeks of study drug administration and study drug will be held during the PCI treatment period. Subjects will resume study drug alone (tarextumab or Placebo)
14 days after completion of PCI, until disease progression or unacceptable treatment-related toxicities or withdrawal of consent (
APPENDIX A Study Schema). Subjects will discontinue study treatment if there is evidence of central nervous system (CNS) metastasis.  
NOTES TO APPENDIX C: (Cont'd) m. Optional tumor biopsy will be done at screening, on Day 8
CONFIDENTIAL
Page 112 of 235 Protocol 59R5-003, Amendment 6
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APPENDIX D: ECOG PERFORMANCE STATUS CRITERIA  
| ECOG Performance Status Scale (Ref 12)   |                                                                                                                                                              |
|------------------------------------------|--------------------------------------------------------------------------------------------------------------------------------------------------------------|
| Grade                                    | Descriptions                                                                                                                                                 |
| 0                                        | Fully active, able to carry on all pre-disease performance without restriction.                                                                              |
| 1                                        | Restricted in physically strenuous activity, but ambulatory and able to carry out work of a  light or sedentary nature (e.g., light housework, office work). |
| 2                                        | Ambulatory and capable of all self-care, but unable to carry out any work activities. Up  and about more than 50% of waking hours.                           |
| 3                                        | Capable of only limited self-care, confined to bed or chair more than 50% of waking hours.                                                                   |
| 4                                        | Completely disabled. Cannot carry on any self-care. Totally confined to bed or chair.                                                                        |
| 5                                        | Dead                                                                                                                                                         |
appendix e recist criteria 1.1
response evaluation criteria in solid

Subjects must have measurable disease at baseline to be eligible for the Phase 2 portion of the study.  
Measurable Disease - the presence of at least one measurable lesion. If the measurable disease is restricted to a solitary lesion, its neoplastic nature should be confirmed by cytology/histology. Measurable Lesions - lesions that can be accurately measured in at least one dimension with the minimum size of:
- 10 mm by CT scan or MRI (no less than double the slice thickness and a minimum of 10 mm).  
- 10 mm caliper measurement by clinical exam (lesions which cannot be accurately measured with calipers should be recorded as non-measureable).  
- 15 mm for nodal disease in short axis - 20 mm by chest X-ray (if clearly defined and surrounded by aerated lung) - Malignant lymph node: 15 mm in short axis when assessed by CT scan (CT scan slice thickness no greater than 5 mm). At baseline and in follow-up only the short axis is to be followed.  
Non-Measurable **Lesions** - all other lesions, including small lesions (longest diameter <10 mm or pathological lymph nodes with >10 to <15 mm short axis) as well as truly non-measurable lesions. Lesions considered truly non-measurable include leptomeningeal disease, ascites, pleural/pericardial effusion, inflammatory breast disease, lymphangitic involvement of skin or lung, abdominal masses/abdominal organomegaly identified by physical examination that is not measurable by reproducible imaging techniques, and nodal disease that is 10 to <15 mm in short axis.  
Special Considerations Regarding Lesion Measurability: Bone lesions, cystic lesions, and lesions previously treated with local therapy require particular comment:
appendix e recist criteria 1.1
bone lesions

Bone scan, PET scan or plain films are not considered adequate imaging techniques to measure bone lesions. However, these techniques can be used to confirm the presence or disappearance of bone lesions. Lytic bone lesions or mixed lytic-blastic lesions, with identifiable soft tissue components, that can be evaluated by cross sectional imaging techniques such as CT or MRI can be considered as measurable lesions if the soft tissue component meets the definition of measurability described above. Blastic bone lesions are non-measurable.
appendix e recist criteria 1.1
cystic lesions

Lesions that meet the criteria for radiographically defined simple cysts should not be considered as malignant lesions (neither measurable nor non-measurable) since they are, by definition, simple cysts. 'Cystic lesions' thought to represent cystic metastases can be considered as measurable lesions, if they meet the definition of measurability described above. However, if noncystic lesions are present in the same subject, these are preferred for selection as target lesions.
appendix e recist criteria 1.1
lesions with prior local treatment

Tumor lesions situated in a previously irradiated area, or in an area subjected to other locoregional therapy, are usually not considered measurable unless there has been demonstrated progression in the lesion. Study protocols should detail the conditions under which such lesions would be considered measurable.
appendix e recist criteria 1.1
measurement of lesions

All measurements should be taken and recorded in metric notation, using calipers if clinically assessed. All baseline evaluations should be performed as closely as possible to the beginning of treatment and never more than 28 days before the beginning of the treatment.
appendix e recist criteria 1.1
methods of measurement

The same method of assessment and the same technique should be used to characterize each identified and reported lesion at baseline and at each subsequent response assessment. Imaging based evaluation should always be done rather than clinical examination unless the lesion(s) being followed cannot be imaged but are assessable by clinical examination. For the case of skin lesions, documentation by color photography, including a ruler to estimate the size of the lesion, is recommended.  
- CT is currently the best currently available and reproducible method to measure target lesions selected for response assessment. The CT scan slice thickness should be 5 mm or less. When the CT scans have a slice thickness that is greater than 5 mm, the minimum size for a measurable lesion should be twice the slice thickness. MRI is also acceptable. Please see Ref 13 for more details concerning the use of CT scan and MRI.  
- Lesions on chest X-ray are acceptable as measurable lesions when they are clearly defined and surrounded by aerated lung. However, CT is preferable.  
- Ultrasound (US) should not be used to measure tumor lesions. The utilization of endoscopy and laparoscopy for objective tumor evaluations not advised.  
- FDG-PET can be used to determine a new lesion if the lesion was absent at baseline on FDG-PET
- Tumor markers alone cannot be used to assess response. If markers are initially above the upper normal limit, they must normalize for a subject to be considered in complete response when all lesions have disappeared.  
- Cytology and histology can be used to differentiate between PR and CR in rare cases (e.g.,
after treatment to differentiate between residual benign lesions and residual malignant lesions in tumor types such as germ cell tumors).
appendix e recist criteria 1.1
baseline documentation of "target" and

- All measurable lesions up to a maximum of two lesions per organ and 5 lesions in total, representative of all involved organs should be identified as **target lesions** and recorded and measured at baseline.  
- Target lesions should be selected on the basis of their size (lesions with the longest diameter)
and be representative of all involved organs, but in addition should lend themselves accurate repeated measurements.
()  
- A sum of the longest diameter (LD) for all target lesions will be calculated and reported as the baseline sum diameters. The baseline sum diameters will be used as reference by which to characterize the objective tumor. If lymph nodes are to be included in the sum, then as noted above, only the short axis is added to the sum.  
- If a target lesion becomes too small to measure, a default value of 5 mm is assigned. If the lesion disappears, the measurement is recorded at 0 mm.  
- If extranodal target lesions fragment, the LDs of the fragmented portion are added in the sum. If targets lesions coalesce and cannot be distinguished, the LD of the coalesced lesion is added to the sum.  
- For a patient with SD or PR, a lesion which disappears and then reappears will continue to be measured and added to the sum. Response will depend upon the status of the other lesions. For a patient with CR, reappearance of a lesion is considered PD.  
- New lesions should be unequivocal and not attributable to differences in scanning technique or findings which may not be tumor. If a new lesion is equivocal, repeat scans are needed to confirm. If confirmed, PD is assessed from the date of the first scan.  
- All other lesions (or sites of disease) should be identified as **non-target lesions** and should also be recorded at baseline. Measurements of these lesions are not required, but the presence or absence of each or in rare case unequivocal progression should be noted at each subsequent response assessment.
,19(67,*$7,21$/1(:'58* ()
appendix e recist criteria 1.1
response criteria evaluation of target

| *Complete Response (CR):   | Disappearance of all target lesions. Any pathological lymph node (whether  target or non-target) must have reduction in short axis to <10 mm                                                                                                                                                                                                                                            |
|----------------------------|-----------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|
| *Partial Response (PR):    | At least a 30% decrease in the sum of the diameters of target lesions, taking as  reference the baseline sum diameters                                                                                                                                                                                                                                                                  |
| *Progressive Disease (PD): | At least a 20% increase in the sum of the diameters of target lesions, taking as  reference the smallest sum on study (this includes the baseline sum if that is the  smallest on study). In addition to the relative increase of 20%, the sum must  also demonstrate an absolute increase of at least 5 mm. The appearance of one  or more new lesions is also considered progression. |
| *Stable Disease (SD):      | Neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify  for PD, taking as reference the smallest sum diameters while on study.                                                                                                                                                                                                                               |
appendix e recist criteria 1.1
evaluation of non-target lesions

| *Complete Response (CR):                                                                                                                              | Disappearance of all non-target lesions and normalization of tumor marker level.  All lymph nodes must be non-pathological in size (i.e., <10 mm short axis)   |
|-------------------------------------------------------------------------------------------------------------------------------------------------------|----------------------------------------------------------------------------------------------------------------------------------------------------------------|
| *Non-CR/Non-PD                                                                                                                                        | Persistence of one or more non-target lesion(s) and/or maintenance of tumor  marker level above the normal limits                                              |
| *Progressive Disease (PD):                                                                                                                            | Unequivocal progression of the existing non-target lesions. The appearance of  one or more new lesions is also considered progressive disease.                 |
| (1) Although a clear progression of "non-target" lesions only is exceptional, in such circumstances, the opinion  of the Investigator should prevail. |                                                                                                                                                                |
appendix e recist criteria 1.1
evaluation of overall response

The overall response is assessed according to the following table.  
| Target lesions    | Non-Target lesions          | New Lesions   | Overall response   |
|-------------------|-----------------------------|---------------|--------------------|
| CR                | CR                          | No            | CR                 |
| CR                | Non-CR/Non-PD               | No            | PR                 |
| CR                | Not evaluated               | No            | PR                 |
| PR                | Non-PD or not all evaluated | No            | PR                 |
| SD                | Non-PD or not all evaluated | No            | SD                 |
| Not all evaluated | Non-PD                      | No            | NE                 |
| PD                | Any                         | Yes or No     | PD                 |
| Any               | PD                          | Yes or No     | PD                 |
| Any               | Any                         | Yes           | PD                 |  
()  
- Subjects with a global deterioration of health status requiring discontinuation of treatment without objective evidence of disease progression at that time should be classified as having "symptomatic deterioration". Every effort should be made to document the objective progression even after discontinuation of treatment.
- In some circumstances it may be difficult to distinguish residual disease from normal tissue.  
When the evaluation of complete response depends on this determination, it is recommended that the residual lesion be investigated (fine needle aspirate/biopsy) to confirm the complete response status. If described in the clinical protocol, FDG-PET may be used to upgrade a response to a CR in a manner similar to a biopsy in cases where a residual radiographic abnormality is thought to represent fibrosis or scarring.
appendix e recist criteria 1.1
confirmation

Confirmation of response is not required in this randomized study since the control arm serves as an appropriate means to interpret the data.
appendix e recist criteria 1.1
reporting of results

All subjects included in the study must be assessed for response to treatment, even if there are major protocol treatment deviations or if they are ineligible. Each subject will be assigned one of the following categories: 1) complete response, 2) partial response, 3) stable disease, 4) progressive disease, 5) inevaluable for response: specify reason such as early death from malignant disease, early death from toxicity, tumor assessments not repeated/incomplete, or other (specify).  
APPENDIX F: SAMPLE INFORMED CONSENT - PHASE 1B
PROTOCOL 59R5-003: A Phase 1b/2 Study of Taretumab (OMP-59R5) in Combination with Etoposide and Platinum Therapy in Subjects with Untreated Extensive Stage Small Cell Lung Cancer
appendix e recist criteria 1.1
principal investigator

Before you decide whether or not to take part in this research study, it is important for you to understand the purpose of the study, what risks may be involved, and what is expected of you during the study. Your participation in this study is entirely voluntary. If you have any questions that are not answered or if there are words that you do not understand in this consent form, your study doctor will give you more information. Once you understand the purpose of this study, and if you decide to volunteer to participate in the study, you will be asked to sign this consent form. Once you sign the consent form, you will be referred to as a "subject".
appendix e recist criteria 1.1
purpose and background

Many current cancer therapies often produce an initial reduction in tumor size but may not have long-term benefits. One possible explanation for this is the presence of a specific type of cancer cell known as a cancer stem cell. Cancer stem cells make up a small part of the tumor but are believed to be responsible for much of the growth and spread of the cancer. Cancer stem cells may also be more resistant to traditional types of therapy, such as chemotherapy and radiation therapy. The study drug, tarextumab (OMP-59R5), used in this study is experimental. That means the United States Food and Drug Administration (FDA) has not approved it for use by the general public. Tarextumab is a humanized monoclonal antibody and was developed to target cancer stem cells. Tarextumab may block the growth of cancer stem cells, the remaining tumor cells. The sponsor for this study is OncoMed Pharmaceuticals. The research study consists of two portions and you will participate in the first portion. The purpose of the first portion is to test the safety and to determine the highest tolerable dose of tarextumab, when given in combination with etoposide and cisplatin or carboplatin. Cisplatin and carboplatin both contain platinum (called platinum therapy). Cisplatin and carboplatin have similar anti-tumor activities, but with slightly different side effects. Etoposide and platinum therapy (either cisplatin or carboplatin) are a standard treatment for extensive small cell lung cancer. The purpose of the second portion is to test if tarextumab, when given in combination with etoposide and platinum therapy (cisplatin or carboplatin), is able to slow tumor growth in subjects with extensive small cell lung cancer or shrink tumors in subjects with extensive small cell lung cancer. You have been asked to participate in this research study because you have small cell lung cancer that has spread to other parts of your body and you have not been treated for this disease, and your doctor feels that etoposide and platinum therapy (cisplatin or carboplatin) in combination with tarextumab, may be a treatment option for you.  
Although tarextumab has been given to cancer patients, it has not been given in combination with etoposide and platinum therapy (cisplatin or carboplatin). It is not known if it will provide any benefit to you and may cause harmful side effects.
appendix e recist criteria 1.1
procedures

The first portion of the study will include approximately 40 subjects at about 12 centers in the United States. During the first portion of the study, initially all subjects will receive tarextumab intravenously
(through vein) on Day 1, etoposide 100mg/m2 on Days 1, 2 and 3, and cisplatin 80 mg/m2 on Day 1 of every 21-day cycle for 6 cycles. After 6 cycles, subjects will continue on tarextumab only on Day 1 of every 21-day cycle. A group of 3 to 6 subjects will be treated at each tarextumab dose with etoposide and cisplatin, until the highest tolerable dose of tarextumab is reached. Once the highest tolerable dose is determined for tarextumab in combination with etoposide and cisplatin, a group of 6 subjects will be entered into the study to receive the highest tolerable dose of tarextumab in combination with etoposide and carboplatin to confirm the tolerability of the highest tolerable dose in combination with etoposide and carboplatin. When the first portion is completed, the study will then proceed to the second portion. The study participation consists of the following periods:
- Screening - Treatment: If you participate in the first portion of the study before the highest tolerable dose is determined, you will receive tarextumab with etoposide and cisplatin for 6 cycles followed by treatment with tarextumab alone. If you are entered into the first portion of the study after the highest tolerable dose is determined, you will receive tarextumab with etoposide and carboplatin. If you participate in the second portion of the study, you may receive either tarextumab with etoposide and cisplatin or carboplatin, or Placebo with etoposide and cisplatin or carboplatin for 6 cycles followed by treatment with tarextumab alone. This period may last until you experience severe side effects or your tumor has grown or spread or you have decided to stop the treatment.  
- Treatment termination: This visit will occur approximately 4 weeks after your last dose of study drug, etoposide, or cisplatin/carboplatin, whichever you discontinue the last, but prior to the start of new anti-cancer therapy that your doctor has chosen for you.  
- Follow-up: You will be followed about every three months to check on your health status and the new type of cancer therapy you are receiving. This may be done by phone or a clinic visit.
appendix e recist criteria 1.1
screening

If you decide to be in this study and you sign this informed consent form, you will be asked to complete the procedures listed below at a screening visit within 28 days before your first dose of study drug to make sure that you are a suitable candidate. Informed Consent: You will read, confirm understanding, and sign this informed consent. No study-related tests will be performed prior to signing this informed consent form. Medical History: Your doctor and/or nurse will ask you questions about your past and current health and medication use. Physical Examination: Your doctor will examine you. Your blood pressure, temperature, heart rate, rate of breathing, height, and weight will also be measured. Electrocardiogram (ECG): You will have an ECG. An ECG traces the electrical activity of the heart. It is a non-invasive test and requires no needles. Blood and Urine Sample Collection: Blood will be taken from a vein in your arm using a needle. The blood (about 1 tablespoon) and a urine sample will be used to check your general health and, if you are a female who is able to get pregnant, to make sure that you are not pregnant. Tumor tissues: If you had your tumor tissue biopsied previously and your doctor still has some of that tissue available, you will be asked to allow your doctor to send some of that tissue for testing for this study. If you don't have previously collected tumor tissues available, your doctor will perform a biopsy at one of your tumor sites. This is a required procedure in order for you to be able to participate in the study. This will help your doctor understand the nature of your cancer and other people's small cell lung cancer and why certain people may be more likely to respond to certain treatment. If you are participating in the second portion of the study, you might not be eligible for the study if your cancer does not contain certain level of gene as determined by a OncoMed appointed laboratory. Optional tumor biopsy: You will sign a separate consent page if you agree to this procedure. If you sign this separate consent, you will be asked to get a tumor biopsy within 28 days of your first study drug administration. This will help to see certain genes and/or proteins that are involved in your cancer development have changed with the study treatment. This procedure is optional. 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 e recist criteria 1.1
treatment phase

If you are found to be eligible to participate, you will be enrolled in the study. You will be assigned to a pre-determined dose level of tarextumab. The dose levels of tarextumab that will be tested in this study will start at 5mg/kg and increase in 2.5 mg/kg increments not to exceed 15 mg/kg(if the lower doses are tolerable) administered through the vein. You will be given the following drugs every 21 days: tarextumab on Day1, etoposide 100 mg/m2 on Days 1, 2, and 3, and cisplatin 80 mg/m2 on Day 1 or carboplatin (if you are entered into the first portion of the study after the highest tolerable dose is determined) at AUC of 5 mg/mL•min - a target drug concentration in your blood that is calculated based on your gender, age, weight and kidney function. The study drug is tarextumab and will be given in "cycles." Each cycle is 3 weeks long for a total of 21 days. The first day of the first cycle will be called "Cycle 1 Day 1", followed by "Cycle 1 Day 2", and so on. Your study drug (tarextumab) 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. You will be treated with platinum therapy, cisplatin or carboplatin as determined by the Investigator prior to randomization. Cisplatin will be given through the vein for 30 minutes to 2 hours. Carboplatin will be given through the vein for 15 minutes or longer depending on your kidney function. On days when the study drug, etoposide and platinum therapy are given together, the study drug will be given first, followed by etoposide, and then cisplatin. You will receive study drug, etoposide, and platinum therapy for 6 cycles. After that, you will receive study drug only on Day 1 of each following cycle. You will receive this combination of drugs until you have experienced severe side effects, or your tumor has grown or spread or you have decided to stop your treatment. If you experience side effects that are related to one of the three drugs, you may continue the other drugs if your tumor has not grown or spread. 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. You will continue study drug treatment between the completion of 6 cycles of chemotherapy and the start of the brain radiation. The study drug will not be given within 2 weeks of the start and completion of the brain radiation and will not be given during the brain radiation. Your doctor and/or nurse will review tests and complete pre-dose procedures once you are at the clinic. If he/she feels that you are in a good health, you will be receiving study drug, etoposide and platinum therapy. During each visit, your doctor will also review any changes in the medications you have been taking or any changes in your health since the previous visit.
appendix e recist criteria 1.1
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 (tarextumab) and/or proteins against tarextumab in your body:  
This is the first day of study treatment (Cycle 1 Day 1).You will receive study drug, etoposide, and platinum therapy on this day. You will have the following procedures done during this visit:  
- 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 - Additional Blood Sample Collection before dosing - about 2 tablespoons of blood to assess the level of certain markers and proteins that might be against tarextumab
- 1 teaspoon of blood taken before starting study drug dosing to check the level of tarextumab 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 platinum therapy.
You will have your blood drawn 1 more time about 5 minutes after completing study drug dosing but before the start of etoposide and platinum therapy treatment. About 1 teaspoon of blood will be collected to measure the amount of tarextumab in your blood.  
You will receive etoposide treatment only on this day. Before your etoposide treatment, the following procedures will be done:  
- Your blood pressure, temperature, heart rate, rate of breathing, and weight will be measured
- 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 receive etoposide treatment only on this day. Before your etoposide treatment, the following procedures will be done:  
- Your blood pressure, temperature, heart rate, rate of breathing, and weight will be measured
- You will also have 1 teaspoon of blood taken before starting etoposide to measure the amount of tarextumab in your blood.  
- 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.
- About 3 tablespoons of blood sample will be taken to check the level of certain markers, the level of tarextumab in the blood and your health status
- 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 receive study drug, etoposide, and platinum therapy on this day. The following procedures will be done prior to study drug dosing:  
- Physical Examination: only if you report changes in your health or how you feel
- Your blood pressure, temperature, heart rate, rate of breathing, and weight will be measured.  
- About 1 tablespoon of blood will be taken to review your health condition. - Urine Sample Collection. - Electrocardiogram (ECG).  
- 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 receive etoposide treatment only on this day. Before your etoposide treatment, the following procedures will be done:  
- Your blood pressure, temperature, heart rate, rate of breathing, and weight will be measured
- About 2 tablespoons of blood will be taken to assess the level of certain markers.  
- 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 receive etoposide treatment only on this day. Before your etoposide treatment, the following procedures will be done:  
- Your blood pressure, temperature, heart rate, rate of breathing, and weight will be measured
- 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.
- About 3 tablespoons of blood will be taken to check the level of certain markers and your health status.  
- Hair follicles: Six hairs will be plucked from your head for additional marker testing. 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.  
- Optional Tumor Biopsy, if you agree to this procedure. If your doctor feels this is not a good time to have the biopsy, your biopsy might be taken later instead
appendix e recist criteria 1.1
end of cycle 2 (about

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 may be repeated as indicated by your doctor  
You will receive study drug, etoposide, and platinum therapy on this day. The following procedures will be done prior to study drug dosing:  
- Physical Examination: only if you report changes in your health or how you feel
- Your blood pressure, temperature, heart rate, rate of breathing, and weight will be measured.  
- Blood Sample Collection (about 2 tablespoons to check your health condition and to measure the level of tarextumab in your blood and proteins that might be against tarextumab.  
- Urine Sample Collection before dosing
- Electrocardiogram (ECG) before dosing
- You will also have your blood drawn 1 more time about 5 minutes after completing study drug dosing but before the start of etoposide and platinum therapy. About 1 teaspoon of blood will be collected to measure the amount of tarextumab in your blood.  
- 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 receive etoposide treatment only on this day. Before your etoposide treatment, the following procedures will be done:
- Your blood pressure, temperature, heart rate, rate of breathing, and weight will be measured
- About 2 tablespoons of blood will be taken to assess the level of certain markers. - 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 receive etoposide treatment only on this day. Before your etoposide treatment, the following procedures will be done:
- Your blood pressure, temperature, heart rate, rate of breathing, and weight will be measured.  
- You will also have 1 teaspoon of blood drawn before starting etoposide to measure the amount of tarextumab in your blood.  
- 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.  
- About 3 tablespoon of blood to check the level of certain markers and your health status.  
- You will also have 1 teaspoon of blood drawn before starting etoposide to measure the amount of tarextumab in your blood.  
- 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.
appendix e recist criteria 1.1
cycles 4-6 day 1

You will receive study drug, etoposide, and platinum therapy on this day. The following procedures will be done prior to study drug dosing:
- Physical Examination: only if you report changes in your health or how you feel
- Your blood pressure, temperature, heart rate, rate of breathing, and weight will be measured
- Blood Sample Collection (about 1 tablespoon) to check your health condition.  
- About 1 tablespoon of blood sample will be taken to check the level of certain markers at Cycles 4 and 5 only
- About 1 tablespoon of blood will also be taken to check proteins that might be against tarextumab and to measure the level of tarextumab in the blood. This sample will be collected at Cycle 4 only if you are participating in the first portion of the study and at Cycle 3 and 5 if you are participating in the second portion of the study
- Urine Sample Collection
- Electrocardiogram (ECG) before dosing - You will also have your blood drawn 1 more time about 5 minutes after completing study drug dosing but before the start of etoposide and cisplatin or carboplatin treatment at Cycle 3. 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.  
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 may be repeated as indicated by your doctor.
appendix e recist criteria 1.1
cycles 4-6 day 2

You will receive etoposide treatment only on Day 2. Before your etoposide treatment, the following procedures will be done:
- Your blood pressure, temperature, heart rate, rate of breathing, and weight will be measured
- 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.
appendix e recist criteria 1.1
cycles 4-6 day 3

You will receive etoposide treatment only on Day 3. Before your etoposide treatment, the following procedures will be done:
- Your blood pressure, temperature, heart rate, rate of breathing, and weight will be measured - 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 have 1 teaspoon of blood drawn to measure the amount of tarextumab in your blood at Cycle 3.
appendix e recist criteria 1.1
end of cycle 6

- 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 may be repeated as indicated by your doctor
- 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 e recist criteria 1.1
cycle 7 and beyond

Starting at cycle 7, you will receive study drug on Day 1 of each cycle only. The following procedures will be performed on Day 1 of Cycle 7 and every cycle thereafter.  
- Physical Examination before dosing: only if you report changes in your health or how you feel
- Your blood pressure, temperature, heart rate, rate of breathing, and weight will be measured
- Blood Sample Collection before dosing (about 1 tablespoon) to check your health condition.  
- Blood sample collection before dosing (about 1 teaspoon) to check proteins that might be against tarextumab. This sample will be collected at Cycle 7 and every 3rd cycle thereafter
(e.g. Cycle 10, Cycle 13, etc).  
- Urine Sample Collection before dosing
- 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.  
- 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, bone scan will be done at every other tumor assessment (approximately every 12 weeks after initial study drug dosing).
appendix e recist criteria 1.1
treatment termination

You will be asked to return to complete the procedures listed below at the termination visit if you will no longer be continuing on study drug, etoposide, or cisplatin/carboplatin. This visit will be done about 4 weeks after your last dose of study, etoposide, or cisplatin/carboplatin whichever is discontinued last.  
- Physical Examination
- Your blood pressure, temperature, heart rate, rate of breathing, and weight will be measured
- Electrocardiogram (ECG)
- Urine Sample Collection
- Blood Sample Collection - about 3 tablespoons of blood to check your health condition and to check the level of certain markers, proteins that might be against tarextumab, and the level of OMP59R5 in the blood
- 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
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. Optional Tumor Biopsy: An optional tumor biopsy will be done only if you agree.
appendix e recist criteria 1.1
follow up

After you stopped study drug and your tumor has not grown, a tumor assessment (CT or MRI approximately every 6 weeks and bone scan approximately every 12 weeks) will be done until your tumor has grown.  
After you have stopped receiving study drug, the study staff will call you about every 3 months after your last clinic visit to follow your health status. If necessary, your doctor may be contacted by OncoMed or OncoMed's designee to obtain this information. If you withdraw from the study treatment but not from study follow-up, the study staff will still contact you about every 3 months after your last visit to check on your health status, or the study staff may use a public information (like county records) to obtain information about your survival status only, which will be reported to OncoMed as part of the data for the study.
appendix e recist criteria 1.1
tarextumab

As of *November 17, 2015*, tarextumab *or placebo* has been tested in 356 subjects who have cancer; The following side effects have been noted in subjects receiving tarextumab *or placebo* and were considered possibly related to tarextumab *or placebo* treatment: Common one (occurred in >10% of the subjects who used the drug):
- Diarrhea  
- Fatigue-tiredness
- Nausea
- Decreased appetite
- Vomiting
- Low red blood counts that might make you feel tired,
- Low blood counts that might make you easy to be bruised
- *Low blood count that might make you easier to get infection*
Less Common (occurring in 5% to 10% of subjects who used the drug):
- *Hands/feet swollen*  
- Low potassium level
- *Hair loss*
- *Nose bleeding*
- Redness of skin and/or rashes/hives
- Dehydration
- Change in taste
Most of the above-mentioned side effects were mild and moderate. Diarrhea was the most common side effect and can be severe if it is not treated immediately. You will be given some medications after your first dose of tarextumab to take home to treat diarrhea. In addition, you will be advised to drink enough fluid and eat a balanced diet to avoid the dehydration and imbalanced electrolytes. Tarextumab will be given as an intravenous infusion. There may be minor discomfort from the needle in your arm. Bruising, swelling, and, in rare instances, infection and blood clot may occur at the infusion site. Tarextumab is a monoclonal antibody. There is the possibility of a reaction to the monoclonal antibody as it is being infused (given) through your vein; these are called infusion reactions. Symptoms can include fever, chills, rash, and/or hives, changes in blood pressure, temperature and heart rate. As of November 17, 2015, twelve of 356 subjects who have been given tarextumab *or placebo* have experienced infusion reactions; all of these infusion reactions were mild or moderate. You will be watched carefully during the infusion and after the completion of the infusion. If you do have a reaction to the study drug, your study doctor may need to give the study drug at a slower rate (over a longer period of time) and /or give you some medications to prevent the reaction. If after slowing the rate of infusion and giving you some medications to prevent the infusion reaction, you continue to have infusion reactions, you may need to stop taking tarextumab. During the course of this study, your blood will be drawn for laboratory tests (1-3 tablespoons will be collected at each blood draw). The risks of drawing blood include some discomfort from the needle in your arm, bruising, swelling at the needle site and, in rare instances, infection or fainting. You should discuss the risk and side effects with your study doctor. There may be other side effects that we cannot predict. You will be informed of any new significant side effects that develop during the course of this research study, or others regarding the use of tarextumab.  
There may be side effects that we cannot predict and in some cases they may be serious, longlasting, or fatal.
appendix e recist criteria 1.1
etoposide

The following side effects have been noted in subjects receiving etoposide: Common one (occurred in > 10% of the subjects who used this drug)  
- Low blood counts: Your white and red blood cells and platelets may temporarily decrease. This may put you at an increased risk for infection, anemia, and/or bleeding
- Nausea - Vomiting
- Feeling weak and low energy  
- Chills
- Fever
- Hair loss
- Poor appetite  
- Sores, ulcers, or white spots on the lips or in the mouth
Less common (occurred in 5 to 10% of the subjects who used this drug)
- Diarrhea - Constipation  
- Taste alteration
- Abdominal pain  
- Dizziness - Injection site inflammation or vein inflammation
Rarely (occurred in < 5% of the subjects who used this drug)  
- Increased or decreased blood pressure
- Allergic reaction: This medicine may cause a serious type of allergic reaction called anaphylaxis that is presented with symptoms such as chills, fever, fast heartbeat, sudden constriction of airway, shortness of breath, excessive sweating, itchiness of the skin or rash, change in blood pressure, and loss of consciousness, etc . Anaphylaxis can be lifethreatening and requires immediate medical attention. Tell your doctor or nurse right away if you have chills; fever; lightheadedness, dizziness, or fainting; fast, pounding heartbeat; swelling of the face, tongue, and throat; or trouble with breathing after you receive the medicine
Other side effects may occur following the administration of etoposide. Your doctor will further explain the side effects of etoposide.
appendix e recist criteria 1.1
cisplatin

The following side effects have been noted in subjects receiving cisplatin: Common one (occurred in > 10% of the subjects who used this drug)  
- Low blood counts: Your white and red blood cells and platelets may temporarily decrease. This may put you at an increased risk for infection, anemia, and/or bleeding
- Nausea
- Vomiting
- Ringing in the ears or Hearing loss - Impairment of kidney function and damages to kidney
- Changes in how food tastes
- Diarrhea
- Damages to nerve that causes pain, numbness, tingling of hands and feet, and sometimes even have the difficulty in motion
- Hair loss
- Imbalance of electrolyte - Extreme fatigue
- Mild elevation of liver enzymes
Less common or rare (occurred in  10% of the subjects who used this drug)  
- Change in vision or inflammation of optic nerve and blindness
- Injection site inflammation or vein inflammation
- Change in blood vessels that trigger heart attack and heart problem, stroke or brain injury
- Allergic reaction: This medicine may cause a serious type of allergic reaction called anaphylaxis that is presented with symptoms such as chills, fever, fast heartbeat, sudden constriction of airway, shortness of breath, excessive sweating, itchiness of the skin or rash, change in blood pressure, and loss of consciousness, etc . Anaphylaxis can be lifethreatening and requires immediate medical attention. Tell your doctor or nurse right away if you have chills; fever; lightheadedness, dizziness, or fainting; fast, pounding heartbeat; swelling of the face, tongue, and throat; or trouble with breathing after you receive the medicine
Other side effects may occur following the administration of cisplatin. The side effects are generally reversible and gradually disappears when treatment ends. However, some side effects might take a long time to disappear. Your doctor will further explain the side effects of cisplatin.
appendix e recist criteria 1.1
carboplatin

The following side effects have been noted in subjects receiving carboplatin: Common ones (occurred in >10% of the subjects who used this drug)  
- Low blood counts: Your white and red blood cells and platelets may temporarily decrease. This may put you at an increased risk for infection, anemia, and/or bleeding
- Nausea
- Vomiting
- Damages to nerve that causes pain, numbness, tingling of hands and feet, and sometimes even have the difficulty in motion
- Ringing in the ears or hearing loss
- Hair loss - Imbalance of electrolytes
- Extreme fatigue - Elevation of liver enzymes
- Pain
- Allergic reaction
- Muscle weakness
Less common or rare (occurred in 10% of the subjects who used this drug)
- Sores, ulcers, or white spots on the lips or in the mouth  
- Loss of vision for light or color
- Impairment of kidney function and damages to kidney. Your carboplatin dose will be modified if you have impairment of kidney function
appendix e recist criteria 1.1
19(67721/1('58

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Other side effects may occur following the administration of carboplatin. The side effects are generally reversible and gradually disappears when treatment ends. However, some side effects might take a long time to disappear. Your doctor will further explain the side effects of carboplatin
appendix e recist criteria 1.1
pregnancy

There is a very high risk that tarextumab may be harmful to an unborn baby (embryo or fetus) or newborn child. Therefore, women who are pregnant or breastfeeding may not participate in this study. Women must have a negative pregnancy test before beginning the study. It is important that both men and women take steps to prevent pregnancy during this study through the use of adequate contraception (for example, a barrier or hormone method or abstinence) 30 days prior to first study drug administration and for the duration of the study until 30 days after the last dose of study drug or etoposide or cisplatin whichever is discontinued last. If you become pregnant or suspect that you are pregnant, or if your partner becomes pregnant or suspects that she is pregnant during the study or within 30 days after the last dose of study drug or etoposide or cisplatin whichever is discontinued last, you must notify the study Investigator immediately. If you become pregnant, you will be taken off of treatment and will undergo assessments listed under the Treatment Termination Section of this document, except for the radiographic studies, which will not be performed. If your partner becomes pregnant, you will remain on the study. 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 e recist criteria 1.1
potential benefits

There is no guarantee that there will be any direct benefit to you if you take part in this research study. The treatments you receive may be harmful. It is possible that the information learned from this study may be helpful in the future to other people with cancer.
appendix e recist criteria 1.1
significant new findings

Any significant new findings regarding tarextumab that become known during the course of this research study, which might reasonably affect your willingness to participate in this study, will be provided to you. If you decide not to participate in this study, you will continue to receive medical care to which you were entitled prior to your participation in this study. Your doctor will discuss other options available to you. Your choice not to participate in this study will not affect your medical care in any way.
appendix e recist criteria 1.1
termination of subject participation

Your participation in this research study may be terminated at any time for medical reasons or because the sponsor finds it necessary to limit or terminate this clinical trial. Some reasons for termination include progression of your disease, any other illness that prevents further administration of study drug, unacceptable adverse events, general or specific changes in your condition that make further treatment unacceptable in the opinion of your doctor, and protocol non-compliance. Your doctor may decide to hold or stop the study drug infusions at any time during the study for safety reasons. If your doctor or the sponsor decides to withdraw you from the study, you will undergo the same assessments listed under **Treatment Termination**.
appendix e recist criteria 1.1
costs and compensation

The cost of all "standard of care" assessments related to your participation in this study and your medical care will be billed to you and/or your insurance company. These are tests that would normally be performed in *subject*s to evaluate their cancer. Due to the investigational nature of this research study, insurance companies or government health care programs may limit their obligation to pay for experimental treatments and their consequences. You may want to discuss this with your insurance company before agreeing to participate. The cost of all non-standard of care assessments will be paid for by OncoMed.  
You will not be paid for participation in this study.
appendix e recist criteria 1.1
compensation for research-related injury

If you are physically injured as a direct result of study drug or study procedure properly performed under the plan for this study and it is not due to a pre-existing medical condition or underlying disease, OncoMed will reimburse you for the reasonable medical expenses for the treatment of that injury which are not covered by another payer, your own insurance or health care program. No other compensation is available from OncoMed if any injury occurs.
appendix e recist criteria 1.1
confidentiality

Every effort will be made to keep your medical information confidential (secret). You will be identified by a code and no information that identifies you will be released without your written permission, except as required by law. To the extent permitted by law and by signing the consent form, you allow access by representatives of the Food and Drug Administration (FDA), other regulatory bodies, Institutional Review Boards, Independent Ethics Committees, and OncoMed monitors/representatives and collaborators to inspect your research and medical records without removal of identifying information, such as your name, initials, date of birth, sex, race, and location of the research study. If information from this study is presented publicly or published in a medical journal, you will not be identified by name, picture, or by any other personally identifying information. You will be asked to review and sign a HIPAA (Health Insurance Portability and Accountability Act) Research Authorization Form requesting your authorization to collect, use, and disclose your medical information,
appendix e recist criteria 1.1
or if site does not

I authorize (give permission to) insert name of study site to use and disclose (share) my health information solely for the purposes of this research study and research directly related to the use of tarextumab. I understand that my health information that I am authorizing to be used and disclosed (Authorized Health Information) includes all health information about me that has been and will be created or received by (SITE) and that is in my medical records maintained by (SITE). I understand that I am free at any time to restrict the (Site's) use and disclosure of my Authorized Health Information, without penalty or other consequences. However, I also understand that I
may be denied participation in, or continued participation in, this research study if at any time I
choose to restrict the (Site's) use and disclosure of Authorized Health Information that is necessary for the completion of this research study.
appendix e recist criteria 1.1
authorized persons and recipients

I authorize the following person(s) and groups of persons to request, receive, and use my Authorized Health Information: representatives of the FDA, other regulatory authorities, the Institutional Review Board/Independent Ethics Committee, OncoMed representatives and monitors, and OncoMed collaborators and licensees. I authorize (SITE) to disclose my Authorized Health Information to these persons and groups or persons.
appendix e recist criteria 1.1
re-disclosures to third parties

I understand that once (Site) discloses my Authorized Health Information to the recipient(s)
identified in the previous section Authorized Persons and Recipients, (Site) cannot guarantee that the recipient(s) will not re-disclose my Authorized Health Information to other persons who may not be bound by this informed consent form.
appendix e recist criteria 1.1
expiration date

My authorization (permission) to use and disclose my Authorized Health Information will continue indefinitely, but that use and sharing will only be for the purposes described in the informed consent form.
appendix e recist criteria 1.1
effect of my revocation of

I understand that my authorization for (site) to use and disclose my Authorized Health Information will remain in effect until I withdraw my permission by sending my written notice of revocation (withdrawal of permission) to the Privacy Office listed in the Questions section of the following page. My written revocation will be effective immediately upon (Site's) receipt of my written notice, except that the revocation will not have any effect on any actions taken by (SITE) in relying on this authorization before it received my written notice of withdrawal of permission.
appendix e recist criteria 1.1
questions

If you have any question about the study and/or its procedure or safety, you may contact Dr. (Name of Investigator) at (telephone number). In the event of any injury, you may contact Dr. (name) at (telephone number). You may also call (Name) at (telephone number) for information on experimental subjects' rights. If at any time during this research study you feel that you have not been adequately informed of your rights with respect to the privacy of your health information, or you feel that the privacy of your health information has not been adequately protected, you may contact or visit (Site's) privacy office during normal working hours at (Privacy Office name) at (telephone number and address).
appendix e recist criteria 1.1
voluntary participation and documentation of

Your decision to participate in this study is entirely voluntary. You may refuse to participate in or withdraw from the study at any time without prejudice or loss of benefits to which you are otherwise entitled. A signed copy of this consent form will be given to you for your records and a copy will be retained by the Investigator for his or her files
,19(67,*$7,21$/1(:'58* ()
By signing the form below, you have read the above information about this research study, and have had a chance to ask questions to help you understand your participation in this study and how your information will be used.  
,19(67,*$7,21$/1(:'58* ()
CONSENT FOR OPTIONAL TUMOR BIOPSY
_______ _________If you give your consent for a punch biopsy of your tumor Initials **Date lesion, please check the box and write your initials and the date in** the space provided.  
_______ _________If you do not give your consent for a punch biopsy of your Initials Date tumor lesion, please check the box and write your initials and the date in the space provided.  
Printed Name of Subject or Subject's Authorized Representative Signature of Subject or Subject's Authorized Representative Date Printed Name of Person Obtaining Informed Consent __________________________________________________________ ____________ Signature of Person Obtaining Informed Consent Date Printed Name of Witness* Signature of Witness* Date
*If the Principal Investigator or Institutional Review Board deems a witness signature is necessary
,19(67,*$7,21$/1(:'58* ()  
Your decision to participate in this study is entirely voluntary. You may refuse to participate in or withdraw from the study at any time without prejudice or loss of benefits to which you are otherwise entitled. A signed copy of this consent form will be given to you for your records and a copy will be retained by the Investigator for his or her files. By signing the form below, you acknowledge that you have read the above information about this research study, and have had a chance to ask questions to help you understand your participation in this study and how your information will be used.  
Signature of Subject or Subject's Authorized Representative Date Printed Name of Person Obtaining Informed Consent Signature of Person Obtaining Informed Consent Date Printed Name of Witness* Signature of Witness* Date
*If the Principal Investigator or Institutional Review Board deems a witness signature is necessary.
appendix e recist criteria 1.1
appendix g sample informed consent

PROTOCOL 59R5-003: A Phase 1b/2 Study of Tarextumab (OMP-59R5) in Combination with Etoposide and Platinum Therapy in Subjects with Untreated Extensive Stage Small Cell Lung Cancer Principal Investigator: _____________________________________________ Before you decide whether or not to take part in this research study, it is important for you to understand the purpose of the study, what risks may be involved, and what is expected of you during the study. Your participation in this study is entirely voluntary. If you have any questions that are not answered or if there are words that you do not understand in this consent form, your study doctor will give you more information. Once you understand the purpose of this study, and if you decide to volunteer to participate in the study, you will be asked to sign this consent form. Once you sign the consent form, you will be referred to as a "subject".
appendix e recist criteria 1.1
purpose and background

Many current cancer therapies often produce an initial reduction in tumor size but may not have long-term benefits. One possible explanation for this is the presence of a specific type of cancer cell known as a cancer stem cell. Cancer stem cells make up a small part of the tumor but are believed to be responsible for much of the growth and spread of the cancer. Cancer stem cells may also be more resistant to traditional types of therapy, such as chemotherapy and radiation therapy. The study drug, tarextumab, used in this study is experimental. That means the United States Food and Drug Administration (FDA) has not approved it for use by the general public. tarextumab is a humanized monoclonal antibody and was developed to target cancer stem cells. tarextumab may block the growth of cancer stem cells, the remaining tumor cells. The sponsor for this study is OncoMed Pharmaceuticals. The research study consists of two portions and you will participate in the second portion. The purpose of the first portion is to test the safety and to determine the highest tolerable dose of tarextumab, when given in combination with etoposide and cisplatin or carboplatin. The purpose of the second portion is to test if tarextumab, when given in combination with etoposide and platinum therapy (cisplatin or carboplatin), is able to slow tumor growth in subjects with extensive small cell lung cancer or shrink tumors in subjects with extensive small cell lung cancer. You have been asked to participate in this research study because you have small cell lung cancer that has spread to other parts of your body and you have not been treated for this disease, and your doctor feels that etoposide and platinum therapy (cisplatin or carboplatin) in combination with tarextumab may be a treatment option for you.  
Although tarextumab has been given to cancer patients, it has not been given in combination with etoposide and platinum therapy (cisplatin or carboplatin). It is not known if it will provide any benefit to you and may cause harmful side effects. In one other study with tarextumab in subjects with cancer of the pancreas (also known as the ALPINE study), a group of independent physicians and statisticians called a "Data Safety Monitoring Board" or DSMB who are responsible for monitoring the safety and efficacy of clinical studies, reviewed the data and made recommendations to OncoMed, the Sponsor of the study, about the pancreatic cancer study. While they did not see unexpected safety findings (sideeffects) between the patients on the study who received tarextumab and placebo, they reported that on average patients treated with tarextumab had a lower chance of their tumors shrinking than those treated with placebo. Also, patients who received tarextumab had their cancer under control for a shorter period of time.Patients treated with tarextumab on the pancreatic cancer study may not seem to be living as long as those treated with placebo. The cancer type that you have is called small cell lung cancer and it is very different from pancreatic cancer. Also, the chemotherapy that you are receiving is very different from the chemotherapy used in the pancreatic cancer study. The PINNACLE study also has a DSMB that has been meeting since the start of this study, consisting of 3 lung cancer doctors and one statistician. This group reviews the data from the clinical study at least 4 times a year. If the DSMB informs OncoMed of any new information regarding the safety of tarextumab on the PINNACLE you and your doctor will be informed immediately.
appendix e recist criteria 1.1
procedures

The second portion of the study will include approximately 135 subjects at about 50 centers in the United States. Your study doctor will determine the type of platinum therapy (cisplatin or carboplatin) you will receive. You will then be randomly assigned (by chance) to one of two treatment arms: Subjects in one arm will receive etoposide and platinum therapy (cisplatin or carboplatin) plus tarextumab. Subjects in the other arm will receive etoposide and platinum therapy (cisplatin or carboplatin) plus Placebo (an inactive substance that looks like tarextumab). The choice of platinum therapy (cisplatin or carboplatin) you will receive will not change during the study once it is selected by your doctor. After 6cycles of treatment, you will continue on tarextumab or Placebo on Day 1 of every 21-day cycle. If you discontinue etoposide and platinum therapy prior to 6 cycles because of side effects, you will still be allowed to stay on the study and receive tarextumab or Placebo. Your chance of being randomized to one of the treatment arms is 50%. Neither you nor your doctor will know whether you are receiving tarextumab or Placebo. Both tarextumab and Placebo are considered "study drug".  
The study participation consists of the following periods:  
- Screening - Treatment: You may receive either tarextumab with etoposide and platinum therapy
(cisplatin or carboplatin), or Placebo with etoposide and platinum therapy (cisplatin or carboplatin) for6 cycles followed by treatment with tarextumab or Placebo alone. This treatment period may last until you experience severe side effects or your tumor has grown or spread or you have decided to stop the treatment.  
- Treatment termination: This visit will occur approximately 4 weeks after your last dose of study drug, etoposide, or platinum therapy (cisplatin or carboplatin), whichever you discontinue the last, but prior to the start of new anti-cancer therapy that your doctor has chosen for you.  
- Follow-up: You will be followed about every three months to check on your health status and the new type of cancer therapy you are receiving. This may be done by phone or a clinic visit.
appendix e recist criteria 1.1
screening

If you decide to be in this study and you sign this informed consent form, you will be asked to complete the procedures listed below at a screening visit within 28 days before your first dose of study drug to make sure that you are a suitable candidate. Informed Consent: You will read, confirm understanding, and sign this informed consent. No study-related tests will be performed prior to signing this informed consent form. Medical History: Your doctor and/or nurse will ask you questions about your past and current health and medication use. Physical Examination: Your doctor will examine you. Your blood pressure, temperature, heart rate, rate of breathing, height, and weight will also be measured. Electrocardiogram (ECG): You will have an ECG. An ECG traces the electrical activity of the heart. It is a non-invasive test and requires no needles. Blood and Urine Sample Collection: Blood will be taken from a vein in your arm using a needle. The blood (about 1 tablespoon) and a urine sample will be used to check your general health and, if you are a female who is able to get pregnant, to make sure that you are not pregnant. Tumor tissues: If you had your tumor tissue biopsied previously and your doctor still has some of that tissue available, you will be asked to allow your doctor to send some of that tissue for testing for this study. If you don't have previously collected tumor tissues available, your doctor will perform a biopsy at one of your tumor sites. This is a required procedure in order for you to be able to participate in the study. This will help your doctor understand the nature of your cancer and other people's small cell lung cancer and why certain people may be more likely to respond to certain treatment. Optional tumor biopsy: You will be asked to sign a separate consent page if you agree to this procedure. If you sign this separate consent, you will be asked to get a tumor biopsy within 28 days of your first study drug administration. This will help to see certain genes and/or proteins that are involved in your cancer development have changed with the study treatment. This procedure is optional. 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 e recist criteria 1.1
treatment phase

If you are found to be eligible to participate, you will be enrolled in the study. You will be randomly (by chance) assigned to one of the two treatment arms, where you will either receive etoposide and platinum therapy (cisplatin or carboplatin) plus tarextumab or etoposide and platinum therapy (cisplatin or carboplatin) plus Placebo (an inactive substance that looks like tarextumab). Your study doctor will determine the type of platinum therapy (cisplatin or carboplatin) you will receive. Then you will be randomized to receive either tarextumab or Placebo. Your chance of being randomized to each of the treatment arm is 50%. Neither you nor your doctor will know whether you are receiving tarextumab or Placebo. The choice of platinum therapy (cisplatin or carboplatin) you will receive will not change during the study once it is selected by your study doctor. The study drug is either tarextumab or Placebo (an inactive substance that looks like tarextumab) and will be given in "cycles." Each cycle is 3 weeks long for a total of 21 days. The first day of the first cycle will be called "Cycle 1 Day 1", followed by "Cycle 1 Day 2", and so on. Your study drug (tarextumab or Placebo) will be given through the vein for 90 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.  
You will be treated with platinum therapy (cisplatin or carboplatin) as determined by your study doctor prior to randomization. Cisplatin will be given through the vein for 30 minutes to 2 hours. Carboplatin will be given through the vein for 15 minutes or longer depending on your kidney function. On days when the study drug, etoposide and platinum therapy (cisplatin or carboplatin) are given together, the study drug will be given first, followed by etoposide, and then cisplatin. You will receive study drug, etoposide, and platinum therapy (cisplatin or carboplatin) for 6 cycles. After that, you will receive study drug only on Day 1 of each following cycle. If you discontinue platinum therapy prior to 6 cycles because of side effects, you will still be allowed to stay on the study and receive study drug. You will receive this combination of drugs until you have experienced severe side effects, or your tumor has grown or spread or you have decided to stop your treatment. If you experience side effects that are related to one of the three drugs, you may continue the other drugs if your tumor has not grown or spread. If your disease is at least stable or has responded to therapy at the end of cycle 6 and your doctor thinks 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. You will continue study drug treatment between the completion of 4 cycles of chemotherapy and the start of the brain radiation. The study drug will not be given within 2 weeks of the start and completion of the brain radiation and will not be given during the brain radiation. Your doctor and/or nurse will review tests and complete pre-dose procedures once you are at the clinic. If he/she feels that you are in a good health, you will be receiving study drug, etoposide and platinum therapy (cisplatin or carboplatin).  
During each visit, your doctor will also review any changes in the medications you have been taking or any changes in your health since the previous visit.  
This is the first day of study treatment (Cycle 1 Day 1).You will receive study drug, etoposide, and platinum therapy (cisplatin or carboplatin) on this day. You will have the following procedures done during this visit:  
- 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 to check your health condition (if this was done more than 7 days ago)
- Weight before dosing - Additional Blood Sample Collection before dosing - about 2 tablespoons of blood to assess the level of certain markers and proteins that might be against tarextumab
- You will also have about 1 teaspoon of blood taken before starting study drug dosing to check the level of tarextumab 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 platinum therapy (cisplatin or carboplatin).  
- You will have your blood drawn 1 more time about 5 minutes after completing study drug dosing but before the start of etoposide and platinum therapy (cisplatin or carboplatin) treatment. About 1 teaspoon of blood will be collected to measure the amount of tarextumab in your blood.
You will receive etoposide treatment only on this day. Before your etoposide treatment, the following procedures will be done:  
- Your blood pressure, temperature, heart rate, rate of breathing, and weight will be measured
- 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 receive etoposide treatment only on this day. Before your etoposide treatment, the following procedures will be done:  
- Your blood pressure, temperature, heart rate, rate of breathing, and weight will be measured
- You will also have 1 teaspoon of blood taken before starting etoposide to measure the amount of tarextumab in your blood.  
- 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.
- About 3 tablespoons of blood sample will be taken to check the level of certain markers, the level of tarextumab in the blood and your health status
- 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 receive study drug, etoposide, and platinum therapy (cisplatin or carboplatin) on this day. The following procedures will be done prior to study drug dosing:  
- Physical Examination: only if you report changes in your health or how you feel
- Your blood pressure, temperature, heart rate, rate of breathing, and weight will be measured.  
- About 1 tablespoon of blood will be taken to review your health condition.  
- Urine Sample Collection.  
- Electrocardiogram (ECG).  
- 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 receive etoposide treatment only on this day. Before your etoposide treatment, the following procedures will be done:  
- Your blood pressure, temperature, heart rate, rate of breathing, and weight will be measured
- About 2 tablespoons of blood will be taken to assess the level of certain markers.  
- 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 receive etoposide treatment only on this day. Before your etoposide treatment, the following procedures will be done:  
- Your blood pressure, temperature, heart rate, rate of breathing, and weight will be measured - 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.
- About 3 tablespoons of blood will be taken to check the level of certain markers and your health status.  
- 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.  
- Optional Tumor Biopsy, if you agree to this procedure. If your doctor feels this is not a good time to have the biopsy, your biopsy might be taken later instead
appendix e recist criteria 1.1
end of cycle 2 (about

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 may be repeated as indicated by your doctorCycle 3 Day 1 You will receive study drug, etoposide, and platinum therapy (cisplatin or carboplatin) on this day. The following procedures will be done prior to study drug dosing:  
- Physical Examination: only if you report changes in your health or how you feel
- Your blood pressure, temperature, heart rate, rate of breathing, and weight will be measured.  
- Blood Sample Collection (about 2 tablespoons to check your health condition and to measure the level of tarextumab in your blood and proteins that might be against tarextumab).  
- Urine Sample Collection before dosing
- Electrocardiogram (ECG) before dosing
- You will also have your blood drawn 1 more time about 5 minutes after completing study drug dosing but before the start of etoposide and platinum therapy (cisplatin or carboplatin). About 1 teaspoon of blood will be collected to measure the amount of tarextumab in your blood.  
- 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 receive etoposide treatment only on this day. Before your etoposide treatment, the following procedures will be done:  
- Your blood pressure, temperature, heart rate, rate of breathing, and weight will be measured
- About 2 tablespoons of blood will be taken to assess the level of certain markers.  
- 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 receive etoposide treatment only on this day. Before your etoposide treatment, the following procedures will be done:
- Your blood pressure, temperature, heart rate, rate of breathing, and weight will be measured. - You will also have 1 teaspoon of blood drawn before starting etoposide to measure the amount of tarextumab in your blood.  
- 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.  
- About 3 tablespoon of blood to check the level of certain markers and your health status.  
- You will also have 1 teaspoon of blood drawn before starting etoposide to measure the amount of tarextumab in your blood.  
- 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.
appendix e recist criteria 1.1
cycles 4-6 day 1

You will receive study drug, etoposide, and platinum therapy (cisplatin or carboplatin) on this day. The following procedures will be done prior to study drug dosing:
- Physical Examination: only if you report changes in your health or how you feel
- Your blood pressure, temperature, heart rate, rate of breathing, and weight will be measured
- Blood Sample Collection (about 1 tablespoon) to check your health condition.  
- About 1 tablespoon of blood sample will be taken to check the level of certain markers at Cycles 4 and 5 only.  
- About 1 tablespoon of blood will also be taken to check proteins that might be against tarextumab and to measure the level of tarextumab in the blood. This sample will be collected at Cycle 3 and 5
- Urine Sample Collection
- Electrocardiogram (ECG) before dosing
- 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.
appendix e recist criteria 1.1
cycles 4-6 day 2

You will receive etoposide treatment only on this day. Before your etoposide treatment, the following procedures will be done:  
- Your blood pressure, temperature, heart rate, rate of breathing, and weight will be measured - 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.
appendix e recist criteria 1.1
cycles 4-6 day 3

You will receive etoposide treatment only on this day. Before your etoposide treatment, the following procedures will be done:  
- Your blood pressure, temperature, heart rate, rate of breathing, and weight will be measured
- 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 have 1 teaspoon of blood drawn to measure the amount of tarextumab in your blood at Cycle 5
appendix e recist criteria 1.1
end of cycles 4 and

- 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 may be repeated as indicated by your doctor
appendix e recist criteria 1.1
after the completion of 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 e recist criteria 1.1
cycle 7 and beyond

Starting at Cycle 7, you will receive study drug on Day 1 of each cycle only. The following procedures will be performed on Day 1 of Cycle 7 and every cycle thereafter.  
- Physical Examination before dosing: only if you report changes in your health or how you feel
- Your blood pressure, temperature, heart rate, rate of breathing, and weight will be measured
- Blood Sample Collection before dosing (about 1 tablespoon) to check your health condition.  
- Blood sample collection before dosing (about 1 teaspoon) to check proteins that might be against tarextumab and the level of study drug in the blood. These samples will be collected at Cycle 7 and every other cycle (i.e., Cycle 7, Cycle 9, Cycle 11, etc.)
- Urine Sample Collection before dosing
- 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.  
- 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, bone scan may be repeated as indicated by your doctor.
appendix e recist criteria 1.1
treatment termination

You will be asked to return to complete the procedures listed below at the termination visit if you will no longer be continuing on study drug, etoposide, or platinum therapy (cisplatin or carboplatin). This visit will be done about 4 weeks after your last dose of study, etoposide, or platinum therapy (cisplatin or carboplatin) whichever is discontinued last.  
- Physical Examination
- Your blood pressure, temperature, heart rate, rate of breathing, and weight will be measured
- Electrocardiogram (ECG)
- Urine Sample Collection
- Blood Sample Collection - about 3 tablespoons of blood to check your health condition, to check the level of certain markers, to check for proteins that might be against tarextumab, and to check the level of OMP59R5 in the blood
- 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
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. Optional Tumor Biopsy: An optional tumor biopsy will be done only if you agree.
appendix e recist criteria 1.1
follow up

After you have stopped receiving study drug and your tumor has not grown, a tumor assessment
(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, bone scan may be repeated as indicated by your doctor) will be done until your tumor has grown. After you have stopped receiving study drug, the study staff will call you about every 3 months after your last clinic visit to follow your health status. If necessary, your doctor may be contacted by OncoMed or OncoMed's designee to obtain this information. If you withdraw from the study treatment but not from study follow-up, the study staff will still contact you about every 3 months after your last visit to check on your health status, or the study staff may use public information (like county records) to obtain information about your survival status only, which will be reported to OncoMed as part of the data for the study.
appendix e recist criteria 1.1
possible risks and discomforts

tarextumab: As of November 17, *2015*, tarextumab *or placebo* has been tested in 356 subjects who have cancer; The following side effects have been noted in subjects receiving tarextumab and were considered possibly related to tarextumab treatment: Common (occurred in >10% of the subjects who used the drug):  
- Low red blood counts that might make you feel tired, easier to get infections or bruised/bleeding
- Diarrhea
- Fatigue-tiredness
- Nausea
- Decreased appetite - Vomiting
Less Common (occurring in 5% to 10% of subjects who used the drug):
- Low potassium level  
- Infusion related or allergic reactions - Weight loss
- Redness of skin and/or rashes/hives
Most of the above-mentioned side effects were mild and moderate, *with the exception of one* subject who experienced fatal cardiac arrest, considered to be related to study drug. Diarrhea was the most common side effect and can be severe if it is not treated immediately. You will be given some medications after your first dose of tarextumab to take home to treat diarrhea. In addition, you will be advised to drink enough fluid and eat a balanced diet to avoid the dehydration and imbalanced electrolytes. Tarextumab will be given as an intravenous infusion. There may be minor discomfort from the needle in your arm. Bruising, swelling, and, in rare instances, infection and blood clots may occur at the infusion site. Tarextumab is a monoclonal antibody. There is the possibility of a reaction to the monoclonal antibody as it is being infused (given) through your vein; these are called infusion reactions. Symptoms can include fever, chills, rash and/or hives, changes in blood pressure, temperature and heart rate. As of November 17, 2015, *eighteen* of 356 subjects who have been given tarextumab *or placebo* have experienced infusion *or hypersensitivity* reactions; *most* of these infusion reactions were mild or moderate. You will be watched carefully during the infusion and after the completion of the infusion. If you do have a reaction to the study drug, your study doctor may need to give the study drug at a slower rate (over a longer period of time) and /or give you some medications to prevent the reaction. If after slowing the rate of infusion and giving you some medications to prevent the infusion reaction, you continue to have infusion reactions, you may need to stop taking tarextumab. During the course of this study, your blood will be drawn for laboratory tests (1-3 tablespoons will be collected at each blood draw). The risks of drawing blood include some discomfort from the needle in your arm, bruising, swelling at the needle site and, in rare instances, infection or fainting. You should discuss the risk and side effects with your study doctor. There may be other side effects that we cannot predict. You will be informed of any new significant side effects that develop during the course of this research study regarding the use of tarextumab.  
There may be side effects that we cannot predict and in some cases they may be serious, longlasting, or fatal.
appendix e recist criteria 1.1
etoposide

The following side effects have been noted in subjects receiving etoposide: Common (occurred in > 10% of the subjects who used this drug)  
- Low blood counts: Your white and red blood cells and platelets may temporarily decrease. This may put you at an increased risk for infection, anemia, and/or bleeding
- Nausea - Vomiting
- Feeling weak and low energy
- Chills - Fever
- Hair loss
- Poor appetite  
- Sores, ulcers, or white spots on the lips or in the mouth
Less common (occurred in 5 to 10% of the subjects who used this drug)
- Diarrhea - Constipation - Taste alteration
- Abdominal pain  
- Dizziness - Injection site inflammation or vein inflammation
Rarely (occurred in < 5% of the subjects who used this drug)  
- Increased or decreased blood pressure - Allergic reaction: This medicine may cause a serious type of allergic reaction called anaphylaxis that is presented with symptoms such as chills, fever, fast heartbeat, sudden constriction of airway, shortness of breath, excessive sweating, itchiness of the skin or rash, change in blood pressure, and loss of consciousness, etc. Anaphylaxis can be life-
Protocol 59R5-003, Amendment 6 Page 156 of 235 2016 CONFIDENTIAL
threatening and requires immediate medical attention. Tell your doctor or nurse right away if you have chills; fever; lightheadedness, dizziness, or fainting; fast, pounding heartbeat; swelling of the face, tongue, and throat; or trouble with breathing after you receive the medicine Other side effects may occur following the administration of etoposide. Your doctor will further explain the side effects of etoposide.
appendix e recist criteria 1.1
cisplatin

The following side effects have been noted in subjects receiving cisplatin: Common (occurred in > 10% of the subjects who used this drug)  
- Low blood counts: Your white and red blood cells and platelets may temporarily decrease. This may put you at an increased risk for infection, anemia, and/or bleeding
- Nausea
- Vomiting
- Ringing in the ears or hearing loss - Impairment of kidney function and damages to kidney
- Changes in how food tastes
- Diarrhea
- Damages to nerve that causes pain, numbness, tingling of hands and feet, and sometimes even have the difficulty in motion
- Hair loss
- Imbalance of electrolyte - Extreme fatigue
- Mild elevation of liver enzymes
Less common or rare (occurred in  10% of the subjects who used this drug)  
- Change in vision or inflammation of optic nerve and blindness
- Injection site inflammation or vein inflammation
- Change in blood vessels that trigger heart attack and heart problem, stroke or brain injury
- Allergic reaction: This medicine may cause a serious type of allergic reaction called anaphylaxis that is presented with symptoms such as chills, fever, fast heartbeat, sudden constriction of airway, shortness of breath, excessive sweating, itchiness of the skin or rash, change in blood pressure, and loss of consciousness, etc. Anaphylaxis can be life-threatening and requires immediate medical attention. Tell your doctor or nurse right away if you have chills; fever; lightheadedness, dizziness, or fainting; fast, pounding heartbeat; swelling of the face, tongue, and throat; or trouble with breathing after you receive the medicine
Other side effects may occur following the administration of cisplatin. The side effects are generally reversible and gradually disappear when treatment ends. However, some side effects might take a long time to disappear. Your doctor will further explain the side effects of cisplatin.
appendix e recist criteria 1.1
carboplatin

The following side effects have been noted in subjects receiving carboplatin: Common (occurred in >10% of the subjects who used this drug)  
- Low blood counts: Your white and red blood cells and platelets may temporarily decrease. This may put you at an increased risk for infection, anemia, and/or bleeding
- Nausea
- Vomiting - Damages to nerve that causes pain, numbness, tingling of hands and feet, and sometimes even have the difficulty in motion
- Ringing in the ears or hearing loss
- Hair loss
- Imbalance of electrolytes
- Extreme fatigue
- Elevation of liver enzymes
- Pain
- Allergic reaction - Muscle weakness
Less common or rare (occurred in 10% of the subjects who used this drug)
- Sores, ulcers, or white spots on the lips or in the mouth  
- Loss of vision for light or color
- Impairment of kidney function and damages to kidney. Your carboplatin dose will be modified if you have impairment of kidney function
appendix e recist criteria 1.1
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()
Other side effects may occur following the administration of carboplatin. The side effects are generally reversible and gradually disappear when treatment ends. However, some side effects might take a long time to disappear. Your doctor will further explain the side effects of carboplatin
appendix e recist criteria 1.1
pregnancy

There is a very high risk that tarextumab may be harmful to an unborn baby (embryo or fetus) or newborn child. Therefore, women who are pregnant or breastfeeding may not participate in this study. Women must have a negative pregnancy test before beginning the study. It is important that both men and women take steps to prevent pregnancy during this study through the use of adequate contraception (for example, a barrier or hormone method or abstinence) 30 days prior to first study drug administration and for the duration of the study until 30 days after the last dose of study drug or etoposide or platinum therapy (cisplatin or carboplatin) whichever is discontinued last. If you become pregnant or suspect that you are pregnant, or if your partner becomes pregnant or suspects that she is pregnant during the study or within 30 days after the last dose of study drug, etoposide, or platinum therapy (cisplatin or carboplatin) whichever is discontinued last, you must notify the study doctor immediately. If you become pregnant, you will be taken off of treatment and will undergo assessments listed under the Treatment Termination Section of this document, except for the radiographic studies, which will not be performed. If your partner becomes pregnant, you will remain on the study. If either you or your partner becomes pregnant during the study or within 30 days after the last dose of study drug, etoposide, or platinum therapy (cisplatin or carboplatin) whichever is discontinued last, you and/or your partner will be followed through outcome of the birth.
appendix e recist criteria 1.1
potential benefits

There is no guarantee that there will be any direct benefit to you if you take part in this research study. The treatments you receive may be harmful. It is possible that the information learned from this study may be helpful in the future to other people with cancer.
appendix e recist criteria 1.1
significant new findings

Any significant new findings regarding tarextumab that become known during the course of this research study, which might reasonably affect your willingness to participate in this study, will be provided to you. If you decide not to participate in this study, you will continue to receive medical care to which you were entitled prior to your participation in this study. Your doctor will discuss other options available to you. Your choice not to participate in this study will not affect your medical care in any way.
appendix e recist criteria 1.1
termination of subject participation

Your participation in this research study may be terminated at any time for medical reasons or because the sponsor finds it necessary to limit or terminate this clinical trial. Some reasons for termination include progression of your disease, any other illness that prevents further administration of study drug, unacceptable adverse events, general or specific changes in your condition that make further treatment unacceptable in the opinion of your doctor, and protocol non-compliance. Your doctor may decide to hold or stop the study drug infusions at any time during the study for safety reasons. If your doctor or the sponsor decides to withdraw you from the study, you will undergo the same assessments listed under Treatment Termination.
appendix e recist criteria 1.1
costs and compensation

The cost of all "standard of care" assessments related to your participation in this study and your medical care will be billed to you and/or your insurance company. These are tests that would normally be performed in subjects to evaluate their cancer. Due to the investigational nature of this research study, insurance companies or government health care programs may limit their obligation to pay for experimental treatments and their consequences. You may want to discuss this with your insurance company before agreeing to participate. The cost of all non-standard of care assessments will be paid for by OncoMed.  
You will not be paid for participation in this study.
appendix e recist criteria 1.1
compensation for research-related injury

If you are physically injured as a direct result of study drug or study procedure properly performed under the plan for this study and it is not due to a pre-existing medical condition or underlying disease, OncoMed will reimburse you for the reasonable medical expenses for the treatment of that injury which are not covered by another payer, your own insurance or health care program. No other compensation is available from OncoMed if any injury occurs.
appendix e recist criteria 1.1
confidentiality

Every effort will be made to keep your medical information confidential (secret). You will be identified by a code and no information that identifies you will be released without your written permission, except as required by law. To the extent permitted by law and by signing the consent form, you allow access by representatives of the Food and Drug Administration (FDA), other regulatory bodies, Institutional Review Boards, Independent Ethics Committees, and OncoMed monitors/representatives and collaborators to inspect your research and medical records without removal of identifying information, such as your name, initials, date of birth, sex, race, and location of the research study. If information from this study is presented publicly or published in a medical journal, you will not be identified by name, picture, or by any other personally identifying information. The description of this clinical trial will be available on http://www.ClinicalTrials.gov, as required by U.S. Law. The website will not include information that can identify you. At most, the website will include a summary of the results. You can search this website at any time You will be asked to review and sign a HIPAA (Health Insurance Portability and Accountability Act) Research Authorization Form requesting your authorization to collect, use, and disclose your medical information, OR IF SITE DOES NOT HAVE OWN HIPAA FORM:
appendix e recist criteria 1.1
authorization to use and disclose

I authorize (give permission to) insert name of study site to use and disclose (share) my health information solely for the purposes of this research study and research directly related to the use of tarextumab. I understand that my health information that I am authorizing to be used and disclosed (Authorized Health Information) includes all health information about me that has been and will be created or received by (SITE) and that is in my medical records maintained by
(SITE).  
I understand that I am free at any time to restrict the (Site's) use and disclosure of my Authorized Health Information, without penalty or other consequences. However, I also understand that I may be denied participation in, or continued participation in, this research study if at any time I choose to restrict the (Site's) use and disclosure of Authorized Health Information that is necessary for the completion of this research study.
appendix e recist criteria 1.1
authorized persons and recipients

I authorize the following person(s) and groups of persons to request, receive, and use my Authorized Health Information: representatives of the FDA, other regulatory authorities, the Institutional Review Board/Independent Ethics Committee, OncoMed representatives and monitors, and OncoMed collaborators and licensees. I authorize (SITE) to disclose my Authorized Health Information to these persons and groups or persons.
appendix e recist criteria 1.1
re-disclosures to third parties

I understand that once (Site) discloses my Authorized Health Information to the recipient(s) identified in the previous section Authorized Persons and Recipients, (Site) cannot guarantee that the recipient(s) will not re-disclose my Authorized Health Information to other persons who may not be bound by this informed consent form.
appendix e recist criteria 1.1
expiration date

My authorization (permission) to use and disclose my Authorized Health Information will continue indefinitely, but that use and sharing will only be for the purposes described in the informed consent form.
appendix e recist criteria 1.1
effect of my revocation of

I understand that my authorization for (site) to use and disclose my Authorized Health Information will remain in effect until I withdraw my permission by sending my written notice of revocation (withdrawal of permission) to the Privacy Office listed in the Questions section of the following page. My written revocation will be effective immediately upon (Site's) receipt of my written notice, except that the revocation will not have any effect on any actions taken by (SITE) in relying on this authorization before it received my written notice of withdrawal of permission.
appendix e recist criteria 1.1
questions

If you have any question about the study and/or its procedure or safety, you may contact Dr.  
(Name of Investigator) at (telephone number). In the event of any injury, you may contact Dr.  
(name) at (telephone number). You may also call (Name) at (telephone number) for information on experimental subjects' rights. If at any time during this research study you feel that you have not been adequately informed of your rights with respect to the privacy of your health information, or you feel that the privacy of your health information has not been adequately protected, you may contact or visit (Site's) privacy office during normal working hours at (Privacy Office name) at (telephone number and address).
appendix e recist criteria 1.1
voluntary participation and documentation of

Your decision to participate in this study is entirely voluntary. You may refuse to participate in or withdraw from the study at any time without prejudice or loss of benefits to which you are
,19(67,*$7,21$/1(:'58* ()
otherwise entitled. A signed copy of this consent form will be given to you for your records and a copy will be retained by the study doctor for his or her files.  
By signing the form below, you have read the above information about this research study, and have had a chance to ask questions to help you understand your participation in this study and how your information will be used.  
,19(67,*$7,21$/1(:'58* ()
CONSENT FOR OPTIONAL TUMOR BIOPSY  
| _______ _________If you give your consent for a core biopsy of your tumor  Initials Date lesion, please check the box and write your initials and the date in   |
|-----------------------------------------------------------------------------------------------------------------------------------------------------------------|  
_______ _________If you do not give your consent for a core biopsy of your Initials Date tumor lesion, please check the box and write your initials and the date in the space provided.  
Printed Name of Subject or Subject's Authorized Representative ________________________________________________________ ___________ Signature of Subject or Subject's Authorized Representative Date _________________________________________________________ Printed Name of Person Obtaining Informed Consent __________________________________________________________ ____________ Signature of Person Obtaining Informed Consent Date Printed Name of Witness* Signature of Witness* Date
*If the Principal Investigator or Institutional Review Board deems a witness signature is necessary
,19(67,*$7,21$/1(:'58* ()  
Your decision to participate in this study is entirely voluntary. You may refuse to participate in or withdraw from the study at any time without prejudice or loss of benefits to which you are otherwise entitled. A signed copy of this consent form will be given to you for your records and a copy will be retained by the study doctor for his or her files. By signing the form below, you acknowledge that you have read the above information about this research study, and have had a chance to ask questions to help you understand your participation in this study and how your information will be used.  
Signature of Subject or Subject's Authorized Representative Date Printed Name of Person Obtaining Informed Consent Signature of Person Obtaining Informed Consent Date Printed Name of Witness* Signature of Witness* Date
*If the Principal Investigator or Institutional Review Board/Ethics Committee deems a witness signature is necessary.
appendix e recist criteria 1.1
what is the purpose of

The cells of your body contain deoxyribonucleic acid, or DNA for short. DNA is passed down from your parents. Genes carry the DNA that determine your physical appearance such as the color of your eyes and hair. Differences in our genes help explain why we all look different. Differences in our genes may also help explain why some drugs work and are safe in some people, but not in others. Differences in our genes also help explain why some people get certain diseases, but others do not. The sponsor would like to study the differences in people's DNA to learn more about diseases and response to drugs. This information will be used to try to develop safer and better drugs. To do this, the Sponsor would like to do DNA tests related to tarextumab and the diseases for which this drug is developed. The DNA tests are only for research. The tests are not for your medical care. All volunteers taking part in the main study are also being invited to take part in DNA research (where possible).
appendix e recist criteria 1.1
what am i being asked

You are being asked to give one small blood sample (10 mL, about 2 teaspoons) on Day 1 of Cycle 1 prior to the administration of study drug. Blood will be drawn from a vein using a needle. DNA will be extracted from your blood sample. Additionally, you are being asked to allow the Sponsor to perform the DNA testing on the mandatory tumor tissues you have provided for the study entry. If you had agreed to have optional tumor biopsies performed, you are also being asked to allow the Sponsor to perform DNA testing on these tissues. Your DNA may be tested for specific genes relevant to tarextumab (the study drug), the Notch/DLL4 pathways (the targets of the tarextumab) and/or other genes related to your cancer. Only DNA research related to tarextumab or to the diseases for which this drug is developed will be performed. The Sponsor will store the tissue samples until there is no DNA left. The Sponsor will also destroy the blood sample used for DNA testing after 10 years. You can also decide not to take part at all in DNA research. No blood sample for DNA research will be taken from you unless you sign and date this Informed Consent Form, and No DNA testing will be performed on the tumor tissues collected from you. Your decision to give, or not to give, a DNA sample will not affect the medical care that you receive from your study doctor or his/her staff. Your participation is voluntary. The Sponsor has taken several steps to keep your identity and results confidential. These are described below.
appendix e recist criteria 1.1
a) coding of your dna

Your DNA sample will not have your name or address on it. Your DNA sample will be coded with your Subject number from the main study. After the study is officially over, the Subject number will be removed from your DNA sample. Your DNA sample and results will be labeled with a new number.
appendix e recist criteria 1.1
b) restricted access to your

The Sponsor will control your DNA sample. Your DNA sample will be stored in a secure room at a facility in Redwood City, CA, or other site designated by the sponsor. Only authorized staff are allowed to enter the room. Your DNA sample may be transferred to other research partners working with the Sponsor. DNA samples transferred to research partners will not contain your Subject number. Your DNA sample will not be sold, loaned, or given to any other independent groups for their own use. Research partners working with the Sponsor are not allowed to share DNA samples with anyone else.
appendix e recist criteria 1.1
c) restricted access to results

Your DNA results will be stored by the Sponsor both on paper and in computer records. You will not be identified by name in these records. Your results will only be labeled with a code number. This is to protect your privacy. Your results will be kept as long as necessary. The following people may see your test results:  
- The Sponsor
- Research partners working with the Sponsor - Independent Ethics Committees/Institutional Review Boards - Regulatory authorities, like the Food and Drug Administration (FDA) or the European Medicines Evaluation Agency (EMEA)
Unless the law requires it, your individual results will not be given to anyone who is not listed above. For example, your results will not be given to employers, insurance companies or family members. Research partners working with the Sponsor may not use or share your results without permission from the Sponsor. DNA results from the study may be published or added to public databases. They also may be presented in public meetings. No publication or presentation will identify you by your code number or name.
appendix e recist criteria 1.1
d) separate storage of dna

Your study doctor will keep your signed DNA informed consent form, and any other DNA forms, separate from your other medical files. People who have access to your medical files (such as insurance companies) would not know that you took part in a DNA research study by looking at your medical files. You will be given a copy of your signed DNA consent form.
appendix e recist criteria 1.1
what if i change my

If you change your mind and decide later that you no longer want to take part in DNA research, you may ask for your DNA sample to be destroyed as long as the study is not officially over. You can stay in the main study even if you change your mind about taking part in DNA research.
appendix e recist criteria 1.1
will i get my dna

The tests will be performed in a research laboratory. Results from a research laboratory may not always be exact. They cannot be used to make a diagnosis about your health. Also, research laboratories cannot give advice on health or health risks. For these reasons, the results of your DNA tests will not be given to you or your study doctor (or his/her staff).
appendix e recist criteria 1.1
what are the benefits?

You will not directly benefit from taking part in this DNA research. This research could provide information about tarextumab or the diseases for which this drug is developed. This information could help others in the future.
appendix e recist criteria 1.1
what are the risks?

There may be some pain or bruising from the needle stick used to draw the blood. Some people may faint when their blood is drawn. Very rarely, there may be an infection at the place where the needle went into the skin. Any problem that you have from drawing blood will be handled the same way as in the main study. Your research results cannot be used to make a diagnosis about your health.
appendix e recist criteria 1.1
will i be paid for

You will not be paid for taking part in the DNA research part of the study. You will not be paid for any use of your DNA sample or results or for any inventions that are made from them. If you take part, you are providing your DNA sample for use by the Sponsor. The Sponsor intends to own any use of the results, treatments, or inventions that can be made from the research.
appendix e recist criteria 1.1
questions

If you have any question about the study and/or its procedure or safety, you may contact Dr.  
(Name of Investigator) at (telephone number). In the event of any injury, you may contact Dr.  
(name) at (telephone number). You may also call (Name) at (telephone number) for information on experimental subjects' rights. If at any time during this research study you feel that you have not been adequately informed of your rights with respect to the privacy of your health information, or you feel that the privacy of your health information has not been adequately protected, you may contact or visit (Site's) privacy office during normal working hours at (Privacy Office name) at (telephone number and address).  
,19(67,*$7,21$/1(:'58*
appendix e recist criteria 1.1
voluntary participation and documentation of

Your decision to participate in this part of the study is entirely voluntary and. you may choose not to participate in this part of the study without prejudice or loss of benefits to which you are otherwise entitled in the remainder of the study. A signed copy of this consent form will be given to you for your records and a copy will be retained by the Investigator for his or her files. By signing the form below, you acknowledge that you have read the above information about  
  
 this research study, and have had a chance to ask questions to help you understand your participation in this study and how your information will be used.  
| _____ _______   | If you give your consent for a small blood sample for DNA research,  please check the box and write your initials and the date in the space  provided.   |
|-----------------|----------------------------------------------------------------------------------------------------------------------------------------------------------|
| _____ _______   | If you do not give your consent for a small blood sample for DNA  research, please check the box and write your initials and the date in the             |
| _____ _______   | If you give your consent to allow DNA testing on the tumor tissue  collected from you, please check the box and write your initials and the              |  
  
_____ _______ If you do not give your consent to allow DNA testing on the tumor tissue  
  
  
collected from you, please check the box and write your initials and the Initials Date date in the space provided.  
Printed Name of Subject or Subject's Authorized Representative  
 ________________________________________________________ ___________ Signature of Subject or Subject's Authorized Representative Date
_________________________________________________________
Printed Name of Person Obtaining Informed Consent  
__________________________________________________________ ____________  
  
 Signature of Person Obtaining Informed Consent Date __________________________________________________________ Printed Name of Witness* _________________________________________________________ ___________  
  
 Signature of Witness* Date  
*If the Principal Investigator or Ethic's Committee deems a witness signature is necessary
appendix i protocol amendment summary
amendment 1 09 may 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 enrollment of current smokers, to exclude concurrent use of therapeutic warfarin, and to allow enrollment of a subject with treated brain metastasis provided that the subject has stable neurologic condition for at least 2 weeks after the completion of the radiation and is not receiving corticosteroid of > 40 mg prednisone daily equivalent dose to control the symptoms, to clarify the definition of DLT for Grade 4 neutropenia, and to clarify study drug preparation and administration. Additional minor changes have been made to improve clarity and consistency.
appendix i protocol amendment summary
summary of changes synopsis

Diagnosis and Main Criteria for Eligibility: (Cont'd) Inclusion Criteria: Previously Read:
d. Prothrombin Time (PT)/International Normalized Ration (INR) 1.5 × ULN, activated partial thromboplastin time (aPTT) 1.5 × ULN unless the subject is on heparin or warfarin or other similar anti-coagulants.  
d. Prothrombin Time (PT)/International Normalized Ration (INR) 1.5 × ULN, activated partial thromboplastin time (aPTT) 1.5 × ULN.  
Additionally, for individuals eligible to participate in Phase 2 portion of the study:
appendix i protocol amendment summary
previously read

2. Prior therapy including radiation, chemotherapy or surgery for newly diagnosed extensive stage small cell lung cancer. Exceptions to this exclusion criterion include: 1) prophylactic cranial irradiation or whole brain radiation (WBRT) prior to the first administration of study drug provided that the subject has stable neurologic condition for at least 2 weeks after the completion of the radiation, 2) focused radiation for symptomatic relief for isolated bone metastases; 3) bisphosphonate or denosumab therapy for bone metastasis initiated prior to study entry.  
3. Symptomatic brain metastases requiring whole brain irradiation within 4 weeks prior to first study drug administration or requiring daily doses of >40mg of oral prednisone, or require use of anti-epileptic drugs.  
4. Presence of uncontrolled Grade  1 diarrhea within 4 weeks prior to the first study drug administration.  
5. Current smoker. 6. Presence of any serious or uncontrolled illness including, but not limited to: ongoing or active infection, symptomatic congestive heart failure unstable angina pectoris, cardiac arrhythmia, arterial thrombosis, symptomatic pulmonary embolism, and psychiatric illness that would limit compliance with study requirement.  
7. History of myocardial infarction, acute coronary syndromes (including unstable angina),
coronary angioplasty and/or stenting within 6 months prior to the first administration of study drug.  
8. 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 c. Any other cancer from which the subject has been disease-free for  3 years 9. Known human immunodeficiency virus (HIV) infection.
10. Females who are pregnant or breastfeeding.  
2. Prior therapy including radiation, chemotherapy or surgery for newly diagnosed extensive stage small cell lung cancer. Exceptions to this exclusion criterion include: 1) prophylactic cranial irradiation or whole brain radiation (WBRT) prior to the first administration of study drug provided that the subject has stable neurologic condition for at least 2 weeks after the completion of the radiation and is not receiving corticosteroid of > 40 mg prednisone daily equivalent dose to control the symptoms, 2) focused radiation for symptomatic relief for isolated bone metastases; 3) bisphosphonate or denosumab therapy for bone metastasis initiated prior to study entry.  
3. Presence of uncontrolled Grade  1 diarrhea within 4 weeks prior to the first study drug administration.  
4. Presence of any serious or uncontrolled illness including, but not limited to: ongoing or active infection, symptomatic congestive heart failure unstable angina pectoris, *uncontrolled* cardiac arrhythmia, *uncontrolled* arterial thrombosis, symptomatic pulmonary embolism, and psychiatric illness that would limit compliance with study requirement.  
5. History of myocardial infarction, acute coronary syndromes (including unstable angina),
coronary angioplasty and/or stenting within 6 months prior to the first administration of study drug.  
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 c. Any other cancer from which the subject has been disease-free for  3 years 7. Known human immunodeficiency virus (HIV) infection. 8. Females who are pregnant or breastfeeding. 9. Concurrent use *of therapeutic warfarin (prophylactic low dose of warfarin, i.e., 1 mg daily* for port catheter is allowed).
appendix i protocol amendment summary
test product dose and mode

OMP-59R5 must be delivered through either polyvinyl chloride (PVC) or non-PVC tubing that contains a 0.22-micron filter and should be infused over 30 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 5% Dextrose in Water (D5W) to a total volume of 250 mL and infuse over 30 minutes.  
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 Protocol 59R5-003, Amendment 6 Page 173 of 235 2016 CONFIDENTIAL
total volume of 250 mL and infuse over 30 minutes (+/- 5 minutes). The diluted study drug should be administered within 4 hours of preparation.
appendix i protocol amendment summary
3.4 clinical background previously read

As of November 5, 2012, a total of thirty-nine subjects have been treated in Study 59R5-001: three at 0.5 mg/kg weekly, three at 1 mg/kg weekly, six at 2.5 mg/kg weekly, nine at 5 mg/kg weekly, six at 5 mg/kg every other week, three at 7.5mg/kg every other week, three at 10 mg/kg every other week, and six at 7.5mg/kg every three weeks. The initial dose levels of OMP-59R5 in this study were 0.5, 1, 2.5, and 5 mg/kg administered IV once weekly. There were no DLTs observed at the 0.5 mg/kg (n=3), 1 mg/kg (n=3) or 2.5 mg/kg (n=3) dose levels. Two of the six subjects treated at 5 mg/kg once weekly experienced DLTs: one had Grade 3 hypokalemia secondary to diarrhea and the other had Grade 3 diarrhea. As a result, 5mg/kg once weekly exceeded the MTD and an additional three subjects were treated at 2.5 mg/kg once weekly. These three additional subjects tolerated treatment without a DLT thus defining an MTD as 2.5mg/kg once weekly for OMP-59R5. Once the initial MTD was defined as described above, the protocol was amended to use a standard treatment algorithm to treat diarrhea and the DLT criteria was revised to define Grade 3 and above diarrhea that does not respond to standard medical treatment within 48 hours as a DLT. An additional three subjects were treated at the dose level of 5 mg/kg weekly with concomitant use of anti-diarrheal medications: all subjects were given a prescription for loperamide at study entry with instructions to take an initial 4 mg dose following the first loose stool, followed by 2 mg after every unformed stool with a maximum of 16 mg per day. Loperamide was continued until the subject was diarrhea-free for 12 hours. If Grade 3 diarrhea develops, loperamide would be discontinued and the subject would be started on second-line therapy (i.e., Lomotil 2 tablets 4 times daily and/or octreotide 100-150 ȝg subcutaneously [sc]
three times daily and up to a maximum 500ȝg 3 times daily). One subject with prostate cancer developed Grade 2 anorexia and Grade 1 diarrhea. The second subject at 5mg/kg weekly, with colorectal cancer, developed Grade 2 diarrhea, Grade 2 dehydration, and Cycle 3 of OMP-59R5 was held at the discretion of the treating physician. The third subject at this dose level with nonsmall cell lung cancer developed Grade 1 diarrhea and Grade 1 abdominal pain. Due to poor tolerability of the 5 mg/kg weekly dose, despite the concomitant use of anti-diarrheal medication, a revised dosing schedule was implemented to define a new MTD with dosing of OMP-59R5 every other week. Three subjects were treated at 5 mg/kg every other week and only Grade 1 diarrhea was noted from each of these three subjects. Dose escalation proceeded to 10 mg/kg every other week and two out of three subjects experienced DLT with Grade 3 diarrhea. Thus, 10 mg/kg every other week was defined as a dose above the MTD and the 5 mg/kg every other week dose level was expanded to enroll three additional subjects. A total of six subjects have been treated at 5 mg/kg Protocol 59R5-003, Amendment 6 Page 174 of 235 2016 CONFIDENTIAL
appendix i protocol amendment summary
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every other week and no DLT was noted. The dosing schedule was revised to explore an intermediary dose of 7.5mg/kg of OMP-59R5 every three weeks. Six subjects were treated at dose of 7.5mg/kg every three weeks with no DLTs noted, establishing the MTD of every three weeks schedule of 7.5 mg/kg. In addition, an intermediary dose of 7.5mg/kg every other week is also being explored. As of November 5, 2012, three subjects have been treated at 7.5mg/kg every other week and no DLT were noted. Exploration of 7.5 mg/kg every other week is ongoing with enrolling 3 additional subjects. Diarrhea has been the most common adverse event, occurring in 58% (21 of 36) of subjects treated on the study regardless of schedule, which was expected based on the observance of diarrhea in the cynomolgus monkey toxicology study. Diarrhea was observed at 2.5 mg/kg weekly and above dose cohorts, and was dose dependent. Table 2 below tabulates the incidence and severity of diarrhea among dose levels according NCI-CTCAE criteria v4.02.  
| Diarrhea   | 0.5 mg/kg            |                        |                      |                       |                         |                          |    |
|------------|----------------------|------------------------|----------------------|-----------------------|-------------------------|--------------------------|----|
| Grade      | QW                   |                        |                      |                       |                         |                          |    |
| (n=0/3)    | 1 mg/kg  QW  (n=0/3) | 2.5 mg/kg  QW  (n=4/6) | 5 mg/kg  QW  (n=8/9) | 5 mg/kg  QoW  (n=2/3) | 10 mg/kg  Q0W   (n=3/3) | 7.5 mg/kg  Q3W   (n=4/6) |    |
| 1          | -                    | -                      | 2                    | 4                     | 2                       | -                        | 2  |
| 2          | -                    | -                      | 2                    | 2                     | -                       | -                        | 2  |
| 3          | -                    | -                      | -                    | 2                     | -                       | 3                        | -  |  
Additional common treatment-related adverse events included fatigue (28%), nausea (22%), decreased appetite (14%), vomiting (11%), dizziness (8%), increased alanine transaminase (ALT) (8%), dehydration (8%), hypokalemia (8%), abdominal pain (8%), anemia (8%), and thrombocytopenia (8%).  
Table 2 and Table 3 summarize all treatment related CTC Grade 3 adverse events that occurred in Study 59R5-001 by body system; there were no Grade 4 or 5 events on study.
appendix i protocol amendment summary
table 3 study 59r5-001 grade

| Body System                                           | Preferred Term                                | Number of Subjects   |
|-------------------------------------------------------|-----------------------------------------------|----------------------|
| Gastrointestinal Disorders                            | Diarrhea                                      | 5                    |
| Blood and Lymphatic System Disorders                  | Anemia                                        | 2                    |
| Investigations                                        | Alanine Aminotransferase  Increased (Grade 3) | 1                    |
| Metabolism and Nutrition Disorders                    | Hypokalaemia                                  | 1                    |
| General Disorders and Administration Site  Conditions | Fatigue                                       | 1                    |
| Protocol 59R5-003, Amendment 6                        | Page 175 of 235                               | 22 April 2016        |
|                                                       | CONFIDENTIAL                                  |                      |  
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). 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.  
As of April 25, *2013*, a total of *forty-two* subjects have been treated in Study 59R5-001: three at 0.5 mg/kg weekly, three at 1 mg/kg weekly, six at 2.5 mg/kg weekly, nine at 5 mg/kg weekly, six at 5 mg/kg every other week, six at 7.5mg/kg every other week, three at 10 mg/kg every other week, and six at 7.5mg/kg every three weeks. Two DLTs occurred in two of nine subjects treated at 5 mg/kg weekly: one Grade 3 hypokalemia secondary to Grade 3 diarrhea in one subject and one Grade 3 diarrhea in another subject, which led to the MTD for weekly dosing schedule to be 2.5 mg/kg. No DLTs occurred in 6 subjects treated at 7.5 mg/kg every three weeks that led to the MTD for every three week schedule to be 7.5 mg/kg. Two DLTs both Grade 3 diarrhea, occurred in two of three subjects treated with a single dose of OMP-59R5 at 10 mg/kg every other week and no DLTs occurred in 6 subjects treated at 7.5 mg/kg every other week, which led to the MTD for every other week schedule to be 7.5 mg/kg every other week. Toxicities observed to date have been mostly Grades 1 and 2, and were manageable with supportive care and/or interruption or dose reduction of OMP-59R5. There were no AEs of a Grade 4 severity reported. AEs with a severity of Grade 3 were uncommon and have been primarily diarrhea. Diarrhea has been the most common adverse event, occurring in 81% (34 of 42) of subjects treated on the study regardless of schedule, which was expected based on the observance of diarrhea in the cynomolgus monkey toxicology study. Diarrhea was observed at 2.5 mg/kg Protocol 59R5-003, Amendment 6 Page 176 of 235 2016 CONFIDENTIAL
appendix i protocol amendment summary
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weekly and above dose cohorts, and was dose dependent. Table 2 below tabulates the incidence and *worse* severity of diarrhea *occurred while receiving OMP-59R5* among dose levels according NCI-CTCAE criteria v4.02.  
| Diarrhea   | 0.5 mg/kg            |                        |                      |                       |                         |                          |                         |    |
|------------|----------------------|------------------------|----------------------|-----------------------|-------------------------|--------------------------|-------------------------|----|
| Grade      | QW                   |                        |                      |                       |                         |                          |                         |    |
| (n=2/3)    | 1 mg/kg  QW  (n=0/3) | 2.5 mg/kg  QW  (n=6/6) | 5 mg/kg  QW  (n=8/9) | 5 mg/kg  QoW  (n=4/6) | 10 mg/kg  QoW   (n=3/3) | 7.5 mg/kg  Q3W   (n=5/6) | 7.5 mg/kg  QoW  (n=6/6) |    |
| 1          | 1                    | -                      | 3                    | 4                     | 3                       | -                        | 4                       | 3  |
| 2          | 1                    | -                      | 3                    | 2                     | -                       | -                        | 1                       | 3  |
| 3          | -                    | -                      | -                    | 2                     | 1                       | 3                        | -                       |    |  
Additional common treatment-related adverse events included *(as of November 17, 2012 data* cutoff with 39 subjects treated) fatigue (*30.8*%), nausea (*28.2*%), decreased appetite (*17.9*%), vomiting (*15.4*%), increased alanine transaminase (ALT) (*10.3*%), hypokalemia (*15.4* and dizziness (*10.3*%). Table 2 and Table 3 summarize all treatment related CTC Grade 3 adverse events that occurred in Study 59R5-001 by body system *as of November 17, 2012*; there were no Grade 4 or 5 events on study. Table 3: Study 59R5-001: Grade 3 Treatment Related Adverse Events by Body System (N=39)  
| Body System                                                               | Preferred Term     | Number of Subjects   |
|---------------------------------------------------------------------------|--------------------|----------------------|
| Gastrointestinal Disorders                                                | Diarrhea           | 6 (15.4%)            |
| Blood and Lymphatic System Disorders                                      | Anemia             | 2 (5.1%)             |
| Alanine Aminotransferase  Increased  Aspartate Aminotransferase  Increase | 1 (2.6%)  1 (2.6%) |                      |
| Investigations                                                            |                    |                      |
| Metabolism and Nutrition Disorders                                        | Hypokalaemia       | 2 (5.1%)             |
| General Disorders and Administration Site  Conditions                     | Fatigue            | 1 (2.6%)             |  
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 OMP-59R5-
Protocol 59R5-003, Amendment 6 Page 177 of 235 2016 CONFIDENTIAL  
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 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.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 59R5001. 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 OMP59R5 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 i protocol amendment summary
5.2 dose limiting toxicity previously

Adverse events will be graded according to the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI-CTCAE) version 4.03 (see Study Reference Binder).  
Dose-limiting toxicity (DLT) is defined as either of the following OMP-59R5 treatment-related toxicities occurring within the first 21 days (Cycle 1):
- Grade 4 neutropenia lasting >7 days in the absence of growth factor support  
Adverse events will be graded according to the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI-CTCAE) version 4.02 (see Study Reference Binder). Dose-limiting toxicity (DLT) is defined as either of the following OMP-59R5 treatment-related toxicities occurring within the first 21 days (Cycle 1):
- Grade 4 neutropenia lasting >7 days
appendix i protocol amendment summary
6.0 selection of study population

d. Prothrombin Time (PT)/International Normalized Ration (INR) 1.5 × ULN, activated partial thromboplastin time (aPTT) 1.5 × ULN unless the subject is on heparin or warfarin or other similar anti-coagulants.  
d. Prothrombin Time (PT)/International Normalized Ration (INR) 1.5 × ULN, activated partial thromboplastin time (aPTT) 1.5 × ULN.
appendix i protocol amendment summary
6.2 exclusion criteria previously read

2. Prior therapy including radiation, chemotherapy or surgery for newly diagnosed extensive stage small cell lung cancer. Exceptions to this exclusion criterion include: 1) prophylactic cranial irradiation or whole brain radiation (WBRT) prior to the first administration of study drug provided that the subject has stable neurologic condition for at least 2 weeks after the completion of the radiation, 2) focused radiation for symptomatic relief for isolated bone metastases; 3) bisphosphonate or denosumab therapy for bone metastasis initiated prior to study entry.  
3. Symptomatic brain metastases requiring whole brain irradiation within 4 weeks prior to first study drug administration or requiring daily doses of >40mg of oral prednisone, or require use of anti-epileptic drugs.  
4. Presence of uncontrolled Grade  1 diarrhea within 4 weeks prior to the first study drug administration.  
5. Current smoker.
6. Presence of any serious or uncontrolled illness including, but not limited to: ongoing or active infection, symptomatic congestive heart failure unstable angina pectoris, cardiac arrhythmia, arterial thrombosis, symptomatic pulmonary embolism, and psychiatric illness that would limit compliance with study requirement.  
7. History of myocardial infarction, acute coronary syndromes (including unstable angina),
coronary angioplasty and/or stenting within 6 months prior to the first administration of study drug.  
8. 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 c. Any other cancer from which the subject has been disease-free for  3 years
9. Known human immunodeficiency virus (HIV) infection. 10. Females who are pregnant or breastfeeding.  
2. Prior therapy including radiation, chemotherapy or surgery for newly diagnosed extensive stage small cell lung cancer. Exceptions to this exclusion criterion include: 1) prophylactic cranial irradiation or whole brain radiation (WBRT) prior to the first administration of study drug provided that the subject has stable neurologic condition for at least 2 weeks after the completion of the radiation and is not receiving corticosteroid of > 40 mg prednisone daily equivalent dose to control the symptoms, 2) focused radiation for symptomatic relief for isolated bone metastases; 3) bisphosphonate or denosumab therapy for bone metastasis initiated prior to study entry.  
3. Presence of uncontrolled Grade  1 diarrhea within 4 weeks prior to the first study drug administration.  
4. Presence of any serious or uncontrolled illness including, but not limited to: ongoing or active infection, symptomatic congestive heart failure unstable angina pectoris, *uncontrolled* cardiac arrhythmia, *uncontrolled* arterial thrombosis, symptomatic pulmonary embolism, and psychiatric illness that would limit compliance with study requirement.  
5. History of myocardial infarction, acute coronary syndromes (including unstable angina),
coronary angioplasty and/or stenting within 6 months prior to the first administration of study drug.
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 c. Any other cancer from which the subject has been disease-free for  3 years  
7. Known human immunodeficiency virus (HIV) infection. 8. Females who are pregnant or breastfeeding.
9. Concurrent use of therapeutic warfarin (prophylactic low dose of warfarin, i.e., 1 mg daily for port catheter is allowed).
appendix i protocol amendment summary
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 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 over 30 minutes *(+/- 5 minute*s) on Day 1 of every 21-day cycle. The subject should not take two consecutive doses of study drug within 18 days.
appendix i protocol amendment summary
7.1 study drug (omp-59r5 or

During Phase 1b and 2, OMP-59R5 must be delivered through tubing that contains a 0.22-micron filter and should be infused over 30 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 5% Dextrose in Water (D5W) to a total volume of 250 mL and infuse over 30 minutes.  
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.
appendix i protocol amendment summary
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 5% dextrose in water, USP, 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 5% dextrose in water, USP, 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 24 hours.  
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.
appendix i protocol amendment summary
7.4 dose modifications or delay

The investigator should hold OMP-59R5/placebo for treatment related toxicity according to Table 5, along with his/her best judgment. Subjects with a starting dose of 5 mg/kg study drug will have dose reduced to 2.5 mg/kg if dose reduction is required. Study drug will be discontinued permanently if study drug dosing is delayed for > 21 consecutive days despite supportive treatment, or if more than 2 dose reductions of study drug are required or dose reduction to < 2.5 mg/kg is required. Subjects continuing EP after discontinuing study drug will continue to receive etoposide on days 1, 2, and 3, and cisplatin on day 1 of each 21-day cycle for ()
a total of 6 cycles. Special attention should be paid to diarrhea as this is an expected adverse event of OMP-59R5 and Section 1.3 describes the recommended diarrhea management approach in this study.  
The investigator should hold OMP-59R5/placebo for treatment related toxicity according to Table 5, along with his/her best judgment. Subjects with a starting dose of 5 mg/kg study drug will have dose reduced to 2.5 mg/kg if dose reduction is required. Study drug will be discontinued permanently if study drug dosing is delayed for > 21 consecutive days *due to* treatment –related toxicity (this is not applicable when PCI is administered as study drug will be held for > 21 consecutive days during PCI administration and will resume  *14 days after the* completion of PCI) despite supportive treatment, or if more than 2 dose reductions of study drug are required or dose reduction to < 2.5 mg/kg is required. Subjects continuing EP after discontinuing study drug will continue to receive etoposide on days 1, 2, and 3, and cisplatin on day 1 of each 21-day cycle for a total of 6 cycles. Special attention should be paid to diarrhea as this is an expected adverse event of OMP-59R5 and Section 1.3 describes the recommended diarrhea management approach in this study.  
| " 3 consecutive weeks of interruption                                                                                         | - 1st episode, no change. Consider                          | prophylactic myeloid growth factor                                          | according to institution's standard   | - 2nd episode: reduce cisplatin dose  by 25% for all subsequent   | administration             | - 3rd episode, reduce cisplatin dose  by 50% from starting dose for all   | subsequent administration                                                           | - 4th episode, discontinue cisplatin   | treatment.                                                                          |                |                            |                     |
|-----------------------------------------------------------------------------------------|-------------------------------------------------------------|-----------------------------------------------------------------------------|---------------------------------------|-------------------------------------------------------------------|----------------------------|---------------------------------------------------------------------------|-------------------------------------------------------------------------------------|----------------------------------------|-------------------------------------------------------------------------------------|----------------|----------------------------|---------------------|
| cisplatin based on timing of recovery and                                               | number of previous episodes  ¾                              | 6 22 April 201                                                              |                                       |                                                                   |                            |                                                                           |                                                                                     |                                        |                                                                                     |                |                            |                     |
| Tarextumab (OMP-59R5)                                                                   | - 1000/ mm3. Resume  Hold cisplatin till ANC                                                             | ¾ > 3 consecutive weeks of interruption,  discontinue cisplatin permanently |                                       |                                                                   |                            |                                                                           |                                                                                     |                                        |                                                                                     |                |                            |                     |
| IND No. 106826, Serial 0037                                                             | Cisplatin Dose Reduction and/or Delay                       | Continue supportive care according to                                       | institution's standard                |                                                                   |                            |                                                                           |                                                                                     |                                        |                                                                                     |                |                            |                     |
| Suggested Guidelines for Study Drug and Etoposide-Cisplatin Dose Modification and Delay | Etoposide Dose Reduction and/or Delay                       | " 3 consecutive weeks of                                                                             | interruption                          | - 1st episode, no change.  Consider prophylactic myeloid          | growth factor according to | institution's standard                                                    | - 2nd episode: reduce etoposide  dose by 25% from starting  dose for all subsequent | administration                         | - 3rd episode, reduce etoposide  dose by 50% from starting  dose for all subsequent | administration | - 4th episode, discontinue | etoposide treatment |
| Resume etoposide based on timing of                                                     | recovery and number of previous episodes  ¾                 | ¾ > 3 consecutive weeks of                                                  | interruption, discontinue etoposide   | permanently  Continue supportive care according to                | institution's standard     |                                                                           |                                                                                     |                                        |                                                                                     |                |                            |                     |
| - 1000/ mm3.  Hold etoposide till ANC                                                                                         |                                                             |                                                                             |                                       |                                                                   |                            |                                                                           |                                                                                     |                                        |                                                                                     |                |                            |                     |
| Absolute Neutrophil Count (ANC)                                                         | CONFIDENTIAL                                                |                                                                             |                                       |                                                                   |                            |                                                                           |                                                                                     |                                        |                                                                                     |                |                            |                     |
| Page 184 of 235                                                                         |                                                             |                                                                             |                                       |                                                                   |                            |                                                                           |                                                                                     |                                        |                                                                                     |                |                            |                     |
| ,19(67,*$7,21$/1(:'58*                                                                                         | 5.3.4.2 Protocol No. 59R5-003 - Amendment 6 - 22 April 2016 | Study Drug Dose Reduction  and/or Delay                                     | No change                             | 6 Protocol 59R5-003, Amendment                                    |                            |                                                                           |                                                                                     |                                        |                                                                                     |                |                            |                     |
| OncoMed Pharmaceuticals, Inc.                                                           | 500 -999/mm3 without                                        | fever                                                                       |                                       |                                                                   |                            |                                                                           |                                                                                     |                                        |                                                                                     |                |                            |                     |
| Adverse Event                                                                           |                                                             |                                                                             |                                       |                                                                   |                            |                                                                           |                                                                                     |                                        |                                                                                     |                |                            |                     |
| Table 5:                                                                                | Added:                                                      |                                                                             |                                       |                                                                   |                            |                                                                           |                                                                                     |                                        |                                                                                     |                |                            |                     |
appendix i protocol amendment summary
7.5 anti-emetics anti-diarrhea and hematopoietic

Hematopoietic growth factors, transfusion of blood and blood products should not be used in Cycle 1 of the dose escalation phase unless absolutely clinically necessary and after discussion with the OncoMed Medical Monitor. However, hematopoietic growth factors, transfusion of blood and blood products may be administered after Cycle 1 in the dose escalation phase or anytime during phase 2 portion as needed.  
Hematopoietic growth factors, transfusion of blood and blood products should not be used prophylactically prior to the dosing of the study drug and EP on Day 1 of Cycle 1, but may be administered per standard clinical practice during the course of the study as needed.
appendix i protocol amendment summary
7.6 concomitant and prohibited therapy

All concomitant medication administered within 28 days prior to the first administration of study drug through 30 days following the administration of the last dose of study drug will be recorded on the Concomitant Medication eCRF. Investigational medicinal products and anticancer agents (e.g., cytotoxic agents and biologics with known activity against small cell lung cancer) may not be administered from enrollment through the first line therapy.  
All concomitant medication administered within 28 days prior to the first administration of study drug through 30 days following the administration of the last dose of study drug will be recorded on the Concomitant Medication eCRF. Investigational medicinal products, therapeutic warfarin
(prophylactic low dose of warfarin, i.e., 1 mg daily is allowed for port catheter) and anticancer agents (e.g., cytotoxic agents and biologics with known activity against small cell lung cancer) may not be administered from enrollment through the first line therapy.
appendix i protocol amendment summary
8.1 adverse events definitions and

Adverse events will be coded in accordance with the Medical Dictionary for Regulatory Activities (MedDRA). The grading of the adverse events will be done using the National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE), version 4.03 (see Study Reference Binder). Now Read: Adverse events will be coded in accordance with the Medical Dictionary for Regulatory Activities (MedDRA). The grading of the adverse events will be done using the National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE), version 4.02 (see Study Reference Binder).
appendix i protocol amendment summary
10.0 biomarkers and exploratory assessments

Optional Tumor Biomarkers: Optional tumor specimens will be collected during study visits and at the time of progression if feasible according to Schedule of Assessments (Appendix B and C)
from subjects who are consented and who have tumor lesions that are amenable to core biopsies. Tumor samples will be analyzed for treatment-induced changes in Notch-related gene expression (i.e., mRNA) and/or protein markers and cancer stem cell–related gene expression.  
Optional Tumor Biomarkers: Optional tumor specimens will be collected during study visits and at the time of *treatment termination,* if feasible according to Schedule of Assessments (APPENDIX B and APPENDIX C) from subjects who are consented and who have tumor lesions that are amenable to core biopsies. Tumor samples will be analyzed for treatmentinduced changes in Notch-related gene expression (i.e., mRNA) and/or protein markers and cancer stem cell–related gene expression.
appendix i protocol amendment summary
11.1 screening deleted

- Hair follicle samples (6 hairs) collected from subjects enrolled in Phase 1b portion only
appendix i protocol amendment summary
11.2 treatment visits previously read

…Study drug administration (OMP-59R5 or placebo) should continue at every 21-day cycle between the completion of chemotherapy and the initiation of PCI.  
…Study drug administration (OMP-59R5 or placebo) should continue at every 21-day (*± 1 day*) cycle between the completion of chemotherapy and the initiation of PCI. 11.2.1 Cycle 1
appendix i protocol amendment summary
11.2.1.1 cycle 1 day 1

The following assessments will be completed prior to study drug infusion. These assessments will be repeated if they were done more than 3 days prior to Cycle 1 Day 1.  
- Physical examination  
- Weight - ECOG performance status - Hematology - Serum chemistry - Coagulation - Urinalysis (dip stick is sufficient) - Electrocardiogram (ECG) including PR interval, RR interval, QRS duration, and QTc interval
The following assessments will be done prior to study drug infusion on Cycle 1 Day 1:  
- Serum sample for anti-OMP-59R5 antibody on all subjects - Blood sample for biomarker - Plasma sample for OMP-59R5 PK from subjects enrolled in Phase 1b portion only - Blood sample for pharmaco-genomics **(Optional and only if subject has signed the**
separate pharmacogenomics Informed Consent Form)
- Concomitant medications - Vital Signs
The following assessments will be completed prior to study drug infusion. These assessments will be repeated if they were done more than 7 days prior to Cycle 1 Day 1.  
- Physical examination  
- ECOG performance status - Hematology
()
- Serum chemistry - Coagulation
- Urinalysis (dip stick is sufficient) - Electrocardiogram (ECG) including PR interval, RR interval, QRS duration, and QTc interval The following assessments will be done prior to study drug infusion on Cycle 1 Day 1:
- *Weight* - Serum sample for anti-OMP-59R5 antibody on all subjects - Blood sample for biomarker - Plasma sample for OMP-59R5 PK from subjects enrolled in Phase 1b portion only - *Hair follicle samples (6 hairs) collected from subjects enrolled in Phase 1b portion only* - Blood sample for pharmaco-genomics (Optional and only if subject has signed the separate pharmacogenomics Informed Consent Form)
- Concomitant medications - Vital Signs Previously Read: 11.2.2.1 Day 1 of Cycles 2-6 Now Reads:
11.2.2.1 Day 1 (*± 1 day***) of Cycles 2-6** Previously Read: 11.2.4.1 Day 1 of Cycle 7 and every cycle thereafter Now Reads: 11.2.4.1 Day 1 *(± 1 day)* **of Cycle 7 and every cycle thereafter**
appendix i protocol amendment summary
11.3 treatment termination previously read

Subjects who have agreed to the optional tumor core biopsy in the Informed Consent and have pre and post-treatment optional tumor biopsy collected, will have tumor core biopsy at the time of progression if feasible.  
Subjects who have agreed to the optional tumor core biopsy in the Informed Consent and have pre and post-treatment optional tumor biopsy collected, will have tumor core biopsy at the time of *treatment termination visit*, if feasible.
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) 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 according to standard of care until documented disease progression or initiation of new anti-cancer therapy, whichever is sooner.
appendix i protocol amendment summary
previously read

…The incidence of adverse events in each treatment group will be tabulated by NCI-CTCAE v 4.03 grade and relationship to study drug. Now Reads: …The incidence of adverse events in each treatment group will be tabulated by NCI-CTCAE v 4.02 grade and relationship to study drug.
appendix i protocol amendment summary
notes to appendix b and

Additional tests were added and the Schedule of Assessments Tables were revised to reflect changes made in the protocol. Footnotes were revised accordingly.