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progression-free survival and duration of

The secondary endpoint of PFS based on the Investigator assessment of tumor response, is defined as the number of days from randomization until death or disease progression as defined by the RECIST v1.1 criteria for the ITT Population. Deaths that occur more than 49 days (1 tumor assessment + 7 days) after the last tumor assessment will not be accounted as PFS events. The Kaplan-Meier method will be used to estimate the proportion of subjects without progression or death over time and the median progression-free survival time. The 95% confidence intervals for median progression-free survival time will also be calculated for each treatment arm. The p-values for the demcizumab treatment effects will be generated using a stratified log rank test. A stratified Cox proportional hazards regression model will be used to estimate the hazard. The stratification factors will be smoking status (current versus former or never) and region (Australia/Europe versus North America). Subjects who have not experienced death or progression by their last contact will be censored at the time of their last radiographic response assessment and the number and percentage of these subjects will be displayed. In addition subjects who receive non-protocol therapy will be censored at the point they start this treatment. Radiotherapy and surgery directed at a disease site will be considered non-protocol therapy. Bisphosphonates and hormones will not be considered non-protocol therapy. If there is a disparity in discontinuation rates between treatment arms or in the types of censoring or in the use of non-protocol therapy, sensitivity analyses will be performed to assess the impact. In addition, for subjects who died or progressed after an extended lost-to-follow-up period (greater than 17 weeks from the previous assessment), PFS will be right censored at the date of the last adequate assessment prior to the lost to follow-up period. Subjects who do not have any tumor assessments will be treated as censored at Day 0. PFS based on the IRF (optional) assessment of tumor response will be similarly defined with performance status and prior history of smoking being the stratification factors. The optional IRF assessment will be performed if the Investigator-assessed efficacy data show a sufficiently positive trend in favor of the combined demcizumab arms. In addition to the log rank test, the wilcoxon test will also be used as a sensitivity analysis to evaluate the impact of treatment on progression free survival. To evaluate the impact of the second course of demcizumab therapy, a cox regression analysis will be used with a time dependnent covariate to capture the affect of the second course of demcizumab. The two demcizumab arms will be pooled and compared with control. A timedependent variable to capture the effect of the second course of demziumab will be used. The variabe will be zero unless a subject has started a second course of demcizumab which case the variable will assume the value of 1. A standard variable will also be included in the model to capture the randomized assignment of subjects to control or demcizumab (pooled).
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14.4.5 continuous variable assessment of

The tumor length will be calculated as the sum of the longest diameters for the target lesions (as defined by RECIST v1.1 criteria and determined by both the Investigator and the IRF [optional]). The data will be displayed graphically with waterfall plots. Summary statistics including mean, standard deviation, median, minimum, and maximum for tumor length will be presented for baseline, as well as 6, 12 and 18 weeks post baseline. These summary statistics will also be presented for differences from baseline at 6, 12 and 18 weeks post baseline. Along with the summary statistics, the 95% confidence intervals of the mean tumor length for each treatment arm at each of the three timepoints will also be presented. An ANCOVA model will be used to test the hypothesis that there is no difference between treatment arms with regard to changes from baseline tumor length at scheduled tumor assessments. Treatment and ECOG PS and region will be factors in the model and baseline tumor length will be used as a covariate. Missing values will not be imputed. In the event that the parametric assumptions are not met, the p-value will be generated using a nonparametric test utilizing ranks. This nonparametric test will be performed at scheduled tumor assessments, using the log of (tumor length at week X divided by tumor length at baseline) as the endpoint. In the case of complete response when the outcome variable is undefined, the best possible rank will be assigned. In the case of death or withdrawal due to AE, the worst possible rank will be assigned.  
In addition, the rate of change in tumor volume at progression (sum of the longest diameters
(SLD) at progression - SLD at nadir)/SLD at nadir as determined by both the Investigator and the IRF (optional) will be compared between the two arms of the study. The rate of change in tumor burden at progression has been associated with survival (references)
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14.4.6 duration of response

The Investigator-assessed and IRF-assessed (optional) duration of response are defined as the time from the first partial or complete response to the time of death or disease progression for subjects with a confirmed response. Subjects who have not experienced death or progression by their last contact will be censored at the time of their last radiographic response assessment. The Kaplan-Meier method will be used to estimate the duration of response. The 95% confidence intervals for duration of response will also be calculated for each treatment arm. The p-value for treatment effect will be generated using a Cox proportional hazards model.
figure 8 percent change in
sites of progression

The sites of progression as determined by the Investigator and by the IRF (optional) will be classified according to organ type and compared between the two arms of the study using a chisquare test. If a subject has a new site of disease, that site will be used as the organ site. If a subject has no new site of disease then the organ site will be classified as existing tumor. Two chi-square tests will be performed, one using the classification existing organ site versus other and the second using the full classification described above.
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14.4.7 overall survival

A comparison of the overall survival for the combined demcizumab arms with control will be performed. Overall survival is defined as the number of days from randomization until death occurs. Subjects who have not experienced death by their last contact date will be censored at that time. No treatment cross-over is permitted in the study. The Kaplan-Meier method will be used to estimate both the survival curves and the median survival time. The 95% confidence interval for the median survival time will be calculated. A p-value for treatment effect will also be generated using a stratified Cox proportional hazards model. The stratification factors will be smoking status (current versus former or never) and region (Australia/New Zealand versus Europe versus North America). The number and percentage of these subjects who are treated as an event and as a censor will be displayed. If there is a disparity in discontinuation rates between treatment arms, a sensitivity analysis will be performed to assess the impact. Two analyses of survival will be undertaken, one at the time of the final analysis for PFS and the second 9 months after the time of the PFS analysis. A number of secondary analyses for OS will be undertaken. First, the log rank test and the hazard ratio estimate will be determined using only patients who survived beyond 10 months. Next, a robust test procedure which adaptively weights which time points receive the greatest weights in the construction of the test will be applied (Ref 36). This test is based on weighted KM curve differences, and the weighting is data-dependent. To supplement the model-based hazard ratio estimate, we will calculate the difference in the area under the KM curves between the control arm and the pooled demcizumab arms restricted up to the time point T, which is the minimum of the two largest observed death times from the two arms combined. Finally we will compare the hazard of death in the pooled demcizumab arms of the trial between those subjects who lived past 10 months and those subjects who did not. The estimate of the hazard will be simply the number of events observed divided by the amount of follow-up time. Testing will be based on a Z test using 1/number of events as the variance for the log(hazard). In addition to the analyses described above, OS analyses will be undertaken to identify a subgroup of subjects who may derive a large benefit from the experimental treatment. First we will evaluate OS between the control arm and the pooled demcizumab arms of the trial in those subjects whose baseline albumin level is greater than 0.7*LLN + 0.3*ULN. Then we will cast a wider net by applying the method of Li et al (Ref 37) to the following list of baseline covariates: baseline albumin, LDH, alkaline phosphatase, ECOG PS, and smoking status (others may be added).
figure 8 percent change in
14.4.8 landmark survival

The Kaplan Meier estimates of survival at 6, 12, 18 and 24 months will be compared between the demcizumab arms and control using a simple Z test. Greenwood's formula for the variance of the survival estimate will be used to construct the Z-test.
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14.4.9 exploratory endpoints

Exploratory endpoints include blood markers (see Section 11.0). These endpoints will be analyzed using the Intent-to-Treat Population. The correlation of changes in these endpoints with tumor response (best response and PFS) and extended survival past 10 months will be explored.
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14.5 termination criteria

Randomization was terminated after 82 subjects had been randomized. All ongoing subjects will continue to be dosed until disease progression, subject withdrawal, or the Investigator withdraws subjects from the study.
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14.6 deviation reporting

The following protocol deviations will be recorded and summarized for the Intent-to-Treat population in the final report: 1) randomization violations, 2) dosing violations, 3) concomitant therapy violations, and 4) continuation of therapy when treatment should have been discontinued.
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15.0 direct access to source

By participating in this trial, the investigator(s)/institution(s) agree to permit trial-related monitoring, audits, IRB/IEC(s) review by OncoMed and its representative and regulatory inspection(s) by providing direct access to all primary source documents, such as medical records, CT scans, etc.
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16.0 ethical considerations

This study will be conducted according to international standards of Good Clinical Practice (ICH guidance E6).
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17.0 investigator requirements 17.1 informed

A sample informed consent form will be provided. OncoMed or PPD must review any proposed deviations from the sample informed consent form prior to submission to the IRB/IEC. The final IRB/IEC-approved document must be provided to OncoMed for regulatory purposes. The informed consent document must be signed and dated by the subject or the subject's legally authorized representative before his/her participation in the study. Documentation is required in each subject's record that informed consent was obtained prior to participation in the study. A copy of the informed consent document must be provided to the subject or the subject's legally authorized representative.  
Signed consent forms must be kept in each subject's study file and must be available for review/verification by study monitors at any time.
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17.2 institutional review board/ethics committee

This protocol, the informed consent documents, and relevant supporting information must be submitted to the IRB or IEC for review and must be approved before the study is initiated. The study will be conducted in accordance with regulatory requirements and IRB or IEC requirements. The Principal Investigator is responsible for keeping the IRB or IEC apprised of the progress of the study and of any changes made to the protocol as deemed appropriate. The IRB or IEC must be updated at least once a year or in accordance with local requirements. The Principal Investigator must also inform the IRB or IEC of any significant AEs.  
Investigators are required to follow their respective IRB or IEC requirements for the reporting of SAEs and written safety reports to the IRB or IEC. Investigators must immediately forward to their IRBs or IECs any written safety report or update provided by OncoMed (e.g., Investigator Brochure, safety amendment, etc.)
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17.3 study monitoring

Site visits will be conducted on a regular basis by an authorized OncoMed representative (e.g., CRA) to inspect study data, subjects' medical records, and remote data capture (RDC)
fields in accordance with current U.S. GCPs. During the site visit, the OncoMed CRA or representative will review the following:  
- Completeness of subject records - Accuracy of entries in the RDC fields - Adherence to the protocol and to GCP - Adherence to specifications for demcizumab storage, dispensing, and accountability
The OncoMed CRA or representative will be responsible for reviewing completed RDC fields and clarifying and resolving any data queries. The CRA will also review regulatory study documents during site visits. The investigator and key study personnel must be available to assist the OncoMed monitor or representative during these visits. The Principal Investigator will permit authorized representatives of OncoMed and any regulatory authority to inspect facilities and records relevant to this study.
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17.4 auditing procedures

A representative of OncoMed may conduct an audit of the clinical research activities to ensure accordance with internal standard operating procedures (SOPs) and to evaluate compliance with the principles of GCP. Any regulatory authority may also conduct an inspection during the study or after its completion. If an inspection is requested by a regulatory authority, the investigator must inform OncoMed of this immediately.
figure 8 percent change in
17.5 data collection

The data will be reported by the site via an internet-based remote data entry capture (RDC). The RDC screens should be completed in accordance with instructions from OncoMed. The RDC screens should be completed by examining personnel, the study coordinator, or designee. The RDC screens must be reviewed by the investigator. The investigator will ensure that all data is completely and accurately recorded on the RDC screens.
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17.6 investigational medicinal product accountability

All IMP required for completion of this study will be provided by OncoMed or its agent. The recipient will acknowledge receipt of this IMP by *confirming receipt in the IWRS system*. Damaged supplies will be replaced. Accurate records of all IMP dispensed from and returned to the pharmacy should be documented by completing the Drug Accountability Log. Sites will destroy and document destruction on the Investigational Medicinal Product Return or Destruction Form, or return all unopened, unused, and expired vials to the drug distribution center along with a completed Investigational Drug Product Return or Destruction Form. Sites must have appropriate processes or SOPs and capabilities, in order to destroy study drug.  
All IMP Accountability Forms will be provided by OncoMed. Upon agreement by OncoMed, the site may use its own IMP Accountability Log if it contains all of the information required on OncoMed's log.
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17.7 disclosure of data and

Subject medical information obtained by this study is confidential, and disclosure to third parties other than those noted below is prohibited. Upon the subject's permission, medical information may be given to his or her personal physician or other appropriate medical personnel responsible for his/her welfare. Data generated by this study must be available for inspection upon request by representatives of any regulatory authority, auditors, OncoMed representatives, and the local IRB or IEC for each study site. OncoMed commits to publish the study results. The manuscript will include all subjects from all sites. The Investigators will participate in writing and reviewing the manuscript. OncoMed will make the final decision on all presentations of study results and submissions of abstracts and manuscripts working in good faith with the Investigators.
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17.8 retention of records

Regulations require that records and documents pertaining to the conduct of this study and the distribution of investigational drug, including consent forms, laboratory test results, study medication inventory records, and regulatory documents, must be retained by the Principal Investigator for 2 years after marketing application approval. If no application is filed, these records must be kept for 2 years after the study is discontinued and the applicable regulatory authorities are notified. OncoMed will notify the Principal Investigator of these events.
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18.0 references

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| Screeninga                                     | On Study                                                       |    |     |    |    |    |    |    |    |    |    |     |     |     |     |     |      |
|------------------------------------------------|----------------------------------------------------------------|----|-----|----|----|----|----|----|----|----|----|-----|-----|-----|-----|-----|------|
| (pemetrexed, carboplatin + demcizumab/placebo) | On Study                                                       |    |     |    |    |    |    |    |    |    |    |     |     |     |     |     |      |
| (pemetrexed maintenance)                       | Termination Visit  Followup  Period                                                                |    |     |    |    |    |    |    |    |    |    |     |     |     |     |     |      |
| Day(s)                                         | -28 to -1                                                      | 0  | 7   | 14 | 21 | 28 | 35 | 42 | 56 | 63 | 84 | 105 | 112 | 126 | 140 | 147 | 168b |
| Informed  consenta                             | X                                                              |    |     |    |    |    |    |    |    |    |    |     |     |     |     |     |      |
| Folic acidc                                    | X……………………..……………………………………………………………………………………………………………….. …………Xc |    |     |    |    |    |    |    |    |    |    |     |     |     |     |     |      |
| Vitamin  B12d                                  | X                                                              | X  | X d |    |    |    |    |    |    |    |    |     |     |     |     |     |      |
| Dexamethasonee                                                | X                                                              | X  | X   | X  | X  | X  | X  | X  | X  | X  |    |     |     |     |     |     |      |
| Pemetrexedf,g                                  | X                                                              | X  | X   | X  | X  | X  | X  | X  | X  |    |    |     |     |     |     |     |      |
| Demcizumab  or placebof,g                      | X                                                              | X  | X   | X  | Xf |    |    |    |    |    |    |     |     |     |     |     |      |
| Carboplatinf,g                                 | X                                                              | X  | X   | X  |    |    |    |    |    |    |    |     |     |     |     |     |      |
| Past medical  history                          | X                                                              |    |     |    |    |    |    |    |    |    |    |     |     |     |     |     |      |
| Height                                         | X                                                              |    |     |    |    |    |    |    |    |    |    |     |     |     |     |     |      |  
| Screeninga                                     | On Study          |                   |    |    |    |    |    |    |    |    |    |     |     |     |     |     |      |
|------------------------------------------------|-------------------|-------------------|----|----|----|----|----|----|----|----|----|-----|-----|-----|-----|-----|------|
| (pemetrexed, carboplatin + demcizumab/placebo) | On Study          |                   |    |    |    |    |    |    |    |    |    |     |     |     |     |     |      |
| (pemetrexed maintenance)                       | Termination Visit | Follow- up Period |    |    |    |    |    |    |    |    |    |     |     |     |     |     |      |
| Day(s)                                         | -28 to -1         | 0                 | 7  | 14 | 21 | 28 | 35 | 42 | 56 | 63 | 84 | 105 | 112 | 126 | 140 | 147 | 168b |
| Physical  examinationh                         | X                 | X                 | X  | X  | X  | X  | X  | X  | X  | X  | X  |     |     |     |     |     |      |
| Weight                                         | X                 | X                 | X  | X  | X  | X  | X  | X  | X  | X  | X  | X   | X   | X   | X   |     |      |
| Vital signsi                                   | X                 | X                 | X  | X  | X  | X  | X  | X  | X  | X  | X  | X   | X   | X   | Xj  |     |      |
| ECOG  performance                              | X                 | X                 | X  | X  | X  | X  | X  | X  | X  | X  | X  | X   | X   | X   | X   |     |      |
| status  CBC with  differential                 | X                 | X                 | X  | X  | X  | X  | X  | X  | X  | X  | X  | X   | X   | X   | X   |     |      |
| and platelet  count  Chemistryk                | X                 | X                 | X  | X  | X  | X  | X  | X  | X  | X  | X  |     |     |     |     |     |      |  
| Screeninga                                     | On Study                            |    |    |    |    |    |    |    |    |    |    |     |     |     |     |     |      |
|------------------------------------------------|-------------------------------------|----|----|----|----|----|----|----|----|----|----|-----|-----|-----|-----|-----|------|
| (pemetrexed, carboplatin + demcizumab/placebo) | On Study                            |    |    |    |    |    |    |    |    |    |    |     |     |     |     |     |      |
| (pemetrexed maintenance)                       | Termination Visit Follow -up Period |    |    |    |    |    |    |    |    |    |    |     |     |     |     |     |      |
| Day(s)                                         | -28 to -1                           | 0  | 7  | 14 | 21 | 28 | 35 | 42 | 56 | 63 | 84 | 105 | 112 | 126 | 140 | 147 | 168b |
| INR/aPTT                                       | X                                   |    |    |    |    |    |    |    |    |    |    |     |     |     |     |     |      |
| Serum  pregnancy                               | X                                   |    |    |    |    |    |    |    |    |    |    |     |     |     |     |     |      |
| testl Urinalysis  with micro                   | X                                   | X  |    |    |    |    |    |    |    |    |    |     |     |     |     |     |      |
| MRI or CT  of brainm                           | X                                   |    |    |    |    |    |    |    |    |    |    |     |     |     |     |     |      |
| Tumor  assessmentm                             | X                                   | X  | X  | X  | X  | X  |    |    |    |    |    |     |     |     |     |     |      |
| Tumor  marker CEA                              | X                                   | Xn | Xn | Xn | Xn | Xn |    |    |    |    |    |     |     |     |     |     |      |
| BNPo                                           | X                                   | X  | X  | X  | X  | X  | X  | X  | Xb | X  |    |     |     |     |     |     |      |
figure 8 percent change in
appendix a schedule of assessments

| Screeninga                                                                                 | On Study                                                           |                   |    |    |    |    |    |    |    |    |    |     |     |     |     |     |      |
|--------------------------------------------------------------------------------------------|--------------------------------------------------------------------|-------------------|----|----|----|----|----|----|----|----|----|-----|-----|-----|-----|-----|------|
| (pemetrexed, carboplatin + demcizumab/placebo)                                             | On Study                                                           |                   |    |    |    |    |    |    |    |    |    |     |     |     |     |     |      |
| (pemetrexed maintenance)                                                                   | Termination Visit                                                  | Follow- up Period |    |    |    |    |    |    |    |    |    |     |     |     |     |     |      |
| Day(s)                                                                                     | -28 to -1                                                          | 0                 | 7  | 14 | 21 | 28 | 35 | 42 | 56 | 63 | 84 | 105 | 112 | 126 | 140 | 147 | 168b |
| ECGp                                                                                       | X                                                                  | X                 | X  | X  | X  | X  | Xb | X  |    |    |    |     |     |     |     |     |      |
| Transthoracic  Doppler                                                                     | X                                                                  | X                 | X  | X  | X  | X  | Xb | X  |    |    |    |     |     |     |     |     |      |
| echocardiogramq CT pulmonary                                                               | If clinically significant pulmonary hypertension is diagnosed,     |                   |    |    |    |    |    |    |    |    |    |     |     |     |     |     |      |
| perform CT pulmonary angiogram (or other appropriate study) to rule out pulmonary embolism |                                                                    |                   |    |    |    |    |    |    |    |    |    |     |     |     |     |     |      |
| angiogram  (if applicable)r Concomitant  medications                                       | X………………………………………….…………………………………………………………………………………….……………X          |                   |    |    |    |    |    |    |    |    |    |     |     |     |     |     |      |
| Adverse event  evaluations                                                                 | X………………………………………….………..………………………………………………………………………………………..…………..Xs |                   |    |    |    |    |    |    |    |    |    |     |     |     |     |     |      |  
| Screeninga                                           | On Study          |                   |    |    |    |    |    |    |    |    |    |     |     |     |     |     |      |
|------------------------------------------------------|-------------------|-------------------|----|----|----|----|----|----|----|----|----|-----|-----|-----|-----|-----|------|
| (pemetrexed, carboplatin + demcizumab/placebo)       | On Study          |                   |    |    |    |    |    |    |    |    |    |     |     |     |     |     |      |
| (pemetrexed maintenance)                             | Termination Visit | Follow- up Period |    |    |    |    |    |    |    |    |    |     |     |     |     |     |      |
| Day(s)                                               | -28 to -1         | 0                 | 7  | 14 | 21 | 28 | 35 | 42 | 56 | 63 | 84 | 105 | 112 | 126 | 140 | 147 | 168b |
| Pharmacokineticst                                                      | X                 | X                 | X  | X  | Xt | X  |    |    |    |    |    |     |     |     |     |     |      |
| Antidemcizumab                                                      | X                 | X                 | X  | X  | Xu | X  |    |    |    |    |    |     |     |     |     |     |      |
| antibodyu Blood for  biomarkersv                     | X                 | X                 | X  |    |    |    |    |    |    |    |    |     |     |     |     |     |      |
| Optional  PharmacoGenomicsw                                                      | X                 |                   |    |    |    |    |    |    |    |    |    |     |     |     |     |     |      |
| Colonoscopy  and/or upper GI                         | X                 |                   |    |    |    |    |    |    |    |    |    |     |     |     |     |     |      |
| endoscopy (if  applicable)x FFPEy                    | X                 |                   |    |    |    |    |    |    |    |    |    |     |     |     |     |     |      |
| Survival data  (with date and                        | Xz                |                   |    |    |    |    |    |    |    |    |    |     |     |     |     |     |      |
| cause of death)z Subsequent                          | Xaa               |                   |    |    |    |    |    |    |    |    |    |     |     |     |     |     |      |
| therapiesaa anti-cancer  Response  assessment databb | Xbb               |                   |    |    |    |    |    |    |    |    |    |     |     |     |     |     |      |
| BNP and  Doppler                                     | Xcc               |                   |    |    |    |    |    |    |    |    |    |     |     |     |     |     |      |
| echocardiogramcc                                                      |                   |                   |    |    |    |    |    |    |    |    |    |     |     |     |     |     |      |
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notes to appendix a

Unless otherwise indicated, all assessments must be performed prior to dosing for all study visits when dosing occurs. All on-study evaluations (i.e., from Day 0 up to Termination visit) must be done within the following timeframes:
Dosing of demcizumab or placebo within ± 2 days of the Study Day Laboratory evaluations within ± 3 days of the Study Day Tumor assessment, tumor marker CEA (if applicable), ECG, and transthoracic Doppler echocardiogram within ± 7 days of the Study Day For subjects who only receive pemetrexed maintenance after discontinuation of carboplatin and demcizumab/placebo, every-three-week visits can be rescheduled accordingly if pemetrexed administration and associated assessments (i.e. physical examination, weight, vital signs, ECOG performance status, CBC, and chemistry) were delayed for adverse or other unforeseen events. In addition, if the timing of a protocol-mandated study visit coincides with a holiday or weekend that precludes the visit, the visit should be scheduled on the nearest following feasible date, with subsequent visits rescheduled accordingly. Pemetrexed cycles may be extended from 3 to up to 4 weeks to realign assessments.  
Subjects who have discontinued all study drugs and have no clinically significant ongoing related adverse events that require close follow-up have to undergo the following assessments only every 42 days (ideally synchronized with tumor assessments and tumor marker CEA, if applicable): physical examination, weight, vital signs, ECOG performance status, CBC, and chemistry.  
However, the schedule for BNP assessments (every 21 days; see footnote o. for more details), for ECG and transthoracic Doppler echocardiogram (every 28 days; see footnotes p.  
and q. for more details), and for tumor assessment and tumor marker CEA, if applicable (every 42 days), is to be maintained.  
a. Subjects must sign and date the Informed Consent Form (Appendix E) that has been approved by the IEC/IRB prior to undergoing any study-related procedures. Once the screening process has been completed, the Investigator must complete a randomization request form and submit it for approval. Once OncoMed or its representative has approved randomization, the investigator/study coordinator will use the IWRS system to randomize the subject. Subjects who are randomized will not be replaced. The IWRS
system will then assign a subject number, and the subject will be officially enrolled in the study. This unique subject number will be on all electronic case report form (eCRF)
pages. Study drug must be administered within 4 days from the date of randomization. Study Day 0 will be the first day of study drug administration.  
b. **The frequency of assessments from Days 168 to 252 (then Days 252 to 336, and so on) is the same as shown for the 84-day time window from Days 84 to 168.**
Four types of assessments are exceptions to this general rule as they are eventually discontinued.  
**BNP: see footnote o.**  
**ECG: see footnote p.**
figure 8 percent change in
doppler echocardiogram see footnote q.

**Pharmacokinetics: see footnote t.**  
c. Subjects must receive oral folic acid ≥400 μg daily for at least 5 days of the 7 days preceding the first dose of pemetrexed and continue folic acid at this dose level during the full course of therapy and for 21 days after the last dose of pemetrexed.  
d. Subjects must receive an IM injection of vitamin B12 1000 μg during the week preceding the first dose of pemetrexed and then every 63 days while receiving pemetrexed.  
e. Unless contraindicated, subjects should also receive dexamethasone 4 mg orally twice daily on the day before, the day of, and the day after pemetrexed administration to reduce the risk of developing skin rash.  
f. Arm 1 - carboplatin, pemetrexed plus placebo every 3 weeks for 4 cycles (i.e., last administration on Day 63), then maintenance pemetrexed once every 3 weeks beginning on Day 84 and a second course of placebo once every 3 weeks for 63 days beginning at Study Day 168 Arm 2 - carboplatin, pemetrexed plus demcizumab every 3 weeks for 4 cycles (i.e., last administration on Day 63), then maintenance pemetrexed once every 3 weeks beginning on Day 84 and a course of placebo once every 3 weeks for 63 days beginning at Study Day 168 Arm 3 - carboplatin, pemetrexed plus demcizumab every 3 weeks for 4 cycles (i.e., last administration on Day 63), then maintenance pemetrexed once every 3 weeks beginning on Day 84 and a second course of demcizumab once every 3 weeks for 63 days beginning at Study Day 168 Subjects will only receive their second 4-cycle course (starting on Day 168) of demcizumab (5 mg/kg) or placebo if they meet the original cardiac-related eligibility criteria (see Exclusion Criterion 21 in Section 6.2), they did not develop pulmonary hypertension or heart failure while on study, and blood pressure is controlled to ≤140/90 mmHg.  
Subjects who do not meet the criteria to receive the second 4-cycle course of placebo or demcizumab will continue to receive maintenance pemetrexed per protocol without demcizumab or placebo.
figure 8 percent change in
notes to appendix a cont'd

g. Demcizumab or placebo, pemetrexed and carboplatin must be dosed as described in Section 8.0. Demcizumab or placebo is to be administered first, followed by pemetrexed and then carboplatin.  
h. A full physical examination will be done at screening. Subsequently, an abbreviated physical examination will be performed at Day 0, every 3 weeks during the on-study part of the protocol and at the termination visit. The abbreviated physical examination must include respiratory rate, auscultatory examination of the heart and lungs, abdominal examination, and assessment for the presence or absence of edema and/or ascites. A more complete physical examination should be conducted when clinically indicated.  
i. On days of demcizumab or placebo dosing, vital signs will be obtained before infusion (- 1 hour), 15 (±5) minutes after start of infusion, end of infusion (+ 5 minutes), and 15 (±5) minutes after end of infusion of demcizumab or placebo.  
Vitals will be obtained once at the visits where demcizumab or placebo is not administered, prior to pemetrexed (and/or carboplatin) infusion, if applicable.  
j. Any subject with hypertension (i.e., >150/90 mmHg) that is considered to be related to demcizumab or placebo at the time of the termination visit will continue to have BPs monitored once every 2 weeks until the BP is ≤150/90 mmHg over a 4-week period with every-2-week BP measurements.  
k. Albumin, alkaline phosphatase, total bilirubin, bicarbonate, BUN, calcium, chloride, creatinine, glucose, LDH, phosphorus, potassium, total protein, AST (SGOT),
ALT (SGPT), sodium l. Serum pregnancy test (women of childbearing potential only) must be obtained within 7 days prior to randomization.  
m. Perform tumor assessment at screening (Study Days -28 to -1), every 6 weeks thereafter until disease progression, and at the termination visit (unless performed within 14 days of termination or at a prior response evaluation that documented progressive disease). The schedule of every 6 weeks is to be maintained throughout the study and will not be shifted if there are dose holds.  
Screening assessments should include CT scans of the chest, abdomen, and pelvis, as well as MRI of the brain. CT scan of the neck or bone scan should be performed if clinically indicated. A documented standard-of-care tumor assessment performed on or after Study Day -28 may be used for the screening assessment provided it meets protocol requirements. Alternative imaging modalities may be used as outlined in Section 10.0. Subsequent tumor assessments must include imaging of chest and abdomen, as well as all other known sites of disease. The same imaging methods used at screening must be used throughout the study. Response assessments will be performed by the investigator according to RECIST v1.1 (Appendix C).  
n. If elevated at baseline o. **BNP must be assessed on the same day prior to each dose of demcizumab/placebo**, and elevations will be managed per Section 8.1.6. After discontinuation of demcizumab or placebo (either as scheduled per protocol or unscheduled for other reasons), BNP assessments are continued every 21 days for another 105 days (5 assessments total). For example, if the last scheduled demcizumab or placebo dose is given on Day 231, a total of 5 more BNP assessments will occur on Days 252, 273, 294, 315 and 336. However, should the BNP result not meet eligibility criteria at the last assessment 105 days after the last demcizumab or placebo dose, BNP assessments have to be continued every 21 days until two consecutive assessments meet eligibility criteria or the termination visit has occurred.  
p. A 12-lead ECG must include assessment of the PR interval, QRS duration, and QTc interval and must be done every 28 days. After discontinuation of demcizumab or placebo
(either as scheduled per protocol or unscheduled for other reasons), ECG assessments are continued every 28 days for ≥105 days. For example, if the last scheduled demcizumab or placebo dose is given on Day 231, a total of 4 more ECG assessments will occur on Days 252, 280, 308 and 336. Clinically significant ECG abnormalities at the last assessment ≥105 days (depending on timing of assessments) after the last demcizumab or placebo dose should be addressed according to standard of care. ECG does not have to be repeated at the termination visit if it was performed within 14 days of the termination visit.  
q. A Doppler echocardiogram with left ventricular ejection fraction and peak tricuspid velocity determination, if measurable, must be done every 28 days. After discontinuation of demcizumab or placebo (either as scheduled per protocol or unscheduled for other reasons), Doppler echocardiogram assessments are continued every 28 days for ≥105 days.  
For example, if the last scheduled demcizumab or placebo dose is given on Day 231, a total of 4 more ECG and Doppler echocardiogram assessments will occur on Days 252, 280, 308 and 336. However, should results of the Doppler echocardiogram not meet eligibility criteria at the last assessment ≥105 days (depending on timing of assessments)
after the last demcizumab or placebo dose, assessments have to be continued every 28 days until two consecutive Doppler echocardiograms meet eligibility criteria or the termination visit has occurred. Doppler echocardiogram does not have to be repeated at the termination visit if it was performed within 14 days of the termination visit.  
r. A CT pulmonary angiogram (CTPA) should be performed if clinically significant pulmonary hypertension is diagnosed (i.e, peak tricuspid velocity >3.4 m/s on Doppler echocardiogram and diagnosed with clinically significant pulmonary hypertension that includes minimal dyspnea by a cardiologist or pulmonologist) to determine if pulmonary embolism might be the cause of the pulmonary hypertension. An MR angiogram or VQ scan may be performed instead per local or country standards or if the subject has a contrast allergy.  
s. To be collected from randomization until 30 days after the termination visit.  
t. Plasma samples for PK analysis will be obtained prior to the demcizumab/placebo infusion, if applicable, on Days 0, 42, 84, 126, 168, 210, 252, 294 and 336, and at the end of the demcizumab/placebo infusion (prior to the chemotherapy infusion, if applicable) on Days 0, 42, 168 and 210, and at the termination visit. Instructions for the collection handling, storage, and shipment of these samples are provided in the Study Reference Binder.  
u. Serum samples for immunogenicity will be obtained at baseline, every 6 weeks (prior to the demcizumab or placebo infusion, if applicable) during the study, and at the termination visit. Instructions for the collection, handling, storage, and shipment are provided in the Study Reference Binder.  
v. A total of 9 mL of blood will be drawn for biomarkers on Days 0 and 28, and at the termination visit, unless one has been obtained during the prior 14 days for subjects continuing on demcizumab/placebo to evaluate changes in plasma proteins (4 mL; e.g., VEGF, βFGF, SDF1, PLGF, TNFα, MCP1, etc.), and Notch-related gene expression of mRNA (5 mL) as described in Section 11.0. Instructions for the collection, handling, storage, and shipment are provided in the Study Reference Binder.  
w. For subjects who sign the optional Pharmacogenomics Informed Consent only, a blood sample (10 mL) will be collected at Day 0 (where local regulations permit). Analysis of genes relevant to Notch/DLL4 target or pathway genes may be performed (e.g., FBW7 and PTEN). Instructions for the collection, handling, storage, and shipment of these samples are provided in the Study Reference Binder x. Colonoscopy and/or upper gastrointestinal endoscopy must be performed in subjects with symptoms suggestive of possible gastrointestinal involvement to rule out gastrointestinal involvement.  
y. If available, archival FFPE tumor tissue (from either the primary tumor, locoregional disease or a metastatic site) obtained by core biopsy or surgical resection will be collected.  
Analysis of candidate genes and/or proteins relevant to the Notch pathway may be performed (e.g., DLL4, Notch1, Hey 1, FBW7, etc.). Archived FFPE specimens may be obtained during screening or post-screening, as long as the trial is active. Instructions for the collection, handling, storage, and shipment of these samples are provided in the Study Reference Binder.  
z. Once a subject has completed the termination visit, overall survival follow-up will be performed every three months ± 1 week for up to 5 years to determine the subject's status and ultimately the date and cause of death. Follow-up may be conducted through telephone calls, review of medical records, and/or clinic visits. In addition, the site may check public data sources to get this information, if needed (e.g., obituaries).  
aa. Subsequent anti-cancer therapies, including systemic therapies, surgery (resection of metastatic disease), and radiation therapy will be collected through telephone calls, review of medical records, and/or clinic visits on the same schedule as for survival data (see note z.).  
bb. Response assessment data (i.e., progressive disease or no progression of disease) will continue to be collected (based on standard-of-care radiographs) on subjects who have not progressed at the time of the termination visit. For these subjects, copies of the standard-of-care radiographs may be provided to the Sponsor in a de-identified manner. These data and radiographs will continue to be collected until the subject starts new anti-cancer treatment or develops progressive disease, whichever occurs first.  
cc. If a subject has a BNP of ≥400 pg/mL and/or a diagnosis of pulmonary hypertension or heart failure at the time of the termination visit, all subsequent standard-of-care BNP
data until the value is <200 pg/mL and all subsequent standard-of-care LVEF and PTV values until they normalize will be collected and entered into the database.
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appendix b ecog performance status

| ECOG Performance Status Scale   |                                                                                                                                                                               |
|---------------------------------|-------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|
| Grade                           | Descriptions                                                                                                                                                                  |
| 0                               | Normal activity. Fully active, able to carry on all pre-disease performance without  restriction.  Symptoms, but ambulatory. Restricted in physically strenuous activity, but |
| 1                               | ambulatory and able to carry out work of a light or sedentary nature (e.g., light  housework, office work).                                                                   |
| 2                               | In bed <50% of the time. 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                               | In bed >50% of the time. Capable of only limited self-care, confined to bed or  chair more than 50% of waking hours.                                                          |
| 4                               | 100% bedridden. Completely disabled. Cannot carry on any self-care. Totally  confined to bed or chair.                                                                        |
| 5                               | Dead                                                                                                                                                                          |
figure 8 percent change in
eligibility

Only subjects with measurable disease at baseline should be included in protocols where objective tumor response is the primary endpoint.  
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:
figure 8 percent change in
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.
figure 8 percent change in
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.
figure 8 percent change in
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.
figure 8 percent change in
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.
figure 8 percent change in
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 Appendix II (Ref 34) 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).
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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 portions 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 subjectwith 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 subjectwith 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.
figure 8 percent change in
response criteria evaluation of target

| Complete Response (CR):   | Disappearance of all target lesions. Any pathological lymph node (whether  target or nontarget) 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  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. |
| Progressive Disease (PD): | Neither sufficient shrinkage to qualify for PR nor sufficient increase to                                                                                                                                                                                                                                                                                                                                                                                                                                       |
| Stable Disease (SD):      | qualify for PD, taking as reference the smallest sum diameters while on  study.                                                                                                                                                                                                                                                                                                                                                                                                                                 |  
| Disappearance of all non-target lesions and normalization of tumor marker                                                                             |                                                                                                                                                |
|-------------------------------------------------------------------------------------------------------------------------------------------------------|------------------------------------------------------------------------------------------------------------------------------------------------|
| Complete Response (CR):                                                                                                                               | 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. |                                                                                                                                                |
figure 8 percent change in
evaluation of non-target lesions evaluation

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. Symptomatic deterioration is not a descriptor of an objective response: it is a reason for stopping study therapy. The objective response status of such patients is to be determined by evaluation of target and non-target disease 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.
figure 8 percent change in
confirmation

Confirmation of response is not required in this randomized study since the control arm serves as an appropriate means to interpret the data.
figure 8 percent change in
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).
figure 8 percent change in
appendix d new york heart

| NYHA  Class   | Symptoms                                                                                                                                                     |
|---------------|--------------------------------------------------------------------------------------------------------------------------------------------------------------|
| I             | Cardiac disease, but no symptoms and no limitation in ordinary physical activity, e.g. no  shortness of breath when walking, climbing stairs etc.            |
| II            | Mild symptoms (mild shortness of breath and/or angina) and slight limitation during  ordinary activity.                                                      |
| III           | Marked limitation in activity due to symptoms, even during less-than-ordinary activity, e.g.,  walking short distances (20-100 m). Comfortable only at rest. |
| IV            | Severe limitations. Experiences symptoms even while at rest. Mostly bedbound subjects.                                                                       |
figure 8 percent change in
appendix e sample informed consent

PROTOCOL M18-007: A 3-Arm Phase 2 Double-Blind Randomized Study of Carboplatin, Pemetrexed Plus Placebo versus Carboplatin, Pemetrexed plus 1 or 2 Truncated Courses of Demcizumab in Subjects with Non-Squamous Non-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. If you have any questions that are not answered or if there are words that you do not understand in this consent form, a member of the research team will give you further 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. You are being asked to participate in this research study because you have been diagnosed with advanced non-squamous non-small cell lung cancer that is no longer operable.
figure 8 percent change in
purpose and background

Current cancer therapies often produce an initial reduction in tumor size but may not have longterm 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 represent 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 purpose of this study is to test the efficacy and safety of a new experimental drug, demcizumab, when given in combination with carboplatin and pemetrexed. To evaluate the efficacy of demcizumab, demcizumab will be compared to placebo (looks like demcizumab, but does not contain any medication). The administration of carboplatin and pemetrexed is a standard treatment for patients with non-squamous non-small cell lung cancer. You will also be given 2 vitamins (folic acid and vitamin B12) and 1 corticosteroid (dexamethasone) to reduce the adverse effects of pemetrexed. Demcizumab is a humanized monoclonal antibody and was developed to target cancer stem cells. Demcizumab may block the growth of cancer stem cells and the remaining cancer cells, and it may also prevent the growth of new blood vessels that tumors need to grow and spread. Demcizumab, used in this study, is experimental. That means that the United States Food and Drug Admininstration (FDA) has not approved it for use by the general public. This study is sponsored by OncoMed Pharmaceuticals, which is referred to as OncoMed or the Sponsor in this consent form.
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what is expected from you?

When deciding whether to participate, consider whether you are able and willing:
To follow the study rules To commit the time required to keep appointments To tell the study doctor truthfully about your complete medical history To report any new problems, illnesses, or changes in medication during the study
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procedures

At least 201 patients will be enrolled at up to approximately 60 to 90 centers in North America, Western Europe and Australia. Up to 28 days (4 weeks) prior to treatment you will undergo testing to determine your eligibility to take part in this study, and then, if enrolled in the study, you will receive intravenous (in the vein) infusions of demcizumab (or placebo), carboplatin, and pemetrexed administered on the same day, every 21 days for 4 cycles, or until it has been shown that your cancer has gotten worse. If your physician decides to delay treatment with one of the agents due to side effects, the other agents may still be administered as scheduled. After 4 cycles, if you have stable or improved disease, you will continue to receive pemetrexed once every 21 days as maintenance therapy. After 8 cycles, if you have stable or improved disease, you will receive demcizumab (or placebo), every 21 days for 4 more cycles. You will undergo assessments every 6 weeks to determine the status of your disease. In addition to routine testing of blood and urine (for complete blood counts with differential and platelets; coagulation studies to determine how quickly your blood is clotting; serum chemistries; B-type natriuretic peptide [BNP], which indicate how well your heart is working; creatinine clearance to measure your kidney function; and urinalysis), special tests will be performed during the study at specific time points listed below. The special tests include the following:
Tumor markers: These are substances that can be detected in higher than normal amounts in blood, urine, or body tissues for certain types of cancer. The tumor marker level may indicate the extent of the cancer in your body and may show how you are responding to treatment. For this study, only blood samples will be taken to check for tumor markers. The tumor marker for non-small cell lung cancer is CEA. If your baseline CEA tumor marker is not elevated, the test will not be repeated during the study. If your baseline CEA is elevated at baseline, the test will be repeated every 6 weeks.  
Antibodies to demcizumab: Antibodies are proteins produced by your body's immune system in response to a foreign substance. In some cases, the development of antibodies to a treatment will not have any impact on the effectiveness of the treatment. In other cases, the development of antibodies to a treatment can cause the treatment to be ineffective. Blood will be drawn every 6 weeks while you are receiving study drugs (demcizumab or placebo, or carboplatin or pemetrexed) and at the termination visit to determine if you are developing antibodies to demcizumab. Additional testing may also be done to provide information on the response seen in the demcizumab test. Various experiments would be performed on the samples taken from you for antibodies to demcizumab testing. These experiments will determine the identity and obtain more detailed information on the anti-drug antibody response.  
Pharmacokinetic Analysis: Blood samples will be obtained prior to your demcizumab (or placebo) infusion on Study Days 0, 42, 84, 126, 168, 210, 252, 294 and 336, and at the end of infusion on Study Days 0, 42, 168 and 210, and at your termination visit, to determine how the demcizumab is distributed and eliminated from your body.  
Biomarkers: On Study Days 0 and 28, and at your termination visit, blood samples will be obtained to assess whether the demcizumab is producing desired changes to the genes and proteins related to your cancer. In addition, archival tumor tissue sections (formalinfixed paraffin-embedded, FFPE) will be collected any time after enrollment, if available, for gene and protein testing of biomarkers related to your cancer. No additional procedures or surgery will be performed to obtain these archival tumor tissue sections. If you agree to have DNA testing on your FFPE tissue, you will sign a separate consent. DNA testing of your tumor may help to identify biomarkers that could be used in the future to predict which patients are more likely to respond to demcizumab, carboplatin and pemetrexed treatment.  
In addition, you will have an electrocardiogram (ECG) and Doppler echocardiogram performed during screening, then every 28 days on study (up to Study Day 336, assuming you receive all doses of demcizumab/placebo) and at your termination visit. Your Doppler echocardiograms may be sent to a cardiologist at another hospital who may perform a central read on some of the Doppler echocardiograms in this study. Finally, you will have imaging of your brain (magnetic resonance imaging [MRI] or computerized tomography [CT]) at baseline, and CT scans and/or other radiographs performed at baseline, then every 6 weeks, and at your termination visit, to assess the status of your tumor. A CT pulmonary angiogram (CTPA; or MR angiogram or VQ scan) may be performed if you are diagnosed with pulmonary hypertension to see if you have a pulmonary embolism.
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screening

If you volunteer to be in this study and you sign this informed consent form, you will be screened within 28 days before study entry to make sure that you are a suitable candidate. No study-related tests will be performed prior to signing this informed consent form. Your doctor will conduct a review of your physical health and medical history, including other cancer treatments that you have had and a review of any medications you are or have been taking. In addition, a physical examination including height and weight will be performed, and vital signs including your pulse, blood pressure, breathing rate and temperature will be measured. Blood and urine samples will be collected for routine testing, including BNP. Blood will also be drawn for testing of the tumor marker CEA. Approximately 3 tablespoons of blood will be taken at this visit. You will also have an ECG, Doppler echocardiogram, and either a CT scan or MRI of your chest, abdomen, pelvis, and head. Finally, if your tumor involves your esophagus, stomach, or intestinal tract or if you have symptoms that suggest that your tumor may involve these areas, you will also have a colonoscopy and/or upper gastrointestinal endoscopy to ensure that your tumor does not currently involve your gastrointestinal tract. If you are a female of childbearing potential, you will have a serum pregnancy test within 7 days prior to randomization (time when you are assigned a treatment arm), to ensure that you are not pregnant at the start of the study.
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treatment phase demcizumab (or placebo)

Once your doctor has evaluated the results of your screening tests to ensure that you meet the criteria for the study and are eligible to participate, you will be randomized in the study and assigned to a treatment arm. You will receive 5 mg/kg demcizumab or placebo as shown in the treatment arms, below. A placebo looks like the demcizumab, but does not contain any medication. The demcizumab or placebo will be administered intravenously (in the vein) over 30 minutes, every 3 weeks for 63 days, starting on Day 0 and again starting on Day 168. With each infusion, your vital signs will be obtained at least four times: before the infusion; 15 minutes after the start of the infusion, at the end of the infusion, and 15 minutes after the end of the infusion. You will be randomly (by chance) assigned to one of the three treatment arms: Arm 1:  
to receive carboplatin, pemetrexed plus **placebo** every 3 weeks for 4 cycles (last dose on Day 63)
then, starting on Day 84, to receive pemetrexed alone every 3 weeks for 4 cycles (last dose on Day 147)
then, starting on Day 168, to receive pemetrexed plus **placebo** every 3 weeks for 4 cycles
(last dose on Day 231)
then, continue to receive pemetrexed every 3 weeks
Arm 2:  
to receive carboplatin, pemetrexed plus demcizumab every 3 weeks for 4 cycles (last dose on Day 63)
then, starting on Day 84, to receive pemetrexed alone every 3 weeks for 4 cycles (last dose on Day 147)
then, starting on Day 168, to receive pemetrexed plus placebo every 3 weeks for 4 cycles
(last dose on Day 231)
then, continue to receive pemetrexed every 3 weeks
Arm 3:  
to receive carboplatin, pemetrexed plus demcizumab every 3 weeks for 4 cycles (last dose on Day 63)
then, starting on Day 84, to receive pemetrexed alone every 3 weeks for 4 cycles (last dose on Day 147)
then, starting on Day 168, to receive pemetrexed plus demcizumab every 3 weeks for 4 cycles (last dose on Day 231)
then, continue to receive pemetrexed every 3 weeks
You will have an equal chance of being assigned to Arm 1, Arm 2 or Arm 3. Neither you nor your doctor will know which treatment arm you have been assigned to or whether you are receiving demcizumab or placebo.
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pemetrexed

Pemetrexed will be administered at a dose of 500 mg/m2 as an intravenous infusion over
≥10 minutes on the first day of every 21-day cycle for 4 cycles, after the administration of demcizumab or placebo. Pemetrexed may be given for 4 cycles unless you have side effects or disease progression that necessitates stopping the drug. After 4 cycles, if you have stable or improved disease, you will continue to receive pemetrexed once every 21 days as maintenance therapy until your tumor progresses. In order to reduce gastrointestinal and hematologic side effects, you will take folic acid of ≥400 µg daily for at least 5 of the 7 days before the first dose of pemetrexed is administered and you will continue to take ≥400 µg of daily folic acid throughout the treatment period and for the first 21 days after the last dose of pemetrexed. You will also receive an intramuscular injection of vitamin B12 at a dose of 1000 μg during the week before the first dose of pemetrexed and every 63 days while you are being treated with pemetrexed (on Days 63, 126, 189, etc.). In order to reduce the occurrence of skin rashes, you will receive dexamethasone, 4 mg orally twice a day on the day before, the day of, and the day after pemetrexed administration, unless your physician determines that this is not right for you.
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carboplatin

Carboplatin will be administered as an intravenous infusion over 15–60 minutes on Day 1 of every 21-day cycle for 4 cycles, after the administration of demcizumab and pemetrexed. The dose will depend on several factors including your kidney function as determined by the creatinine clearance test and your serum creatinine level. Carboplatin may be given for 4 cycles unless you have side effects or disease progression that necessitates stopping the drug. Your physician may prescribe medication to prevent nausea and vomiting from the administration of pemetrexed and carboplatin therapy. If you develop side effects during this time period, your physician may decide to hold or reduce the carboplatin and/or pemetrexed. If this occurs, the demcizumab or placebo may still be administered as scheduled. Study Day 0: The following assessments will be done prior to the infusion of demcizumab or placebo, carboplatin, and pemetrexed: abbreviated physical examination including weight; review of medications you are taking, including any changes in medication since the screening visit; changes in your medical status; and vital signs. Approximately 4 tablespoons of blood will be drawn for routine tests, antibody testing, pharmacokinetic testing (before and after your infusion) and biomarkers. If you agree to the optional pharmacogenomics testing, you will sign the optional Pharmacogenomics Informed Consent, and a blood sample will be collected. Study drug will be administered and you will be monitored for at least 15 minutes after the demcizumab (or placebo) has been stopped. Pemetrexed will then be administered, followed by carboplatin. Study Days 7, 14, 21, 28, 35, and 42: Demcizumab or placebo, carboplatin, and pemetrexed will be given on Study Days 21and 42 only. The following assessments will be obtained weekly: weight; review of the medications you are taking and any changes in medication since the previous visit; changes in your medical status or new health problems since the previous study visit; and vital signs. An abbreviated physical examination will be performed on the days that you receive demcizumab or placebo. Blood will be taken weekly for routine testing (including BNP on Day 21 and Day 42). At Day 42 only, blood will also be obtained to test for pharmacokinetic testing and antibodies to demcizumab, and blood will be taken for testing tumor markers (if your CEA was elevated at your screening visit). On Day 28, blood will also be obtained for biomarkers. Approximately 3 tablespoons of blood will be drawn on Study Days 7, 14, 21, 28, 35, and 42. On Day 28, an ECG and Doppler echocardiogram will be done. In addition, on Day 42, you will undergo a CT scan or MRI of the chest, abdomen, and other parts of your body, if your cancer has spread there, to assess whether your cancer has improved, progressed, or is stable. If the CT scan or MRI shows that you have stable or improved disease, you may continue to receive demcizumab/placebo, carboplatin and pemetrexed. If the CT scan or MRI shows disease progression, you will be taken off the study and will undergo assessments listed under **Termination Visit**. Study Day 56: The following assessments will be obtained: changes in your medical status or new health problems since the previous study visit. An ECG and Doppler echocardiogram will be done. Study Day 63: Demcizumab or placebo, carboplatin, and pemetrexed will be given. The following assessments will be obtained prior to the infusion of drug: weight; review of the medications you are taking and any changes in medication since the previous visit; changes in your medical status or new health problems since the previous study visit; and vital signs. An abbreviated physical examination will be performed. Blood, approximately 3 tablespoons, will be taken for routine testing (including BNP). Study Day 84: Pemetrexed will be given. The following assessments will be obtained: weight; review of the medications you are taking and any changes in medication since the previous visit; changes in your medical status or new health problems since the previous study visit; and vital signs. An abbreviated physical examination will be performed on the day that you receive pemetrexed. Blood will be taken for routine testing (including BNP). Blood will also be obtained for testing for antibody formation to demcizumab and for pharmacokinetic testing, and blood will be taken for testing tumor markers (if your CEA was elevated at your screening visit). Approximately 3 tablespoons of blood will be drawn. An ECG and Doppler echocardiogram will be done. You will undergo a CT scan or MRI of the chest, abdomen, and other parts of your body, if your cancer has spread there, to assess whether your cancer has improved, progressed, or is stable. If the CT scan or MRI shows that you have stable or improved disease, you may continue to receive demcizumab/placebo, carboplatin and pemetrexed. If the CT scan or MRI shows disease progression, you will be taken off the study and will undergo assessments listed under **Termination Visit**. Study Day 105: The following assessments will be obtained prior to the infusion of pemetrexed: abbreviated physical examination including weight; review of the medications you are taking and any changes in medication since the previous visit; changes in your medical status or new health problems since the previous study visit; and vital signs. Approximately 3 tablespoons of blood will be taken for routine testing, including BNP. As long as your disease is stable or shows a response, you may continue to receive pemetrexed every 3 weeks. You will undergo the tests listed for Study Day 105 during each of these 3-week cycles. You will receive intramuscular injection of vitamin B12 at a dose of 1000 μg every 63 days while receiving pemetrexed. In addition, every 6 weeks you will undergo a CT scan or MRI of the chest, abdomen and other parts of your body, if your cancer has spread there, to assess whether your cancer has improved, progressed, or is stable. Every 6 weeks blood will be taken for antibodies to demcizumab, and blood will be obtained for tumor markers, if applicable. You will also have an ECG and a Doppler echocardiogram every 4 weeks. Starting on Day 168, you will receive demcizumab or placebo every 3 weeks for four 21-day cycles. On Day 168 (before and after your infusion), Day 210 (before and after your infusion) and Days 252, 294 and 336 (before infusion) only, blood samples will be taken for pharmacokinetic testing.
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termination visit

When you have discontinued receiving study drugs (demcizumab or placebo, carboplatin, and pemetrexed, or pemetrexed alone), and you are no longer being followed with study assessments, including CT scans or MRIs every 6 weeks to assess whether your cancer has improved, progressed, or is stable, the following assessments will be performed: abbreviated physical exam with weight; review of medications you are taking and any changes in medication since the previous visit; changes in your medical status or new health problems since the previous study visit; and vital signs. Blood samples will be obtained for routine testing (including BNP), antibody formation to demcizumab, and pharmacokinetic testing. Blood will also be obtained for biomarkers unless obtained within the previous 14 days. Blood will also be obtained for tumor marker testing if applicable and for BNP unless obtained within the previous 28 days. A urine specimen will be obtained. An ECG and a Doppler echocardiogram will be performed. A repeat CT scan or MRI of the chest, abdomen, and other parts of your body, if your cancer has spread there, will be obtained unless performed within 14 days of Termination visit. Approximately 3 tablespoons of blood will be drawn during this visit.
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follow-up after termination visit

If your blood pressure was too high at the Terminiation visit (greater than 150/90 mmHg), your blood pressure will be determined every 2 weeks until your blood pressure is less or equal to 150/90 mmHg for a 4-week period. You will be contacted every 3 months for up to 5 years by the clinic study staff to check on your condition. This contact may be by telephone or medical record review. Information regarding any anti-cancer therapies that you receive will also be collected through telephone calls, review of medical records, and/or clinic visits. In addition, if your tumor has not progressed at the time of your Termination visit, your tumor response outcome will continue to be followed until you begin receiving alternative anti-cancer treatment or your tumor progresses, whichever occurs first, and a copy of the corresponding radiographs (e.g., CT scans and/or MRIs) may be provided to OncoMed, the Sponsor of the trial. If you have a BNP ≥400 pg/mL and/or a diagnosis of pulmonary hypertension or heart failure at the time of termination, all subsequent standard of care BNP data will be collected until the value is <200 pg/mL and all subsequent standard of care left ventricular ejection fraction (LVEF) and peak tricuspid velocity (PTV) values will be collected until they normalize. LVEF and PTV are tests that provide information on how your heart is functioning.
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possible risks and discomforts demcizumab

The following are the side effects that were observed in >10% (common) and 5-10% (less common) of the 55 patients treated in the initial **single-agent study** of demcizumab and were considered to be possibly related to demcizumab.
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common (occurred in >10% of

Hypertension, fatigue, anemia, diarrhea, headache, nausea, decreased protein in the blood and shortness of breath
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less common (occurred in 5-10%

Low sodium in blood, dizziness, weight loss, heart failure, shortness of breath with activity, laboratory values indicating a decrease in liver or kidney function, decreased white blood count in the blood, abdominal pain, chills, fever, insomnia and cough The following are the side effects that were observed in >10% (common) and 5-10% (less common) of the 99 patients treated in the 4 studies of **demcizumab plus chemotherapy** and were considered to be possibly related to demcizumab.
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common (occurred in >10% of

Fatigue, nausea, hypertension, swelling of tissue due to increased fluid, diarrhea, appetite decreased, increased BNP (suggesting possible early damage to the heart), anemia, decreased platelet count in the blood, decreased white blood count in the blood, shortness of breath, headache, increased pressure in the lungs, constipation and rash.
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less common (occurred in 5-10%

Change in taste, hair loss and laboratory values indicating a decrease in liver function The majority of the side effects observed in these studies were mild to moderate. The most common adverse event across these studies that was clearly related to demcizumab was hypertension which occurred in 14-60% of the patients. Thus, if you participate in this study, your blood pressure will be checked frequently and, if necessary, you will be treated with medication(s) to lower your blood pressure. If your increased blood pressure is not controlled by medications, administration of demcizumab will be discontinued. In addition, in these studies, 7 patients developed serious bleeding in the gastrointestinal tract. Two patients died as a result of this bleeding. Because of that, you will not be treated in this study if you have tumor in one or more locations that carries an increased risk for bleeding.  
If you participate in the study, your hemoglobin (a measurement of the amount of red blood cells) will be tested regularly. If your hemoglobin decreases, your physician will look carefully for the reason. If you develop active significant bleeding, administration of demcizumab will be discontinued. One patient in the single-agent study died as a result of complications relating to a tumor within the brain. As a result, if you choose to participate in this study, prior to treatment you will have a scan of the brain to ensure that there is no tumor within the brain. Patients who have a tumor within the brain will not be able to participate in the study. Finally, approximately 40% of patients treated in these trials developed rises in a laboratory test (BNP) suggesting possible early damage to their heart. In addition, approximately 5-10% of the patients had symptoms of heart failure (such as shortness of breath and/or extra fluid in their legs). These patients typically improved after discontinuation of demcizumab and treatment with medications to reduce their symptoms. In addtition, the heart failure typically developed in patients who received demcizumab for at least 3 months. Also, an increase in the blood pressure in the lungs which can also result in heart failure has been observed in some patients that were typically treated for more than than 3 months. As a result, demcizumab will not be given on an ongoing basis in this study. Instead, a shortened regimen of 4 doses over 63 days will be administered either once or twice during your time on study. Approximately 50 patients have received this type of shortened treatment schedule, and none have developed serious heart failure or increased blood pressure in the lungs. However, it is anticipated that heart failure and /or increased blood pressure in the lungs will likely still occur in some patients receiving this shortened duration of treatment with demcizumab. Finally, no patients have been previously treated with a 2nd 63-day course of demcizumab that some patients will be receiving in this study, so the risks of this approach are unknown. You will not be treated in this study if you have an elevated BNP value, evidence of heart failure or evidence of disease in the vessels in your heart, or have a significant decrease in the amount of blood your heart is pumping on Doppler echocardiogram. Your heart and lung function will be watched closely while you are on study using blood tests and echocardiograms. If these side effects are noted, you will be referred to a heart specialist who may be able to treat the side effects with drugs. If further increases in your BNP occur or the amount of blood your heart is pumping declines further, your demcizumab therapy will be discontinued. As with all antibody treatments, there is the possibility of an allergic reaction, such as fever, chills, rash, and/or hives associated with the infusion of demcizumab. Rarely, a severe or serious allergic reaction can occur during or following the administration of an antibody. Not enough patients have yet been treated with demcizumab to fully understand the side effects that may be associated with this antibody. The following side effects have been observed in other drugs that have an anti-angiogenic effect (drugs that prevent the growth of new blood vessels that tumors need to grow and spread) and in other drugs that may inhibit the growth of cancer stem cells. It is not known if the administration of demcizumab will result in any of these findings:
· Gastrointestinal perforation sometimes associated with intra-abdominal abscess  
· Diarrhea, weight loss, constipation, vomiting, abdominal pain, nausea, and fever · Wound healing complications · Hemorrhage including minor bleeding events such as nose bleeds or more serious, sometimes fatal bleeding events
· Arterial or venous thromboembolic events, including cerebral (brain) infarction, transient ischemic attacks (TIAs), myocardial infarction (MI), angina, and other sometimes fatal events
· Hypertension including episodes of severe increased blood pressure · Neutropenia and/or infection
· Proteinuria (loss of protein through your kidneys)  
· Congestive heart failure
· Diarrhea · Rashes · Somnolence (sleepiness)  
· Fatigue
· Prolonged QT interval (irregular heart rhythm)
Pemetrexed: The following side effects have been reported in >10% of patients receiving pemetrexed:  
· Low blood counts. Your white and red blood cells, neutrophils and platelets may decrease. This may put you at an increased risk for infection, anemia, and/or bleeding
· Decreased kidney function
· Fatigue · Nausea  
· Sensory neuropathy. Neuropathy (nerve damage). You may feel weakness, pain, numbness, and/or a tingling sensation especially in your fingers and toes
· Taste disturbance · Rash, peeling of the skin, hives · Increases in liver enzymes
Carboplatin: The following side effects have been reported in >10% of patients receiving carboplatin:
· Low blood counts. Your white and red blood cells, neutrophils, and platelets may decrease. This may put you at an increased risk for infection, anemia, and/or bleeding.  
· Infection · Bleeding
· Nausea · Vomiting · Peripheral neuropathy · Hearing loss · Central neurologic toxicity · Decreased kidney function · Elevation of liver function tests · Electrolyte imbalances · Pain · Weakness · Cardiovascular abnormalities · Respiratory problems · Mouth and lip sores and sore throat  
· Allergic reaction such as hives, redness and itching · Serious allergic reactions such as anaphylaxis · Hair loss
Other less frequent adverse events occur following the administration of carboplatin and pemetrexed.
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infusions

Demcizumab or placebo, carboplatin and pemetrexed will be given as intravenous infusions. 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.
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blood draws

During the course of this study, your blood will be drawn for laboratory tests (3-4 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 will also be informed of any new significant side effects that develop during the course of this research study, or others regarding the use of demcizumab.
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radiation exposure

Risk relevant to the radiation exposure due to the following procedures: Radiographic evaluation: Conventional CT, Spiral CT, or MRI of the chest, abdomen, and pelvis performed in screening, the same radiographic technique of each region must be used consistently throughout the study. Radiographic evaluation: Conventional CT, Spiral CT, or MRI of the head performed in screening.
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pregnancy

There is a very high risk that demcizumab 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) prior to study entry and for the duration of the study until 6 months after the last dose of demcizumab. 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 6 months after the last dose of demcizumab, 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 Termination Visit 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 3 months after the last dose of demcizumab, you and/or your partner will be followed through the first well-baby visit or longer if any abnormality is present.
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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.
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significant new findings

Any significant new findings regarding demcizumab that become known during the course of this research study that might reasonably affect your willingness to participate in this study, will be provided to you in a timely manner.
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alternative treatments and procedures

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.
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termination of patient 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 demcizumab, unacceptable adverse events, unacceptable BNP and/or LVEF values, 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 demcizumab or placebo injections 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 **Termination Visit**. In addition, your doctor will discuss with you alternate therapies for your disease.
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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 patients 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. You may be reimbursed for any reasonable travel expenses (bus/train/taxi fares) incurred as a result of taking part in this study on production of a receipt.
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compensation for research-related injury

If you are physically injured as a direct result of demcizumab or a study procedure properly performed under the plan for this study and it is not due to a pre-existing medical condition or underlying disease, or your failure to follow the instructions provided by your doctor or another member of the study team, OncoMed will reimburse you for the reasonable medical expenses for medically necessary treatment of that injury which are not covered by another payor, your own insurance or health care program. No other compensation is available from OncoMed if any injury occurs.
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confidentiality

A description of this clinical trial will be available on http://www.ClinicalTrials.gov, as required by U.S. Law. This 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 anytime.
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how will your confidentiality be

You have the right to control the use and disclosure of your personal information. Basic personal information will be recorded including your name, contact details, gender, height, weight and racial origin, as well as information on your medical history, and clinical data collected about your participation in the study. All this information will be used for research and clinical purposes only, including without limitation the pharmacokinetic and optional DNA research described in this consent form. The following people may also have access to these records: representatives of the FDA, other regulatory authorities, the Institutional Review Board/Independent Ethics Committee, OncoMed representatives and monitors, and OncoMed collaborators and licensees. All personnel accessing your records are required to respect your confidentiality at all times. To ensure privacy, your name and other identifying information will not be attached to records or samples released for research purposes. Instead, you will only be identified by a code. Only the study doctor and authorized personnel will be able to connect this code to your name, by a list that will be kept securely by the study site for "[insert retention period]" years. Your date of birth (Amend the sentence to account for any country-specific rules) may also be recorded to help identify your study record. Your coded data will be forwarded to OncoMed and its service providers for activities related to the study e.g., laboratory analysis. It will be transferred into a computer database and processed to allow the results of this study to be analyzed and reported or published. If the results of the study are published, your identity will remain confidential, you will not be identified by name, picture, or by any other personally identifying information. A list of companies to whom your coded information is transferred is available from OncoMed via your study doctor. EMEA: Under data protection law [identification of national law] your study site and OncoMed Pharmaceuticals shall be jointly responsible as 'controllers' for ensuring that your information is safeguarded. OncoMed has appointed [PPD local company name] as its 'representative' in your country to fulfill its obligations under this law.  
The information that we collect from you may be transferred to, and stored at, a destination outside the European Economic Area ("EEA"). It may also be processed by staff operating outside the EEA who work for us or for our representative. By participating in the research study, you agree to this transfer, storing or processing outside of the EEA. When transferring such information to destinations outside of the EEA, we will also make sure that your information will be treated with an adequate level of protection as required under your local data protection laws. APAC: Under data protection law [identification of national law] your study site shall be responsible for ensuring that your named personal information is safeguarded. USA: Because of the research goals of this study, however, your study records cannot be kept completely confidential. The sponsor of this study is OncoMed Pharmaceuticals. The study data may be transferred to other countries for processing, including countries not covered by data protection legislation similar in scope to the data protection legislation of your country, or at all. The laws of your state may provide further protection. CANADA: Under federal data protection law, The Personal Information Protection and Electronic Documents Act (PIPEDA) and regional specific regulations, your study site shall be responsible for ensuring that your information is safeguarded. You have the right to access, through your study doctor, all the information collected about you and, if applicable, ask for corrections. But, in order to protect the scientific integrity of the study, the treatment you received in this study needs to remain unknown (i.e., blinded) until the study data is analyzed. Recipients of your information may be in countries that do not have data protection safeguards and rights. In such case, OncoMed and its authorized representatives, and regulatory authorities, shall anyway seek to maintain confidentiality within the limits of local laws in these countries and comply with the data export requirements of your country, including any requirements to ensure an adequate level of protection. If you should withdraw from the study, data collected prior to your withdrawal may still be processed along with other data collected as part of the study. Normally no new information will be collected for the study database unless you specifically consent to such collection. However, the law does require that any side effects you may suffer are documented and reported. To complete the study findings, your long term health status may also be recorded (unless you object). You have the right to require that any previously retained samples are destroyed.
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what will happen to your

This clinical study may only be performed by collecting and using your medical information. Data protection laws give you the right to control the use of your personal information. Therefore, by signing this form you specifically authorize your information to be checked, transferred and processed as follows:  
The authorized representatives of Oncomed, the Ethics Committee and regulatory authorities' inspectors may review your medical information by direct access to your medical records.  
Study data, including your coded medical information, may be used and shared for legitimate study and scientific purposes, including if you do not object, for future use in medical or pharmaceutical research.  
I agree to the use of my coded medical information for future research purposes.  
Signature: _______________________________
I don´t agree to the use of my coded medical information for future research purposes.  
Signature: _______________________________
Study data may be transferred to other countries for processing, including countries not covered by data protection legislation similar in scope to the data protection legislation of your country, or at all.
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has the study received medical

The Ethics Committee has given this study a positive opinion. 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.
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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 demcizumab. 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.
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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 of persons.
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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.
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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 this informed consent form.
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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. 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 take by (SITE) in relying on this authorization before it received my written notice of withdrawal of permission.
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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 patients' 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).
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voluntary participation and documentation of

PROTOCOL M18-007: A Three Arm Phase 2 Double-Blind Randomized Study of Carboplatin, Pemetrexed Plus Placebo versus Carboplatin, Pemetrexed plus 1 or 2 Truncated Courses of Demcizumab in Subjects with Non-Squamous Non-Small Cell Lung Cancer 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 Patient or Patient'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.
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appendix f pharmacogenomics informed consent

PROTOCOL M18-007: A Three Arm Phase 2 Double-Blind Randomized Study of Carboplatin, Pemetrexed Plus Placebo versus Carboplatin, Pemetrexed plus 1 or 2 Truncated Courses of Demcizumab in Subjects with Non-Squamous Non-Small Cell Lung Cancer This Informed Consent Form is linked to the main ICF for the trial Master ICF version 1.0. This Informed Consent Form is only valid in addition to the main ICF described above.
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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 demcizumab 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).
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what am i being asked

You are being asked to give one small blood sample (10 mL, about 2 teaspoons) at Study Day 0. Blood will be drawn from a vein using a needle. DNA will be extracted from your blood sample. Your DNA may be tested for specific genes relevant to demcizumab, carboplatin and/or pemetrexed (the study drugs), the Notch/DLL4 pathways (the targets of demcizumab) and/or other genes related to your cancer. Only DNA research related to demcizumab, carboplatin, or pemetrexed or to the diseases for which these drugs are developed will be performed. No blood sample for DNA research will be taken from you unless you sign and date this Informed Consent Form. In addition, if a piece of your tumor was previously collected as part of your diagnosis, you are being asked to have DNA testing performed on your tumor. DNA will be extracted to help to identify biomarkers that could be used in the future to predict which patients are more likely to respond to demcizumab, carboplatin and pemetrexed treatment. Analysis of candidate genes and/or proteins relevant to the Notch pathway may be performed (e.g., Notch1, Hey L, FBW7, etc.). No DNA research will be performed on your tumor unless you sign and date this Informed Consent Form. The Sponsor will store the samples until there is no DNA left. The sampes will be retained at OncoMed Pharmaceuticals, 800 Chesapeake Dr., Redwood City, California, U.S.A, 94063.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. 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.
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how will my identity and

A Federal law, called the Genetic Information Nondiscrimination Act (GINA), generally makes it illegal for health insurance companies, group health plans, and most employers to discriminate against you based on your genetic information.  
This law generally will protect you in the following ways:  
Health insurance companies and group health plans may not request your genetic information that we get from this research.  
Health insurance companies and group health plans may not use your genetic information when making decisions regarding your eligibility or premiums.  
Employers with 15 or more employees may not use your genetic information that we get from this research when making a decision to hire, promote, or fire you or when setting the terms of your employment.
Be aware that this Federal law does not protect you or your family against genetic discrimination by companies that sell life insurance, disability insurance, or long-term care insurance. Also, GINA does not prohibit discrimination of individuals with a genetic disorder that has been diagnosed. The Sponsor has taken several steps to keep your identity and results confidential. These are described below.
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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 Patient number from the main study. After the study is officially over, the Patient number will be removed from your DNA sample. Your DNA sample and results will be labeled with a new number.
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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 Patient 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.
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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 Australian Health Authority or EMA
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.
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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.
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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.
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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).
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what are the benefits?

You will not directly benefit from taking part in this DNA research. This research could provide information about demcizumab or the diseases for which this drug is developed. This information could help others in the future.
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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.
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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.
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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 patients' 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).
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voluntary participation and documentation of

PROTOCOL M18-007: A Three Arm Phase 2 Double-Blind Randomized Study of Carboplatin, Pemetrexed Plus Placebo versus Carboplatin, Pemetrexed plus 1 or 2 Truncated Courses of Demcizumab in Subjects with Non-Squamous Non-Small Cell Lung Cancer 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. I consent to the processing of my personal data, including any sensitive personal data, as set out above and to the transfer of such data to countries outside of the European Economic Area Yes No I consent to provide the Optional Pharmacogenomics Specimen Yes No I consent to allow my tumor specimen to be analyzed for DNA
Yes No Printed Name of Patient or Patient's Authorized Representative ________________________________________________________ ___________ Signature of Patient or Patient's Authorized Representative Personally Date _________________________________________________________ Printed Name of Person Obtaining Informed Consent __________________________________________________________ ____________ Signature of Person Obtaining Informed Consent Personally Date __________________________________________________________ Printed Name of Witness* _________________________________________________________ ___________ Signature of Witness* Personally Date *If the Principal Investigator or Institutional Review Board deems a witness signature is necessary.
appendix g protocol amendment summary
amendment 1 8 october 2014

The changes in the protocol described below are being made to comply with the request made by the FDA. Italics below and in the protocol indicate new text. Strike-through indicates text that has been removed. Additional changes were made to improve clarity.
appendix g protocol amendment summary
previously read

2. NSCLC with known EGFR mutation or anaplastic lymphoma kinase (ALK) gene translocation (such as EML4-ALK)
appendix g protocol amendment summary
now reads

2. NSCLC with EGFR mutation or anaplastic lymphoma kinase (ALK) gene translocation (such as EML4-ALK)
The following change in Section 4.1, Study Objectives (Endpoints, Primary Endpoint) was made to improve clarity. Section 6.2, Exclusion Criteria
appendix g protocol amendment summary
previously read

2. NSCLC with known EGFR mutation or anaplastic lymphoma kinase (ALK) gene translocation (such as EML4-ALK). Note: testing for these mutations is not a prerequisite to study entry.
appendix g protocol amendment summary
now reads

2. NSCLC with EGFR mutation or anaplastic lymphoma kinase (ALK) gene translocation (such as EML4-ALK)  
Negative results for these genetic aberrations must be documented in order for a subject to be eligible.
appendix g protocol amendment summary
amendment 2 4 march 2016

Study M18-007 has been amended for the following reasons. 1. To provide more specific information regarding the criteria that need to be met for further treatment with demcizumab/placebo starting on Day 168 (Section 3.5, Section 5.0 and Section 8.1.1).  
2. To remove the requirement for mandatory FFPE tumor tissue in order to make the study available to more NSCLC subjects (Section 6.0 and Section 11.0).  
FFPE tumor tissue, if available, must be provided for exploratory biomarker analyses.  
3. To clarify that subjects with metastatic disease after initial NSCLC resection with curative intent and no adjuvant therapy are allowed to enter the study regardless of time from NSCLC resection, as metastatic disease must have been present at time of initial diagnosis but was not detected (Section 6.0).  
4. To add additional eligibility criteria for albumin, prior radiation to chest wall or mediastinum, arterial aneurysms, interstitial lung disease and pneumonitis (Section 6.0).  
Ongoing feedback from investigators of this study indicated that these additions may further enhance the safety of subject participants.  
5. To base creatinine clearance calculations as it pertains to pemetrexed-related safety on the Cockcroft and Gault formula using actual body weight, as was done for pemetrexed safety data summarized in the pemetrexed prescribing information (Section 6.0 and 8.2.6).  
6. To clarify the terms of 'women of childbearing potential' and 'effective forms of contraception (Section 6.0).  
7. To clarify and correct some aspects of demcizumab-related treatment modification and termination criteria (Section 8.1.6).  
8. To specify a second approach to pemetrexed and carboplatin dose modification in which chemotherapy is delivered 3 or more days after the fixed day of demcizumab/placebo administration for chemotherapy-related or other reasons (Section 8.4 with Figure 20). This enables dose modification for chemotherapy that is more in line with what is typically done in daily practice.  
9. To stop BNP, ECG and Doppler echocardiogram assessments after ≥105 days of regularly scheduled assessments after the last dose of demcizumab/placebo (depending on when discontinuation occurred), unless results for BNP and Doppler echocardiogram do not meet eligibility criteria (Sections 9.2.3 and 9.4, Appendix A).  
It was deemed acceptable for subject safety to stop the outlined assessments at a time point when more than six half-lives of demcizumab have passed.  
10. To simplify PK assessments for demcizumab and stop them after Day 336 (Section 9.6 and Appendix A).  
11. To reduce the number of assessments for blood biomarkers to one on-study assessment seven days after demcizumab/placebo administration (Day 28) and remove assessments for circulating tumor cells (Section 11.0 and Appendix A).  
This reduces the amount of blood drawn from subjects and will provide adequate information regarding blood-based pharmacodynamics biomarkers, considering that >50 subjects will have undergone more extensive blood biomarker assessments by the time this amendment is active.  
12. To simplify protocol text for study visit schedule and assessments and make Appendix A the primary reference (Section 12.0).  
13. To provide additional flexibility in the timing of pemetrexed administrations and associated assessments after discontinuation of carboplatin and demcizumab/placebo (Section 12.2).  
14. To clarify which assessments are required in case of discontinuation of all study drugs
(Section 12.2).  
15. To reduce the frequency of chemistry assessments to every three weeks and of hematology assessments to every three weeks starting with Day 42 (Cycle 3 of carboplatin and paclitaxel, assuming no dosing delays; Appendix A).  
This reduces the amount of blood drawn from subjects, is more in line with standard of care and poses no safety risk to subjects given the large clinical safety experience with pemetrexed and carboplatin.  
16. To clarify and revise tables for protocol assessments to make them consistent with protocol changes (Appendix A).  
17. To clarify and revise the informed consent form to make it consistent with protocol changes
(Appendix E).
appendix g protocol amendment summary
summary of changes

As a result, all the corresponding sections in the table below have been updated to reflect the changes outlined above. Additional minor changes have been made to improve clarity and consistency. Substantive new information appears in italics. This amendment represents cumulative changes to the previous amendments.  
| Synopsis Section 3.2   | Stage IV Non-Small Cell Lung Cancer                                       |
|------------------------|---------------------------------------------------------------------------|
| Section 3.3.2          | Potential for Immune-Mediated Mechanism of Action for Anti-DLL4           |
| Section 3.4.2.1        | Phase 1b Efficacy Data                                                    |
| Section 3.4.2.2        | Phase 1b Safety Data                                                      |
| Section 3.5            | Dose Rationale                                                            |
| Section 4.1            | Study Objectives                                                          |
| Section 4.2            | Endpoints                                                                 |
| Section 5.0            | OVERALL STUDY DESIGN AND PLAN - DESCRIPTION                               |
| Section 6.1            | Inclusion Criteria                                                        |
| Section 6.2            | Exclusion Criteria                                                        |
| Section 7.0            | REMOVAL OF SUBJECTS FROM ON-STUDY PART OF PROTOCOL                        |
| Section 8.1.1          | Administration                                                            |
| Section 8.1.4          | Drug Ordering, Storage, and Accountability                                |
| Section 8.1.6          | Treatment Modification and Termination Criteria                           |
| Section 8.2.5          | Vitamin Supplementation and Dexamethasone Administration                  |
| Section 8.2.6          | Renally Impaired Subjects                                                 |
| Section 8.3.1          | Administration                                                            |
| Section 8.4            | Pemetrexed and Carboplatin Dose Modification/Treatment Delay              |
| Section 9.1.2          | Definition of Serious Adverse Event                                       |
| Section 9.1.4          | Serious Adverse Event Reporting Procedures                                |
| Section 9.2            | Clinical Laboratory Assessments                                           |
| Section 9.2.1          | Hematology                                                                |
| Section 9.2.3          | BNP Assessment                                                            |
| Section 9.3            | Vital Signs and Other Physical Findings                                   |
| Section 9.4            | Cardiopulmonary Studies                                                   |
| Section 9.5            | Immunogenicity Assessments                                                |
| Section 9.6            | Pharmacokinetic Assessments                                               |
| Section 10.0           | EFFICACY ASSESSMENTS                                                      |
| Section 11.0           | EXPLORATORY ASSESSMENTS                                                   |
| Section 12.0           | STUDY VISIT SCHEDULE AND ASSESSMENTS                                      |
| Section 12.1           | Screening                                                                 |
| Section 12.2           | Assessments for On-study Part of Protocol (Day 0 up to Termination Visit) |
| Section 12.3           | Termination Visit                                                         |
| Section 12.4           | Follow-up after Termination Visit                                         |
| Section 14.0           | STATISTICAL PLAN                                                          |  
| Section 14.3                     | Treatment Exposure                               |
|----------------------------------|--------------------------------------------------|
| Section 14.4.1                   | Safety Endpoints                                 |
| Section 14.4.2                   | Immunogenicity Endpoints                         |
| Section 14.4.4                   | Efficacy Endpoints                               |
| Section 14.4.9                   | Exploratory Endpoints                            |
| Section 17.6                     | Investigational Medicinal Product Accountability |
| Section 18.0                     | REFERENCES                                       |
| Appendix A                       | SCHEDULE OF ASSESSMENTS                          |
| Notes to Appendix A  Appendix E: | SAMPLE INFORMED CONSENT                          |
| Appendix F:                      | PHARMACOGENOMICS INFORMED CONSENT                |
appendix g protocol amendment summary
amendment 3 29 november 2016

The M18-007 protocol has been amended in order to update the primary and secondary endpoints of the study, as well as, the statistical plan. The reason for this amendment is that enrollment of the full 201 subject trial is not feasible given major competition for enrollment, and the study should test an efficacy hypothesis with a smaller sample size. Due to significant enrollment competition in the first-line metastatic non-small cell lung cancer (NSCLC) treatment setting it has become apparent that enrollment of the planned 201 subjects would take a very long time and be very cost prohibitive. The M18-007 study achieved firstpatient-in in February 2015 and was planned to complete enrollment of 201 subjects by March 2016, however, as of October 2016 the study had enrolled 82 subjects. Over the course of the last 6 months the M18-007 study has enrolled between 1 and 6 subjects per month (on average 2.5 patients per month) across 40 open study sites--thus, completion of the planned enrollment of 201 subjects would take several more years. The challenge to enrollment is driven by many competing clinical trials of novel immune-oncology agents that have been initiated recently in the first-line NSCLC treatment space. This includes over 7 global Phase 3 trials with many thousands of subjects to be enrolled. These studies are directly competing with the M18-007 trial due to the overlapping eligibility criteria and the significant enthusiasm that exists for immune-oncology agents (particularly anti-PD1 and anti-PDL1 therapy) in NSCLC. Due to the above, the sponsor (OncoMed) and our corporate partner (Celegene) have made the decision to discontinue enrollment on the M18-007 study. However, 82 subjects have been enrolled on this double-blinded Phase 2 M18-007 study. It is the feeling of OncoMed and the participating investigators that there are informative data that can be derived from this clinical trial. In this amendment, OncoMed will continue to treat and follow subjects enrolled (as per protocol) and will change the primary endpoint of the study to be more suitable for a double blinded 82 subject Phase 2 experiment. OncoMed will pool the two demcizumab experimental arms (arms 2 and 3 in the study) to compare the outcome of these subjects to the outcome of the control arm (arm 1). The primary endpoint will be changed from progression free survival to response rate. The Phase 1b data for demcizumab with carboplatin and pemetrexed chemotherapy in NSCLC suggested that the addition of demcizumab augmented response rate in these subjects. As such OncoMed feels that response rate is an acceptable and scientifically based efficacy endpoint for the M18-007 study. The statistical plan has been amended for this primary endpoint of response rate and to accommodate the smaller sample size of 82 subjects. The progression free survival endpoint has been changed from a primary to a secondary efficacy endpoint.
appendix g protocol amendment summary
summary of changes

As a result, all the corresponding sections in the table below have been updated to reflect the changes outlined above. Additional minor changes have been made to improve clarity and consistency. Substantive new information appears in italics. This amendment represents cumulative changes to the previous amendments.  
| Sponsor Contacts Synopsis Section 4.1   | Study Objectives                            |
|-----------------------------------------|---------------------------------------------|
| Section 4.2                             | Endpoints                                   |
| Section 5.0                             | OVERALL STUDY DESIGN AND PLAN - DESCRIPTION |
| Section 14.0                            | STATISTICAL PLAN                            |
| Section 14.1                            | Subject Populations for Analysis            |
| Section 14.4.4                          | Efficacy Endpoints                          |
| Section 14.4.4.7                        | Overall Survival                            |
| Section 14.5                            | Termination Criteria                        |
| Section 18.0                            | REFERENCES                                  |