clinical protocol
7.5 dose modifications or delay

The Investigator should try his/her best to assess whether an adverse event is possibly related to study drug only, etoposide only, cisplatin or carboplatin only, or a combination of the drugs, and treat the subject accordingly. This section and Table 5 provides suggested guidelines for the management of various study drug related toxicities in subjects receiving study drug, etoposide, and cisplatin or carboplatin. Etoposide dosing should be withheld for  Grade 2 etoposide-related toxicities and resumed at the same dose or at a 25% dose reduction, which refers to a decrease of 25 mg/m2 depending on the timing of recovery and number of episodes occurred (see Table 5). If etoposide dosing is delayed for > 21 consecutive days despite supportive treatment per standard clinical practice or more than 2 dose reductions of etoposide ( 50 mg/m2) is required, stop etoposide therapy or call the Sponsor's Medical Monitor to discuss resuming etoposide treatment after more than 21 consecutive days interruption or further dose reduction beyond 50 mg/m2 if clinically indicated.  
Study drug and platinum therapy may continue as scheduled in the event of delay or discontinuation of etoposide. Cisplatin dosing should be withheld for Grade 2 cisplatin-related toxicities (except for peripheral neuropathy that cisplatin dosing should be held for  Grade 3), and resumed at the same dose or at a 25% dose reduction, depending on the timing of recovery and number of episodes occurred (see Table 5). If cisplatin dosing is delayed for > 21 consecutive days despite supportive treatment per standard clinical practice or more than 2 dose reductions of cisplatin
(< 35 mg/m2) is required, stop cisplatin therapy, or call the Sponsor's Medical Monitor to discuss resuming cisplatin treatment after more than 21 consecutive days interruption or further dose reduction beyond 35 mg/m2 if clinically indicated. Study drug and etoposide may continue as scheduled in the event of delay or discontinuation of cisplatin. Carboplatin dosing should be withheld for Grade 2 carboplatin-related toxicities, and resumed at the same dose or at reduced to AUC of 4 mg/mL•min, depending on the timing of recovery and number of episodes occurred (see Table 5). If carboplatin dosing is delayed for >21 consecutive days despite supportive treatment per standard clinical practice or carboplatin-related toxicities recurred after the dose has been reduced to AUC of 4 mg/mL•min, stop carboplatin therapy or call the Sponsor's Medical Monitor to discuss resuming carboplatin treatment after more than 21 consecutive days interruption or further dose reduction beyond AUC of 4 mg/mL•min if clinically indicated. Study drug and etoposide may continue as scheduled in the event of delay or discontinuation of carboplatin. The Investigator should hold tarextumab/Placebo for treatment related toxicity according to suggested guideline in Table 5, along with his/her best judgment. Subjects with a starting dose of 5 mg/kg study drug will have dose reduced to 2.5 mg/kg if dose reduction is required. Study drug will be discontinued permanently if study drug dosing is delayed for >21 consecutive days due to treatment –related toxicity (this is not applicable when PCI is administered as study drug will be held for >21 consecutive days during PCI administration and will resume 14 days after the completion of PCI) despite supportive treatment, or if more than 2 dose reductions of study drug are required or dose reduction to <2.5 mg/kg is required or the Investigator should call the Sponsor's Medical Monitor to discuss to resume study drug after > 21 days consecutive days interruption or further dose reduction if clinically indicated. Subjects continuing EP after discontinuing study drug will continue to receive etoposide on days 1, 2, and 3, and platinum therapy on day 1 of each 21-day cycle for the completion of planned cycles. Special attention should be paid to diarrhea as this is an expected adverse event of tarextumab and Section 7.5 describes the recommended diarrhea management approach in this study.  
| Tarextumab (OMP-59R5) OncoMed Pharmaceuticals, Inc.   |
|-------------------------------------------------------|  
,19(67,*$7,21$/1(:'58*  
CONFIDENTIAL  
| Hold carboplatin till ANC - 1000/  mm3. Resume carboplatin based on  timing of recovery and number of  previous episodes  ¾ " 3 consecutive weeks of  interruption  - 1st episode, no change. Consider  prophylactic myeloid growth  factor according to institution's  standard                                                                                                | - 2nd episode: reduce carboplatin  dose to AUC of 4 mg/mL•min for  all subsequent administration  - 3rd episode: discontinue  carboplatin treatment or call the  Sponsor's Medical Monitor to  discuss further dose reduction if                                                                                                                                                                                                                                                           | clinically indicated.  ¾ > 3 consecutive weeks of  interruption, discontinue  carboplatin or call the Sponsor's  Medical Monitor to discuss   | resuming the treatment of  carboplatin if clinically  indicated  Continue supportive care  according to institution's standard                                                                                                   |                                                                                                                                                      |                                                                                                                             |
|------------------------------------------------------------------------------------------------|--------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|-----------------------------------------------------------------------------------------------------------------------------------------------|----------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|------------------------------------------------------------------------------------------------------------------------------------------------------|-----------------------------------------------------------------------------------------------------------------------------|
| Carboplatin Dose Reduction and/or  Delay                                                       | No change. Continue supportive care  according to institution's standard                                                                                                                                                                                                                                                                                                                                                                                                                   | 22 April 2016                                                                                                                                 |                                                                                                                                                                                                                                  |                                                                                                                                                      |                                                                                                                             |
| Suggested Guidelines for Study Drug and Etoposide-Platinum Therapy Dose Modification and Delay | Hold cisplatin till ANC - 1000/ mm3.  Resume cisplatin based on timing of  recovery and number of previous  episodes  ¾ " 3 consecutive weeks of  interruption  - 1st episode, no change. Consider  prophylactic myeloid growth  factor according to institution's  standard                                                                                                                                                                                                                                                                                                                                                                                                                                                                                            | - 2nd episode: reduce cisplatin dose  by 25% for all subsequent  administration                                                               | - 3rd episode, reduce cisplatin dose  by 50% from starting dose for all  subsequent administration  - 4th episode, discontinue cisplatin  treatment or call the Sponsor's  Medical Monitor to discuss  further dose reduction if | clinically indicated  ¾ > 3 consecutive weeks of  interruption, discontinue cisplatin  permanently or call the Sponsor's  Medical Monitor to discuss | resuming the treatment of  cisplatin if clinically indicated  Continue supportive care according to  institution's standard |
| Cisplatin Dose Reduction and/or  Delay                                                         | No change. Continue supportive care  according to institution's standard                                                                                                                                                                                                                                                                                                                                                                                                                   |                                                                                                                                               |                                                                                                                                                                                                                                  |                                                                                                                                                      |                                                                                                                             |
| Absolute Neutrophil Count (ANC)                                                                | Page 46 of 235                                                                                                                                                                                                                                                                                                                                                                                                                                                                             |                                                                                                                                               |                                                                                                                                                                                                                                  |                                                                                                                                                      |                                                                                                                             |
| Hold etoposide till ANC - 1000/ mm3.  Resume etoposide based on timing of  recovery and number of previous  episodes  ¾ " 3 consecutive weeks of  interruption  - 1st episode, no change. Consider  prophylactic myeloid growth  factor according to institution's  standard                                                                                                | - 2nd episode: reduce etoposide dose  by 25% from starting dose for all  subsequent administration  - 3rd episode, reduce etoposide dose  by 50% from starting dose for all  subsequent administration  - 4th episode, discontinue etoposide  treatment or call the Sponsor's  Medical Monitor to discuss  further dose reduction if clinically  indicated  ¾ > 3 consecutive weeks of  interruption, discontinue etoposide  permanently or call the Sponsor's  Medical Monitor to discuss | resuming the treatment of  etoposide if clinically indicated  Continue supportive care according to  institution's standard                   |                                                                                                                                                                                                                                  |                                                                                                                                                      |                                                                                                                             |
| Etoposide Dose Reduction and/or  Delay  Reduction and/or Delay                                 | No change. Continue supportive care  according to institution's standard                                                                                                                                                                                                                                                                                                                                                                                                                   |                                                                                                                                               |                                                                                                                                                                                                                                  |                                                                                                                                                      |                                                                                                                             |
| Adverse Event Study Drug Dose                                                                  | Protocol 59R5-003, Amendment 6                                                                                                                                                                                                                                                                                                                                                                                                                                                             |                                                                                                                                               |                                                                                                                                                                                                                                  |                                                                                                                                                      |                                                                                                                             |
| No change.                                                                                     | No change 500 -999/mm3                                                                                                                                                                                                                                                                                                                                                                                                                                                                     | without fever                                                                                                                                 |                                                                                                                                                                                                                                  |                                                                                                                                                      |                                                                                                                             |
| •1000/mm3                                                                                                |                                                                                                                                                                                                                                                                                                                                                                                                                                                                                            |                                                                                                                                               |                                                                                                                                                                                                                                  |                                                                                                                                                      |                                                                                                                             |
| Table 5:                                                                                       |                                                                                                                                                                                                                                                                                                                                                                                                                                                                                            |                                                                                                                                               |                                                                                                                                                                                                                                  |                                                                                                                                                      |                                                                                                                             |  
()  
  
Suggested Guidelines for Study Drug and Etoposide-Platinum Therapy Dose Modification and Delay (Cont'd)  
  
,19(67,*$7,21$/1(:'58* Table 5:  
| Carboplatin Dose Reduction and/or  Delay  Hold carboplatin till ANC - 1000/  mm3. Resume carbplatin based on  timing of recovery and number of  previous episodes  ¾ " 3 consecutive weeks of  interruption  - 1st episode, reduce carboplatin  dose to be AUC of 4 mg/mL•min  for all subsequent administration  - 2nd episode, discontinue  carboplatin treatment or call the  Sponsor's Medical Monitor to  discuss further dose reduction if                                                                | clinically indicated  ¾ >3 consecutive weeks of  interruption, discontinue  carboplatin permanently or call  the Sponsor's Medical Monitor  to discuss resuming the treatment  of carboplatin if clinically  indicated  Continue supportive care according to  institution's standard   | No change                                                                                                                                                                                                                                                                                                                                                                                                         |                                                                                                                             |
|----------------------------------------------------------------|-----------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|-------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|-----------------------------------------------------------------------------------------------------------------------------|
| Hold cisplatin till ANC - 1000/ mm3.  Resume cisplatin based on timing of  recovery and number of previous  episodes  ¾ " 3 consecutive weeks of  interruption  - 1st episode, reduce cisplatin dose  by 25% for all subsequent  administration                                                                | - 2nd episode, reduce cisplatin dose  by 50% from starting dose for all  subsequent administration  - 3rd episode, discontinue cisplatin  treatment or call the Sponsor's  Medical Monitor to discuss  further dose reduction if                                                        | clinically indicated  ¾ > 3 consecutive weeks of  interruption, discontinue cisplatin  permanently or call the Sponsor's  Medical Monitor to discuss                                                                                                                                                                                                                                                              | resuming the treatment of  cisplatin if clinically indicated  Continue supportive care according to  institution's standard |
| Hold etoposide till ANC - 1000/  mm3 Resume etoposide based on  timing of recovery and number of  previous episodes  ¾ " 3 consecutive weeks of  interruption  - 1st episode, reduce etoposide  dose by 25% from starting  dose for all subsequent  administration                                                                | - 2nd episode, reduce etoposide  dose by 50% from starting  dose for all subsequent  administration                                                                                                                                                                                     | - 3rd episode, discontinue  etoposide treatment or call  the Sponsor's Medical  Monitor to discuss further  dose reduction if clinically  indicated  ¾ > 3 consecutive weeks of  interruption, discontinue  etoposide permanently or call  the Sponsor's Medical  Monitor to discuss resuming  the treatment of etoposide if  clinically indicated  Continue supportive care  according to institution's standard |                                                                                                                             |
| Cisplatin Dose Reduction and/or  Delay                         | No change.                                                                                                                                                                                                                                                                              |                                                                                                                                                                                                                                                                                                                                                                                                                   |                                                                                                                             |
| Thrombocytopenia                                               |                                                                                                                                                                                                                                                                                         |                                                                                                                                                                                                                                                                                                                                                                                                                   |                                                                                                                             |
| Etoposide Dose Reduction  and/or Delay  Reduction and/or Delay | No change.                                                                                                                                                                                                                                                                              |                                                                                                                                                                                                                                                                                                                                                                                                                   |                                                                                                                             |
| Study Drug Dose                                                | No change.                                                                                                                                                                                                                                                                              | No change.                                                                                                                                                                                                                                                                                                                                                                                                        |                                                                                                                             |
| Fever - 38.30C  (1010F) with either  500 -999/mm3 or <  500/mm3 OR  < 500/mm3 without  fever                                                                |                                                                                                                                                                                                                                                                                         |                                                                                                                                                                                                                                                                                                                                                                                                                   |                                                                                                                             |
| Adverse Event                                                  | •75,000/mm3                                                                                                                                                                                                                                                                                         |                                                                                                                                                                                                                                                                                                                                                                                                                   |                                                                                                                             |  
CONFIDENTIAL
Page 47 of 235 Protocol 59R5-003, Amendment 6  
22 April 2016  
| Consider to hold carboplatin till  platelet count - 75,000/ mm3 Resume  carboplatin based on timing of  recovery and number of previous  episodes  ¾ " 3 consecutive weeks of  interruption  - 1st episode, no change to  carboplatin dose  - 2nd episode, reduce carboplatin  dose to AUC of 4 mg/mL•min for all subsequent administration  - 3rd episode, discontinue                               | carboplatin treatment or call the  Sponsor's Medical Monitor to  discuss further dose reduction if                                                                          | clinically indicated.                                                        | ¾ > 3 Consecutive weeks of  interruption, discontinue                                                                                               | cisplatin permanently or call the  Sponsor's Medical Monitor to  discuss resuming the treatment   | of carboplatin if clinically  indicated                                                                                                                                     |                           |                                                                                                                                                   |                                                                 |                                                                                                                             |
|-------------------------------|-----------------------------------------------------------------------------------------------------------------------------------------------------------------------------|------------------------------------------------------------------------------|-----------------------------------------------------------------------------------------------------------------------------------------------------|---------------------------------------------------------------------------------------------------|-----------------------------------------------------------------------------------------------------------------------------------------------------------------------------|---------------------------|---------------------------------------------------------------------------------------------------------------------------------------------------|-----------------------------------------------------------------|-----------------------------------------------------------------------------------------------------------------------------|
| Consider to hold cisplatin till platelet  count - 75,000/ mm3 Resume cisplatin  based on timing of recovery and  number of previous episodes  ¾ " 3 consecutive weeks of  interruption  - 1st episode, no change to cisplatin  dose                               | - 2nd episode, reduce cisplatin dose  by 25% from starting dose for all  subsequent administration  - 3rd episode, reduce cisplatin dose  by 50% from starting dose for all | subsequent administration                                                    | - 4th episode, discontinue cisplatin  treatment or call the Sponsor's  Medical Monitor to discuss further  dose reduction if clinically  indicated. | ¾ > 3 Consecutive weeks of  interruption, discontinue cisplatin                                   | permanently or call the Sponsor's  Medical Monitor to discuss                                                                                                               | resuming the treatment of | cisplatin if clinically indicated                                                                                                                 |                                                                 |                                                                                                                             |
| Tarextumab (OMP-59R5)         | Carboplatin Dose Reduction  and/or Delay                                                                                                                                    |                                                                              |                                                                                                                                                     |                                                                                                   |                                                                                                                                                                             |                           |                                                                                                                                                   |                                                                 |                                                                                                                             |
| IND No. 106826, Serial 0037   | Suggested Guidelines for Study Drug and Etoposide-Platinum Therapy Dose Modification and Delay (Cont'd)                                                                     | Etoposide Dose Reduction and/or Delay Cisplatin Dose Reduction and/or  Delay | Thrombocytopenia (Cont'd)                                                                                                                           | Consider to hold etoposide till platelet  count - 75,000/ mm3 Resume etoposide  based on timing of recovery and number of  previous episodes  ¾ " 3 consecutive weeks of interruption  - 1st episode, no change to etoposide  dose                                                                                                   | - 2nd episode, reduce etoposide dose by  25% from starting dose for all  subsequent administration  - 3rd episode, reduce etoposide dose by  50% from starting dose for all | subsequent administration | - 4th episode, discontinue etoposide  treatment or call the Sponsor's  Medical Monitor to discuss further  dose reduction if clinically indicated | ¾ > 3 Consecutive weeks of  interruption, discontinue etoposide | permanently or call the Sponsor's  Medical Monitor to discuss resuming  the treatment of etoposide if clinically  indicated |
| ,19(67,*$7,21$/1(:'58*                               | 5.3.4.2 Protocol No. 59R5-003 - Amendment 6 - 22 April 2016                                                                                                                 | Adverse Event Study Drug Dose  Reduction and/or  Delay                       |                                                                                                                                                     |                                                                                                   |                                                                                                                                                                             |                           |                                                                                                                                                   |                                                                 |                                                                                                                             |
| OncoMed Pharmaceuticals, Inc. | No change. 50,000- 74,999/mm3, or  25,000-49,999/mm3                                                                                                                        |                                                                              |                                                                                                                                                     |                                                                                                   |                                                                                                                                                                             |                           |                                                                                                                                                   |                                                                 |                                                                                                                             |
| Table 5:                      |                                                                                                                                                                             |                                                                              |                                                                                                                                                     |                                                                                                   |                                                                                                                                                                             |                           |                                                                                                                                                   |                                                                 |                                                                                                                             |  
Protocol 59R5-003, Amendment 6
()  
| Hold carboplatin till platelet count  - 75,000/ mm3 Resume carboplatin  based on timing of recovery and  number of previous episodes  ¾ " 3 consecutive weeks of  interruption  - 1st episode, reduce carboplatin  dose to AUC of 4 mg/mL•min  for all subsequent administration  - 2nd episode, discontinue  carboplatin treatment or call the  Sponsor's Medical Monitor to  discuss further dose reduction if                                                                                                         | clinically indicated  ¾ > 3 Consecutive weeks of  interruption, discontinue  carboplatin permanently or call  the Sponsor's Medical Monitor  to discuss resuming the  treatment of carboplatin if  clinically indicated  Platelet transfusions should be   | administered prophylactically if  platelets "10,000/mm3 or as clinically  indicated if there is bleeding.                                                                                               |    |
|---------------------------------------------------------------------------------------------------------|------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|-----------------------------------------------------------------------------------------------|----|
| Carboplatin Dose Reduction  and/or Delay                                                                |                                                                                                                                                                                                                                                            |                                                                                               |    |
| Suggested Guidelines for Study Drug and Etoposide-Platinum Therapy Dose Modification and Delay (Cont'd) | Hold cisplatin till platelet count - 75,000/ mm3. Resume cisplatin based  on timing of recovery and number of  previous episodes  ¾ " 3 consecutive weeks of  interruption  - 1st episode, reduce cisplatin dose  by 25% from starting dose for all  subsequent administration  - 2nd episode, reduce cisplatin dose  by 50% from starting dose for all  subsequent administration  - 3rd episode, discontinue cisplatin  treatment or call the Sponsor's  Medical Monitor to discuss further  dose reduction if clinically  indicated  ¾ > 3 Consecutive weeks of  interruption, discontinue cisplatin  permanently or call the Sponsor's  Medical Monitor to discuss                                                                                                                                                                                                                                                            | resuming the treatment of cisplatin  if clinically indicated  Platelet transfusions should be | administered prophylactically if  platelets "10,000/mm3 or as clinically  indicated if there is bleeding.    |
| Etoposide Dose Reduction and/or Delay Cisplatin Dose Reduction and/or  Delay                            | Thrombocytopenia (Cont'd)                                                                                                                                                                                                                                  | Hold etoposide till platelet count  - 75,000/ mm3. Resume etoposide based  on timing of recovery and number of  previous episodes  ¾ " 3 consecutive weeks of interruption  - 1st episode, reduce etoposide dose by  25% from starting dose for all  subsequent administration  - 2nd episode, reduce etoposide by 50%  from the starting dose for all  subsequent cycles  - 3rd episode, discontinue etoposide  treatment or call the Sponsor's  Medical Monitor to discuss further  dose reduction if clinically indicated  ¾ > 3 Consecutive weeks of  interruption, discontinue etoposide  permanently or call the Sponsor's  Medical Monitor to discuss resuming  the treatment of etoposide if clinically  indicated  Platelet transfusions should be                                                                                               | administered prophylactically if platelets  "10,000/mm3 or as clinically indicated if  there is bleeding.    |
| Adverse Event Study Drug Dose  Reduction and/or  Delay                                                  | <25,000/mm3 No change                                                                                                                                                                                                                                      |                                                                                               |    |
| Table 5:                                                                                                |                                                                                                                                                                                                                                                            |                                                                                               |    |  
,19(67,*$7,21$/1(:'58* Protocol 59R5-003, Amendment 6  
| Monitor renal function and consider  IV hydration   |                                                                                                         |                                         |                                                   |                                  |    |                                    |          |    |                                                                     |                               |                                                                                                    |                            |                          |                                                       |                       |                                     |                              |                  |
|-----------------------------------------------------|---------------------------------------------------------------------------------------------------------|-----------------------------------------|---------------------------------------------------|----------------------------------|----|------------------------------------|----------|----|---------------------------------------------------------------------|-------------------------------|----------------------------------------------------------------------------------------------------|----------------------------|--------------------------|-------------------------------------------------------|-----------------------|-------------------------------------|------------------------------|------------------|
| Tarextumab (OMP-59R5)                               | Recalculate carboplatin dose with  the creatinine and GFR to have the                                   | AUC of 5 mg/mL•min                      |                                                   |                                  |    |                                    |          |    |                                                                     |                               |                                                                                                    |                            |                          |                                                       |                       |                                     |                              |                  |
| Carboplatin Dose Reduction  and/or Delay            |                                                                                                         |                                         |                                                   |                                  |    |                                    |          |    |                                                                     |                               |                                                                                                    |                            |                          |                                                       |                       |                                     |                              |                  |
| IND No. 106826, Serial 0037                         | Suggested Guidelines for Study Drug and Etoposide-Platinum Therapy Dose Modification and Delay (Cont'd) | Cisplatin Dose Reduction and/or  Delay  | Monitor renal function and consider  IV hydration | Consider to hold cisplatin until | creatinine returns to Grade " 1.  Resume cisplatin based on timing    | of recovery and number of previous | episodes | ¾ " 3 consecutive weeks of  interruption    | - 1st episode, reduce cisplatin dose  by 25% from starting dose for | all subsequent administration | - 2nd episode, reduce cisplatin  dose by 50% from starting dose  for all subsequent administration | - 3rd episode, discontinue | cisplatin administration | ¾ > 3 consecutive weeks of  interruption, discontinue | cisplatin permanently | Consider increasing the duration of | cisplatin infusion and other | supportive cares |
| Renal (creatinine)                                  |                                                                                                         |                                         |                                                   |                                  |    |                                    |          |    |                                                                     |                               |                                                                                                    |                            |                          |                                                       |                       |                                     |                              |                  |
| Etoposide Dose Reduction  and/or Delay              | No change                                                                                               | No change                               |                                                   |                                  |    |                                    |          |    |                                                                     |                               |                                                                                                    |                            |                          |                                                       |                       |                                     |                              |                  |
| ,19(67,*$7,21$/1(:'58*                                                     | 5.3.4.2 Protocol No. 59R5-003 - Amendment 6 - 22 April 2016                                             | Study Drug Dose Reduction  and/or Delay | No change. Grade 2 (>1.5-3x ULN                   | or >1.5-3.0 x baseline)          |    |                                    |          |    |                                                                     |                               |                                                                                                    |                            |                          |                                                       |                       |                                     |                              |                  |
| No change                                           |                                                                                                         |                                         |                                                   |                                  |    |                                    |          |    |                                                                     |                               |                                                                                                    |                            |                          |                                                       |                       |                                     |                              |                  |
| OncoMed Pharmaceuticals, Inc.                       | Grade 1 (> ULN-1.5x  ULN or > 1-1.5 x  baseline)                                                        |                                         |                                                   |                                  |    |                                    |          |    |                                                                     |                               |                                                                                                    |                            |                          |                                                       |                       |                                     |                              |                  |
| Adverse Event                                       |                                                                                                         |                                         |                                                   |                                  |    |                                    |          |    |                                                                     |                               |                                                                                                    |                            |                          |                                                       |                       |                                     |                              |                  |
| Table 5:                                            |                                                                                                         |                                         |                                                   |                                  |    |                                    |          |    |                                                                     |                               |                                                                                                    |                            |                          |                                                       |                       |                                     |                              |                  |  
22 April 2016 CONFIDENTIAL
Page 50 of 235 Protocol 59R5-003, Amendment 6  
| Hold carboplatin until creatinine  returns to Grade " 1 Resume  carboplatin based on timing of  recovery and number of previous  episodes  ¾ " 3 consecutive weeks of  interruption                                                                                                         | - 1st episode, reduce carboplatin  dose to AUC of 4 mg/mL•min  for all subsequent  administration   | - 2nd episode, discontinue  carboplatin treatment  ¾ > 3 Consecutive weeks of  interruption, discontinue  carboplatin permanently                                                                                                                                                       | 22 April 2016                  |
|---------------------------------------------------------------------------------------------------------|-----------------------------------------------------------------------------------------------------|-----------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|--------------------------------|
| Carboplatin Dose Reduction  and/or Delay                                                                |                                                                                                     |                                                                                                                                                                                                                                                                                         |                                |
| Suggested Guidelines for Study Drug and Etoposide-Platinum Therapy Dose Modification and Delay (Cont'd) | Hold cisplatin until creatinine  returns to Grade " 1. Resume  cisplatin based on timing of  recovery and number of previous  episodes  ¾ " 3 consecutive weeks of  interruption  - 1st episode, reduce cisplatin dose  by 25% from starting dose for  all subsequent administration  - 2rd episode, reduce cisplatin dose  by 50% from starting dose for  all subsequent administration  - 3rd episode, discontinue cisplatin  treatment  ¾ > 3 Consecutive weeks of  interruption, discontinue  cisplatin permanently  Consider supportive care according  to institution's standard, and  decrease the infusion rate                                                                                                     |                                                                                                                                                                                                                                                                                         |                                |
| Cisplatin Dose Reduction and/or  Delay Renal (creatinine) Cont'd                                        | CONFIDENTIAL                                                                                        |                                                                                                                                                                                                                                                                                         |                                |
| No change if creatinine returns  to Grade "1 before the next  scheduled etoposide  administration after withholding  one dose of cisplatin or reduced  carboplatin dose.  Hold etoposide until creatinine  returns to Grade "1. Resume  etoposide based on timing of  recovery and number of previous  episodes  ¾ " 3 consecutive weeks of  interruption  - 1st episode, reduce etoposide  dose by 25% from starting  dose for all subsequent  administration                                                                                                         | - 2nd episode, reduce etoposide  dose by 50% from starting  dose for all subsequent  administration | - 3rd episode, discontinue  etoposide treatment  ¾ > 3 Consecutive weeks of  interruption, discontinue  etoposide permanently or call  the Sponsor's Medical  Monitor to resume the  treatment if clinically  indicated  Consider supportive care  according to institution's  standard | Page 51 of 235                 |
| Etoposide Dose Reduction  and/or Delay Adverse Event Study Drug Dose Reduction  and/or Delay            | No change if creatinine returns  to Grade " 1 before the next  study drug administration after  withholding cisplatin or  etoposide for one cycle.  Hold study drug if creatinine  does not return to Grade "1  after holding cisplatin or  etoposide for one cycle.  Resume study drug if creatinine  returns to Grade "1 within 3                                                                                                     | weeks.  ¾ " 3 consecutive weeks of  interruption  - Resume study drug at the  next lower dose  ¾ > 3 Consecutive weeks of  interruption, discontinue or  call the Sponsor's Medical  Monitor to resume the  treatment if clinically  indicated                                                                                                                                                                                                                                                                                         | Protocol 59R5-003, Amendment 6 |
| Grade - 3 (>3-6x  ULN/>3 baseline                                                                                                         | or >6 ULN)                                                                                          |                                                                                                                                                                                                                                                                                         |                                |
| Table 5:                                                                                                |                                                                                                     |                                                                                                                                                                                                                                                                                         |                                |  
,19(67,*$7,21$/1(:'58*
()  
  
| Hold carboplatin if diarrhea does  not improve to "Grade 1 after  withholding study drug for three  weeks.  Resume carboplatin according to  the number of episodes that  resolved to "Grade 1 within 3                                                                                                         | weeks of study drug interruption:  - 1st episode: resume at the  same dose   | - 2rd episode: reduce  carboplatin dose to AUC of 4  mg/mL•min for all  subsequent administration  - 3rd episode: discontinue  carboplatin permanently or  call the Sponsor's Medical  Monitor to discuss further  dose reduction if clinically  indicated   |                                                                                                                                                      |                                                                                                                                                       |                                                                                                                                                                                                                                                                                   |
|---------------------------------------------------------------------------------------------------------|------------------------------------------------------------------------------|--------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|------------------------------------------------------------------------------------------------------------------------------------------------------|-------------------------------------------------------------------------------------------------------------------------------------------------------|-----------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|
| Carboplatin Dose Reduction  and/or Delay                                                                | No change. Supportive care  according to standard practice                   |                                                                                                                                                                                                                                                              |                                                                                                                                                      |                                                                                                                                                       |                                                                                                                                                                                                                                                                                   |
| Suggested Guidelines for Study Drug and Etoposide-Platinum Therapy Dose Modification and Delay (Cont'd) | Cisplatin Dose Reduction and/or  Delay                                       | Hold cisplatin if diarrhea does not  improve to "Grade 1 after  withholding study drug for three  weeks.  Resume cisplatin according to the  number of episodes that resolved  to "Grade 1 within 3 weeks of  study drug interruption:  - 1st episode: resume at the  same dose                                                                                                                                                                                                                                                              | - 2rd episode: reduce cisplatin  dose by 25% from starting  dose for all subsequent  administration                                                  | - 3rd episode: reduce cisplatin  dose by 50% from starting  dose for all subsequent  administration                                                   | - 4th episode: discontinue  cisplatin permanently or call  the Sponsor's Medical  Monitor to discuss further  dose reduction if clinically  indicated                                                                                                                             |
| No change. Supportive care  according to standard practice                                              | Hold etoposide if diarrhea does  not improve to "Grade 1 after  withholding study drug for one  cycle.  Resume etoposide according to the  number of episodes that resolved  to "Grade 1 within 3 weeks of  study drug interruption:  - 1st episode: resume at the  same dose                                                                              | - 2rd episode: reduce etoposide  dose by 25% from starting  dose for all subsequent  administration                                                                                                                                                          | - 3rd episode: reduce etoposide  dose by 50% from starting  dose for all subsequent  administration                                                  | - 4th episode: discontinue  etoposide permanently or call  the Sponsor's Medical  Monitor to discuss further  dose reduction if clinically  indicated |                                                                                                                                                                                                                                                                                   |
| Etoposide Dose Reduction  and/or Delay                                                                  | Diarrhea                                                                     | No change. Supportive care  according to standard practice  No change. Supportive care  according to standard practice and  diarrhea management described in  the protocol (Section 7.5 below)  Hold study drug, supportive care  according to standard practice.  Resume study drug according to  the number of episodes that  resolved to "Grade 1 within 3                                                                                                                                                                                                                                                              | weeks of treatment interruption:  - 1st episode: resume at the next  lower dose (reduce by 2.5  mg/kg or to discuss the  increment of dose reduction | with the Sponsor's Medical  Monitor)  - 2rd episode: reduce by 5 mg/kg  from starting dose or to  discuss alternative increment                       | of dose reduction with the  Sponsor's Medical Monitor  - 3rd episode: discontinue study  drug permanently or call the  Sponsor's Medical Monitor to  discuss further dose reduction  if clinically indicated  diarrhea management  described in the protocol  (Section 7.5 below) |
| Study Drug Dose Reduction  and/or Delay  Adverse Event                                                  |                                                                              |                                                                                                                                                                                                                                                              |                                                                                                                                                      |                                                                                                                                                       |                                                                                                                                                                                                                                                                                   |
| Table 5:                                                                                                | "Grade 2                                                                              | •Grade 3                                                                                                                                                                                                                                                              |                                                                                                                                                      |                                                                                                                                                       |                                                                                                                                                                                                                                                                                   |  
()
,19(67,*$7,21$/1(:'58* Protocol 59R5-003, Amendment 6 22 April 2016  
| Tarextumab (OMP-59R5)                    | Hold carboplatin for one cycle to  see if peripheral neuropathy  improves to Grade "2.  Resume carboplatin according to  the number of episodes that  improved to Grade "2 within 3  weeks of study drug interruption:  - 1st episode: Reduce  carboplatin dose to AUC of 4  mg/mL•min for all  subsequent cycles  - 2rd episode: discontinue  carboplatin permanently or  call the Sponsor's Medical  Monitor to discuss further  dose reduction if clinically  indicated                                                                                                         | Call the Sponsor's Medical  Monitor to discuss resume                                                                                                 | carboplatin if the event does not  recover to Grade " 2 after one                                                       | cycle of carboplatin interruption.   |
|------------------------------------------|---------------------------------------------------------------------------------------------------------|-------------------------------------------------------------------------------------------------------------------------------------------------------|-------------------------------------------------------|--------------------------------------|
| Carboplatin Dose Reduction  and/or Delay |                                                                                                         |                                                                                                                                                       |                                                       |                                      |
| IND No. 106826, Serial 0037              | Suggested Guidelines for Study Drug and Etoposide-Platinum Therapy Dose Modification and Delay (Cont'd) | No change                                                                                                                                             |                                                       |                                      |
| Cisplatin Dose Reduction and/or  Delay   | Hold cisplatin for one cycle to see  if peripheral neuropathy improves  to Grade "2.  Resume cisplatin according to the  number of episodes that improved  to Grade "2 within 3 weeks of  study drug interruption:  - 1st episode: Reduce cisplatin  dose by 25% from starting  dose for all subsequent cycles  - 2rd episode: reduce cisplatin  dose by 50% from starting  dose for all subsequent  administration.                                                                                                         | - 3rd episode: discontinue  cisplatin permanently or call  the Sponsor's Medical  Monitor to discuss further  dose reduction if clinically  indicated | Call the Sponsor's Medical  Monitor to discuss resume | cisplatin if the event does not  recover to Grade " 2 after one  cycle of cisplatin interruption.                                      |
| No change                                |                                                                                                         |                                                                                                                                                       |                                                       |                                      |
| Peripheral Neuropathy                    |                                                                                                         |                                                                                                                                                       |                                                       |                                      |
| Etoposide Dose Reduction  and/or Delay   | No change                                                                                               | No change                                                                                                                                             |                                                       |                                      |
| ,19(67,*$7,21$/1(:'58*                                          | 5.3.4.2 Protocol No. 59R5-003 - Amendment 6 - 22 April 2016                                             | Study Drug Dose Reduction  and/or Delay                                                                                                               | No change                                             | No change                            |
| OncoMed Pharmaceuticals, Inc.            | Adverse Event                                                                                           |                                                                                                                                                       |                                                       |                                      |
| Table 5:                                 | Grade " 2                                                                                                         | Grade - 3                                                                                                                                                       |                                                       |                                      |  
22 April 2016 CONFIDENTIAL
Page 53 of 235 Protocol 59R5-003, Amendment 6
clinical protocol
7.5.1 infusion reaction management

The administration of monoclonal antibodies may result in an infusion reaction that may consist of a symptom complex characterized by fever, chills, nausea, vomiting, headache, dizziness, bronchospasm, dyspnea, hypotension, and/or rash including urticaria. If an infusion reaction occurs, the infusion should be stopped and any appropriate medical care should be administered. For subjects whose infusion-associated events were either Grade 1 or 2, and completely resolved on the day of the infusion, the infusion may be resumed at the discretion of the Investigator at a rate that is slower than the initial rate of infusion. *If a Grade 1 or 2 reaction occurs during the* first cycle (also with complete resolution of symptoms), the infusion may be resumed at either a slower rate or at the initial rate of infusion (i.e. over 180 minutes). Please refer to the Pharmacy Manual for details on study drug administration. All subsequent infusions for that subject should then be administered at the reduced rate of infusion.  
Subjects experiencing a Grade 2 infusion reaction should be premedicated prior to subsequent infusions. Premedications may include medications such as corticosteroids, diphenhydramine, and/or bronchodilators as indicated. If the Grade 2 infusion reaction recurs during subsequent infusions despite the premedications, the subject should be removed from treatment. In addition, permanently discontinue the study drug therapy in any subject who experiences a Grade 3 or 4 infusion reaction or acute allergic reaction (e.g., symptomatic bronchospasm with or without urticaria, edema, angioedema, or hypotension). Grade 3 or 4 acute allergic reactions should be medically managed as appropriate and treatment may include the administration of epinephrine, corticosteroids, diphenhydramine, bronchodilators, and/or oxygen as indicated.
clinical protocol
7.6 anti-emetics anti-diarrhea and hematopoietic

Antiemetic therapy and anti-diarrheal medications may be administered at the discretion of the Investigator. However, since diarrhea is the main adverse event associated with tarextumab as a single agent it is recommended that the Investigator follow diarrhea management guidelines below. It is recommended that all subjects enrolled on the study are to be given a prescription for loperamide at study entry with instructions to take an initial 4 mg dose following the first loose stool, followed by 2 mg after every unformed stool with a maximum of 16 mg per day. Loperamide should be continued until the subject was diarrhea-free for 12 hours. If Grade 3 diarrhea develops, loperamide should be discontinued and the subject would be started on second-line therapy (i.e., Lomotil 2 tablets 4 times daily and/or octreotide 100-150 μg SC three times daily up to a maximum 500 μg 3 times daily).  
Hematopoietic growth factors, transfusion of blood and blood products should not be used prophylactically prior to the dosing of the study drug and EP on Day 1 of Cycle 1, but may be administered per standard clinical practice during the course of the study as needed.
clinical protocol
7.7 concomitant and prohibited therapy

All concomitant medication administered within 28 days prior to the first administration of study drug through 30 days following the administration of the last dose of study drug will be recorded on the Concomitant Medication eCRF. Investigational medicinal products, therapeutic warfarin (prophylactic low dose of warfarin, i.e., 1 mg daily is allowed for port catheter) and anticancer agents (e.g., cytotoxic agents and biologics with known activity against small cell lung cancer) may not be administered from enrollment through the first line therapy. Subjects planning to initiate intravenous bisphosphonate or denosumab therapy after study entry must begin within the first 30 days of the first administration of study drug. Oral bisphosphonate may be initiated at any point in the study for the treatment of osteoporosis. Subjects can switch intravenous bisphosphonate to denosumab or vice versa during the study, but the initiation of a new intravenous bisphosphonate or denosumab therapy beyond 30 days after the first administration of study drug is prohibited. After the completion of 6 cycles of EP, subjects who do not have disease progression and have not had prophylactic cranial irradiation (PCI) or whole brain radiation (WBRT) prior to study entry and are good candidates for PCI per the Investigators should receive PCI within 8 weeks after the last dose of chemotherapy at a total dose of 25 Gy in 10 fractions. If subjects discontinue EP with treatment-related toxicities prior to completing 6 cycles and are good candidates for PCI per the Investigators, PCI can be initiated at the time that is determined appropriated per the Investigator. Subjects who do not receive PCI within 8 weeks after the last dose of chemotherapy can have PCI later during the study as determined by the Investigator. Study drug administration should continue at every 21-day cycle between the completion of chemotherapy and the initiation of PCI. PCI should not be initiated within 2 weeks of study drug administration and study drug will be held during the PCI treatment period. Subjects will resume study drug alone  14 days after completion of PCI, until disease progression or unacceptable treatment-related toxicities or withdrawal of consent (Appendix A). Subjects will discontinue study treatment if there is evidence of central nervous system (CNS) metastasis.
clinical protocol
7.8 treatment compliance

Tarextumab, Placebo, etoposide and cisplatin or carboplatin will be administered IV by study site personnel. Thus, compliance with each infusion will be documented in the subject's medical records and then recorded on the appropriate electronic data capture (EDC) screen. In addition, drug accountability will be performed.
clinical protocol
8.0 safety assessments

Safety will be assessed by adverse event monitoring (including attribution of AEs and SAEs), physical examination, vital signs, clinical laboratory testing, anti-tarextumab testing, and subject interview on an ongoing basis as outlined in the Schedule of Assessments (see Appendix B, and Appendix C). Samples that test positive for tarextumab antibodies will be assessed for neutralizing capability. The impact of positive samples on safety and biologic activity will be assessed.
clinical protocol
8.1 adverse events definitions and

All Adverse Events from the time of the first administration of study drug through 30 days after the last dose of study drug or EP whichever is discontinued last **must** be documented in the medical record and reported on the AE Case Report Form (CRF). Adverse events will be coded in accordance with the Medical Dictionary for Regulatory Activities (MedDRA). The grading of the adverse events will be done using the National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE), version 4.02 (see Study Reference Binder).
clinical protocol
8.1.1 definition of adverse event

An adverse event is any untoward or unfavorable medical occurrence in a human subject, including any abnormal sign (for example, abnormal physical exam or laboratory finding), symptom, or disease temporally associated with the subject's participation in the research, whether or not considered related to the subject's participation in the research. Any medical condition or clinically significant laboratory abnormality with an onset date before the first administration of study drug is a pre-existing condition that must be listed on the Medical History CRF and should not be considered an adverse event unless the condition worsens in intensity or frequency after enrollment (e.g., Grade 2 nausea prior to the first administration of study drug becomes Grade 3 nausea after the first administration of study drug).
clinical protocol
8.1.2 adverse event -causality rating

The causality of each adverse event should be assessed and classified by the Investigator as "related" or "not related". An event is considered related if the administration of study drug and the occurrence of the AE are reasonably related in time AND the event could not be explained equally well by factors or causes other than exposure to study drug. An event is considered unrelated if the administration of study drug and the occurrence of the AE are not reasonably related in time AND the event is likely to be related to an etiology other than the use of study drug; that is, there are facts, evidence or arguments to suggest a causal relationship to study drug.
clinical protocol
8.1.3 definition of serious adverse

A **serious adverse event** is any event that results in the following:
,19(67,*$7,21$/1(:'58*  
- death - life-threatening condition (places the subject at immediate risk of death) - subject hospitalization or prolongation of existing hospitalization - persistent or significant disability/incapacity - congenital anomaly/birth defect, or any other adverse event that, based upon the Investigators medical judgment, may require medical or surgical intervention to prevent one of the outcomes listed above (examples of such events include allergic bronchospasm requiring intensive treatment in the emergency room or at home, blood dyscrasias or convulsions that do not result in subject hospitalization, or the development of drug dependency or drug abuse)
clinical protocol
8.1.3.1 disease progression and death

Disease progression (including progression of small cell lung cancer, and death due to disease progression) is generally recorded as part of the efficacy evaluation and should not be reported as an AE or SAE. When an AE resulting from disease progression meets the requirements to be considered serious, the SAE verbatim term should be reported as the sign/symptom that best describes the event rather than as disease progression. For instance, a subject with pleural effusion presents with shortness of breath. The cause of the shortness of breath is a pleural effusion resulting from disease progression. The event term may be reported as "pleural effusion" instead of disease progression. Death should not be reported as a serious adverse event, but as a clinical outcome of a specific SAE. The cause of death, reported on a source document such as the Death Certificate or autopsy report, should be used as the event term for the SAE.
clinical protocol
8.1.4 serious adverse event reporting

SAEs that occur during the study must be clearly documented in the medical record. In addition, the SAE form must be completed for each event and promptly submitted to OncoMed designated fax number. Details of SAE reporting procedures will be available in Study Reference Manual. The Investigator is encouraged to discuss with the Medical Monitor any AEs for which the issue of seriousness is unclear or questioned. Contact information for the Medical Monitor is as follows: Primary:  
 Backup:  
 OncoMed Pharmaceuticals, Inc. 800 Chesapeake Drive Redwood City, CA 94063 The reporting period for SAEs is the period from the first administration of the study drug through 30 days after the last administration of study drug or EP whichever is discontinued last. SAEs reported to the Investigator outside of this reporting period will be reported to OncoMed or its designee if in the judgment of the Investigator there is "a reasonable possibility" that the event may have been caused by the product. All SAEs will continue to be followed until the end of the Study or until such events have resolved or the Investigator, in conjunction with the Sponsor, deems them to be chronic or stable.
clinical protocol
8.2 clinical laboratory assessments 8.2.1

Hematology includes complete blood count (CBC) with differential, hemoglobin (Hgb), and platelet count. Coagulation test of PT/INR and aPTT will be obtained on Day 1 of each treatment cycle. The results need to be reviewed by the Investigator prior to each study drug administration.
clinical protocol
8.2.2 chemistry

For Phase 1b, Serum Chemistry includes sodium, potassium, chloride, bicarbonate, blood urea nitrogen (BUN), creatinine, glucose, ALT, AST, alkaline phosphatase, total bilirubin, direct bilirubin, lactate dehydrogenase (LDH), total protein, albumin, calcium, phosphorus, and magnesium. The results for BUN, bicarbonate, creatinine, glucose, chloride, potassium, and sodium need to be reviewed by the Investigator prior to each study drug administration.  
For Phase 2, Chemistry (Serum or Plasma) includes sodium, potassium, chloride, bicarbonate, blood urea nitrogen (BUN), creatinine, glucose, ALT, AST, alkaline phosphatase, total bilirubin, direct bilirubin, lactate dehydrogenase (LDH), total protein, albumin, calcium, phosphorus, and magnesium. The results for BUN, bicarbonate, creatinine, glucose, chloride, potassium, and sodium need to be reviewed by the Investigator prior to each study drug administration.
clinical protocol
8.2.3 urinalysis

For Phase 1b, Urinalysis (dip stick is sufficient) includes color, appearance, pH, ketones, specific gravity, bilirubin, protein, blood, glucose and urobilinogen. For Phase 2, Urinalysis (dip stick is sufficient) includes pH, ketones, specific gravity, bilirubin, protein, blood and glucose.
clinical protocol
8.3 vital signs and other

A full physical examination will be done at screening, clinically indicated during the study and treatment termination. Targeted physical examinations will be done at all other times, with areas of the body to be examined at the Investigator's discretion. Vitals signs (blood pressure, pulse, respiratory rate, and temperature) will be done at screening and during study visits as specified in the Schedule of Assessments (Appendix B and Appendix C).
clinical protocol
8.4 cardiac studies

Twelve-lead electrocardiograms (ECGs) with assessment of PR interval, QRS duration, and QTc interval will be obtained at Screening and during study visits as specified in the Schedule of Assessments (APPENDIX B and APPENDIX C).
clinical protocol
8.5 immunogenicity assessments

During Phase 1b, serum samples will be obtained for immunogenicity assessment (Antitarextumab) prior to study drug administration on Day 1 of Cycle 1, every three cycles thereafter
(Day 1 of Cycle 4, 7, 10, etc.), at other times as clinically indicated such as when significant toxicities occur and at the time of treatment termination for all subjects enrolled in Phase 1b. Samples that test positive will be assessed for neutralizing capability. During Phase 2, serum samples will be obtained for immunogenicity assessment (Anti-tarextumab) prior to study drug administration on Day 1 of Cycle 1, every other cycle thereafter (Day 1 of Cycle 3, 5, 7, etc.), at other times as clinically indicated such as when significant toxicities occur and at the time of treatment termination for all subjects enrolled in Phase 2. Samples that test positive will be assessed for neutralizing capability.  
Instructions for sample collection, handling, storage, and shipping can be found in the Study Reference Binder.
clinical protocol
8.6 pharmacokinetic assessments

For subjects enrolled in Phase 1b portion only: Plasma samples from all subjects enrolled in Phase 1b portion will be obtained for pharmacokinetic analysis of tarextumab at pre-dose and 5 minutes post tarextumab infusion on Day1 of Cycles 1 and 3, on Days 3 and 8 of Cycles 1 and 3, at other times as clinically indicated such as when significant toxicities occur as well as at the time of treatment termination, as outlined in the Schedule of Assessments (Appendix B). ()
For subjects enrolled in Phase 2 portion only: Plasma samples from all subjects enrolled in Phase 2 portion will be obtained for pharmacokinetic analysis of tarextumab on Day 1 of Cycles 1 and 3, at pre-dose and 5 minutes post tarextumab infusion Day 3 of Cycle 1 and Cycle 3 prior to etoposide administration; Day 8 of Cycle 1 and Cycle 3 when blood sample is taken for biomarker evaluation; Day 1 of every other cycle staring from Cycle 5 prior to study drug infusion and, at other times as clinically indicated such as when significant toxicities occur as well as at the time of treatment termination, as outlined in the Schedule of Assessments ( Appendix C). Pharmacokinetic parameters (i.e. area under the curve [AUC], clearance, volume of distribution and apparent half life) of tarextumab will be assessed for each evaluable subject. Instructions for sample collection, handling, storage, and shipping can be found in the Study Reference Binder.
clinical protocol
9.0 efficacy assessments

Subjects will be assessed for response using Response Evaluation Criteria in Solid Tumors (RECIST) criteria 1.1. The first response assessment will occur approximately 6 weeks/42 days (± 5 days) after the first dose of the study drug. Subsequent response assessments will occur every 6 weeks/42 days (± 5 days). Subjects who discontinue study treatment for any reason other than disease progression will be followed with tumor assessment every 6 weeks/42 days (±5 days) during Follow-up until documented disease progression or initiation of new anti-cancer therapy, whichever is sooner.
clinical protocol
10.0 biomarkers and exploratory assessments

Instructions for biomarker sample collection, handling, labeling, and shipping are provided in the Study Reference Binder. Notch Expression: Notch3*, Hes1, Hey2, Hey1 and Hes6* expression levels will be assessed in FFPE tumor specimens, either archived or fresh core needle biopsied at study entry (two fresh cores preferred whenever possible). FFPE samples must be obtained during screening for Notch3*, Hes1, Hey2, Hey1 and Hes6* levels to be measured by immunohistochemistry and/or gene expression assays. Notch 2 and other Notch-related genes and proteins may also be measured. In addition, DNA testing may be performed on the FFPE tumor specimens for subjects who sign the optional FFPE Informed Consent for DNA testing. Exploratory analysis of these tumors may help to identify biomarkers that could be used in the future to predict which subjects are more likely to respond to tarextumab treatment. Analysis of candidate genes relevant to the Notch pathway may be performed (e.g. Notch2, Notch3, etc.). ()
Blood Biomarkers: A pre-dose sample of a total of 19 mL of blood will be drawn during study visits according to Schedule of Assessments (Appendix B and Appendix C) to evaluate changes in plasma proteins by immunochemistry (e.g., EGFR, PLGF, ENA-78, etc.), circulating tumor cells(CTCs), and Notch-related gene expression of mRNA, e.g., Affymetrix microarrays, quantitative PCR. Plasma microRNAs may also be evaluated by microRNA expression profiling. A sample will also be obtained at the time of treatment termination unless one has been obtained during the prior 14 days. A pre-dose blood sample will also be obtained on Day 1 of Cycles 4 and 5 to explore effects of treatment on CTCs. CTCs will be enumerated in blood and correlation with response to EP plus tarextumab will be assessed. Biomarker proteins and mRNA expression in the CTCs (e.g., Notch3, Notch2, CD44, ALDH1, etc.) may also be evaluated. Circulating endothelial cells may also be evaluated. Hair Follicle mRNA Expression for subjects in Phase 1b only: Predose hair samples (6 hairs) will be collected during study visits according to Schedule of Assessments (Appendix B) for gene expression RT-PCR analysis of Notch-pathway related mRNA expression, e.g., heyl, hey2, etc. RNA extracted from hair samples may be analyzed on microarrays, e.g., Affymetrix platform to measure tarextumab–affected gene expression changes in samples. Pharmacogenomics: A blood sample (10 mL) will be collected on Day 1 of Cycle 1. Pharmacogenomic analysis of candidate genes relevant to tarextumab may influence safety, tolerability, or pharmacodynamic effects of tarextumab for the treatment of extensive stage small cell lung cancer. Analysis of genes relevant to Notch/DLL4 target or pathway genes or disease genes may be performed (e.g., Notch 2, Notch3, FBW7 and PTEN). Pharmacogenomic samples will be destroyed after 10 years. Optional Tumor Biomarkers: Optional tumor specimens will be collected during study visits and at the time of treatment termination, if feasible according to Schedule of Assessments (Appendix B and Appendix C) from subjects who are consented and who have tumor lesions that are amenable to core biopsies. Tumor samples will be analyzed for treatment-induced changes in Notch-related gene expression (i.e., mRNA) and/or protein markers and cancer stem cell– related gene expression.
clinical protocol
11.0 study visit schedule and

Subjects must sign and date the Informed Consent Form that has been approved by the IEC/IRB prior to undergoing any study-related procedures. The enrollment and cohort assignment will be centrally managed by OncoMed and its designee. When a treatment cohort is open for enrollment during Phase 1b portion, the site will fax in a Subject Registration Form along with subject eligibility supporting documents for each potential subject to OncoMed and its designee after the subject's screening process has been completed.  
OncoMed and its designee will assign a subject number and treatment cohort for each subject that is accepted into the study. Sites cannot enroll or start dosing a subject without receiving the assigned subject number and treatment cohort from OncoMed or its designee during Phase 1b portion. During Phase 2 portion, the Investigator/study coordinator will use a randomization method that is detailed in the Study Reference Manual to enroll the subject after OncoMed or its representative has signed and approved the enrollment form. Study drug must be administered within 4 days from the date of enrollment/randomization. The following study evaluations must be performed at the indicated timepoints.
clinical protocol
11.1 screening

The following evaluations and procedures will be performed within 28 days prior to the first study drug administration (Cycle 1 Day 1):
- Informed Consent **(must be obtained before any study specific procedures are**
performed)  
- Medical and oncology history including demographics - Radiographic evaluation: CT with contrast, or MRI of the chest, abdomen, pelvis, and brain, and bone scan performed as outlined by the RECIST criteria 1.1 (see Appendix E). Note: PET/CT can be used in lieu of bone scan to identify and follow up bone lesions. The same method (CT or MRI, bone scan or PET/CT for bone lesions) must be used consistently throughout the study to follow the same anatomical location.  
- FFPE tumor tissues, either archived or fresh core needle biopsied available for Notch3, Hes1, Hey1, Hey2, and Hes6 analysis (two fresh cores preferred whenever possible). In addition, DNA testing may be performed on the FFPE tumor specimens for subjects who sign the optional Pharmacogenomics/DNA Testing Informed Consent form. Details of the requirement of tissue specimen will be provided in the Study Reference Manual
- Tumor core biopsy (**Optional and only if subject has signed the optional tumor core**
biopsy consent)
- Concomitant medications
The following evaluations and procedures will be performed within 14 days prior to the first administration of study drug (Cycle 1 Day 1):
- Physical examination  
- Vital signs - Height - Weight - ECOG performance status - Hematology - Chemistry - Coagulation - Serum pregnancy test for all females of childbearing potential (a negative result must be obtained prior to enrollment)
- Urinalysis (dip stick is sufficient) - Electrocardiogram (ECG) including PR interval, RR interval, QRS duration, and QTc interval
- Concomitant medications
clinical protocol
11.2 treatment visits - phase

If the subject meets all inclusion/exclusion criteria after the screening visit(s), the site will complete an enrollment form and submit it to OncoMed along with supporting source documents for approval. Once OncoMed or its representative has approved the enrollment form, the Investigator/study coordinator will receive a subject number and dose cohort assignment from OncoMed and its designees to enroll a subject into Phase 1b portion of the study.  
The subject will start treatment of study drug on Day 1 in combination with etoposide 100 mg/m2 on Days 1, 2, and 3, and cisplatin 80 mg/m2 for Phase 1b or carboplatin at AUC of 5 mg/mL•min on Day 1 of every 21-day cycle. On days when study drug is given together with etoposide and platinum therapy, study drug should be given prior to etoposide and platinum therapy administration. Hematology, BUN, bicarbonate, creatinine, glucose, chloride, potassium, and sodium lab results must be available and reviewed by the Investigator prior to each study drug dosing. For subjects who have study drug held or discontinued for tolerability reasons, EP chemotherapy should continue to the completion of 6 cycles. After the completion of 6 cycles of EP, subjects who do not have disease progression and have not had prophylactic cranial irradiation (PCI) or whole brain radiation (WBRT) prior to study entry and are good candidates for PCI per the Investigators should receive PCI within 8 weeks after the last dose of chemotherapy at a total dose of 25 Gy in 10 fractions. If subjects discontinue EP with treatment-related toxicities prior to completing 6 cycles and are good candidates for PCI per the Investigators, PCI can be initiated at the time that is determined appropriated per the Investigator. Subjects who do not receive PCI within 8 weeks after the last dose of chemotherapy can have PCI later during the study as determined by the Investigator. Study drug administration (tarextumab or Placebo) should continue at every 21-day (± 1 day) cycle between the completion of chemotherapy and the initiation of PCI. PCI should not be initiated within 2 weeks of study drug administration and study drug will be held during the PCI treatment period. Subjects will resume study drug alone (tarextumab or Placebo)  14 days after completion of PCI, until disease progression or unacceptable treatment-related toxicities or withdrawal of consent. Subjects will discontinue study treatment if there is evidence of central nervous system (CNS) metastasis.
clinical protocol
11.2.1 cycle 1 11.2.1.1 cycle

The following assessments will be completed prior to study drug infusion. These assessments will be repeated if they were done more than 7 days prior to Cycle 1 Day 1.  
- Physical examination - ECOG performance status - Hematology - Serum chemistry - Coagulation
- Urinalysis (dip stick is sufficient) - Electrocardiogram (ECG) including PR interval, RR interval, QRS duration, and QTc interval
The following assessments will be done prior to study drug infusion on Cycle 1 Day 1:  
- Weight
- Serum sample for anti-tarextumab antibody on all subjects  
- Blood sample for biomarker - Plasma sample for tarextumab PK from all subjects - Hair follicle samples (6 hairs)
()  
- Blood sample for pharmaco-genomics **(Optional and only if subject has signed the**
separate pharmacogenomics Informed Consent Form)
- Concomitant medications
- Vital Signs
Administration of study drug, etoposide, and cisplatin or carboplatin: Hematology, BUN, bicarbonate, creatinine, glucose, chloride, potassium, and sodium lab results must be reviewed by the Investigator prior to study drug dosing. Study drug will be administered first, followed by etoposide infusion, and then cisplatin or carboplatin infusion. The following procedures will be completed after administration of study drug:  
- Plasma samples for tarextumab PK only from all subjects: 5 (±2) minutes after the end of tarextumab infusion, but prior to EP administration.  
- Adverse event recording
clinical protocol
11.2.1.2 cycle 1 day 2

The following assessments will be completed prior to etoposide infusion:
- Vital signs - Weight - Concomitant medications  
- Adverse event recording
Administration of etoposide: Etoposide dosing will be given.
clinical protocol
11.2.1.3 cycle 1 day 3

The following assessments will be completed prior to etoposide infusion:
- Vital signs  
- Weight
- Plasma sample for tarextumab PK from all subjects enrolled  
- Concomitant medications - Adverse event reporting
Administration of etoposide: Etoposide dosing will be given.  
- Adverse event recording 11.2.1.4 Cycle 1 Day 8  
- Blood sample for biomarker - Plasma sample for tarextumab PK from all subjects - Hematology - Concomitant medications
- Adverse event recording
clinical protocol
11.2.2 cycles 2-6 11.2.2.1 day

The following assessments will be completed prior to study drug infusion (laboratory assessments can be performed up to 3 days prior to Day 1 of Cycles 2-6):
- Targeted physical examination at the Investigator's discretion  
- Vital signs - Weight
- ECOG performance status  
- Hematology - Serum chemistry - Coagulation
- Urinalysis (dip stick is sufficient) - Electrocardiogram (ECG) including PR interval, RR interval, QRS duration, and QTc interval
- Concomitant medications - Serum sample for anti-tarextumab antibody on all subjects **(Collect at Cycle 4, only)** - Blood sample for CTCs (collect at Cycles 4 and 5 only) - Plasma sample for tarextumab PK from all subjects enrolled **Collect at Cycle 3 only**
()  
- Tumor assessment with CT (with contrast), or MRI scan of chest, abdomen, and pelvis will be done every 6 weeks+5 days after Day 1 of Cycle 1 (Day 1 of Cycle 3 and every 6 weeks+5 days thereafter). The same method should be used throughout the study to follow the same anatomical location. Bone scan will be only performed at the investigator's discretion if clinically indicated
Administration of study drug, etoposide, and cisplatin or carboplatin: Hematology, BUN, bicarbonate, creatinine, glucose, chloride, potassium, and sodium lab results must be reviewed by the Investigator prior to study drug dosing. Study drug will be administered first, followed by etoposide infusion, and then cisplatin or carboplatin infusion.  
- Adverse event recording The following procedures will be completed after administration of study drug at Cycle 3 only for all subjects and for subjects enrolled in Phase 2 portion:
- Plasma samples for tarextumab PK at Cycle 3 only: 5 (±2) minutes after the end of tarextumab infusion, but prior to EP administration.
clinical protocol
11.2.2.2 day 2 of cycles

The following assessments will be completed prior to etoposide infusion:
- Vital signs  
- Weight
- Blood sample for biomarker (**Collect at Cycles 2 and 3 only**)  
- Concomitant medications - Adverse event recording
Administration of etoposide: Etoposide dosing will be given.  
,19(67,*$7,21$/1(:'58* ()
11.2.2.3 Day 3 of Cycles 2-6 The following assessments will be completed prior to etoposide infusion:
- Vital signs - Weight - Plasma sample for tarextumab PK **at Cycle 3 only**  
- Concomitant medications - Adverse event reporting
Administration of etoposide: Etoposide dosing will be given. 11.2.2.4 Day 8 of Cycles 2 and 3 Only
- Plasma sample for tarextumab PK from all subjects **(Collect at Cycle 3 only)**  
- Blood sample for biomarker - Hematology
- Hair follicle samples (6 hairs) **(Collect at Cycle 2 only.)**  
- Tumor core biopsy (**Optional and only if subject has signed the optional tumor core**
biopsy consent; collect at Cycle 2 only). The site can call the Sponsor's medical monitor to discuss an alternative timepoint if it is not feasible to collect the optional tumor biopsy on Day 8 (±2) of Cycle 2.  
- Concomitant medications - Adverse event recording
clinical protocol
11.2.3 after cycle 6 of

After the completion of 6 cycles of EP, subjects who do not have disease progression and have not had prophylactic cranial irradiation (PCI) or whole brain radiation (WBRT) prior to study entry and are good candidates for PCI per the Investigators should receive PCI within 8 weeks after the last dose of chemotherapy at a total dose of 25 Gy in 10 fractions. If subjects discontinue EP with treatment-related toxicities prior to completing 6 cycles and are good candidates for PCI per the Investigators, PCI can be initiated at the time that is determined appropriated per the Investigator. Subjects who do not receive PCI within 8 weeks after the last dose of chemotherapy can have PCI later during the study as determined by the Investigator. tarextumab administration should continue at every 21-day cycle between the completion of chemotherapy and the initiation of PCI. PCI should not be initiated within 2 weeks of study drug administration and study drug will be held during the PCI treatment period. Subjects will resume study drug alone 14 days after completion of PCI, until disease progression or unacceptable treatment-related toxicities or withdrawal of consent (Appendix A Study Schema). Subjects will discontinue study treatment if there is evidence of central nervous system (CNS) metastasis.
clinical protocol
11.2.4 cycle 7 and every

After the subject completes 6 cycles of EP, only tarextumab will be given on Day 1 of subsequent cycles. The first dose of tarextumab after the completion of prophylactic cranial irradiation (PCI) should be given > 14 days after the last dose of radiation. The following assessments will be completed prior to study drug infusion (laboratory assessments can be done up to 3 days prior to Day 1 of each cycle):
- Targeted physical examination at the Investigator's discretion  
- Vital signs - Weight - ECOG performance status - Hematology - Serum chemistry - Coagulation - Urinalysis (dip stick is sufficient)
- Concomitant medications  
- Serum sample for anti-tarextumab antibody on all subjects (Phase 1b Subjects: collect at Cycle 7, 10 and every 3rd cycle thereafter, only)
- Tumor assessment with CT (with contrast), or MRI scan of chest, abdomen, pelvis, will be done every 6 weeks +5 days after Day 1 of Cycle 1 (Day 1 of Cycle 7 and every 6 weeks +5 days thereafter). The same method should be used throughout the study to follow the same anatomical location. Bone scan will be only performed at the investigator's discretion if clinically indicated
clinical protocol
administration of study drug

Hematology, BUN, bicarbonate, creatinine, glucose, chloride, potassium, and sodium lab results must be reviewed by the Investigator prior to study drug dosing. Only study drug will be given on day 1 of each cycle beginning at Cycle 7.  
- Adverse event recording
clinical protocol
11.3 treatment visits - phase

If the subject meets all inclusion/exclusion criteria after the screening visit(s), the site will complete an enrollment form and submit it to OncoMed along with supporting source documents for approval. Once OncoMed or its representative has approved the enrollment form, OncoMed will use a randomization system to enroll a subject into Phase 2 portion of the study.  
The subject will start treatment of study drug on Day 1 in combination with etoposide 100 mg/m2 on Days 1, 2, and 3, and cisplatin 75 mg/m2 or carboplatin at AUC of 5 mg/mL•min on Day 1 of every 21-day cycle. On days when study drug is given together with etoposide and platinum therapy, study drug should be given prior to etoposide and platinum therapy administration. Hematology, BUN, bicarbonate, creatinine, glucose, chloride, potassium, and sodium lab results must be available and reviewed by the Investigator prior to each study drug dosing. For subjects who have study drug held or discontinued for tolerability reasons, EP chemotherapy should continue to the completion of 6 cycles.
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After the completion of 6 cycles of EP, subjects who do not have disease progression and have not had prophylactic cranial irradiation (PCI) or whole brain radiation (WBRT) prior to study entry and are good candidates for PCI per the Investigators should receive PCI within 8 weeks after the last dose of chemotherapy at a total dose of 25 Gy in 10 fractions. If subjects discontinue EP with treatment-related toxicities prior to completing 6 cycles and are good candidates for PCI per the Investigators, PCI can be initiated at the time that is determined appropriated per the Investigator. Subjects who do not receive PCI within 8 weeks after the last dose of chemotherapy can have PCI later during the study as determined by the Investigator. Study drug administration (tarextumab or Placebo) should continue at every 21-day (± 1 day) cycle between the completion of chemotherapy and the initiation of PCI. PCI should not be initiated within 2 weeks of study drug administration and study drug will be held during the PCI treatment period. Subjects will resume study drug alone (tarextumab or Placebo)  14 days after completion of PCI, until disease progression or unacceptable treatment-related toxicities or withdrawal of consent (Appendix A Study Schema). Subjects will discontinue study treatment if there is evidence of central nervous system (CNS) metastasis.
clinical protocol
11.3.1 cycle 1 11.3.1.1 cycle

The following assessments will be completed prior to study drug infusion. These assessments will be repeated if they were done more than 7 days prior to Cycle 1 Day 1.  
- Physical examination - ECOG performance status - Hematology - Chemistry - Coagulation
- Urinalysis (dip stick is sufficient) - Electrocardiogram (ECG) including PR interval, RR interval, QRS duration, and QTc interval
The following assessments will be done prior to study drug infusion on Cycle 1 Day 1:  
- Weight
- Serum sample for anti-tarextumab antibody on all subjects
- Blood sample for biomarker - Plasma sample for tarextumab PK - Blood sample for pharmaco-genomics **(Optional and only if subject has signed the**
separate pharmacogenomics Informed Consent Form)
- Concomitant medications - Vital Signs
Administration of study drug, etoposide, and cisplatin or carboplatin: Hematology, BUN, bicarbonate, creatinine, glucose, chloride, potassium, and sodium lab results must be reviewed by the Investigator prior to study drug dosing. Study drug will be administered first, followed by etoposide infusion, and then cisplatin or carboplatin infusion. The following procedures will be completed after administration of study drug:  
- Plasma samples for tarextumab PK: 5 (±2) minutes after the end of study drug infusion, but prior to EP administration.  
- Adverse event recording
clinical protocol
11.3.1.2 cycle 1 day 2

The following assessments will be completed prior to etoposide infusion:
- Vital signs  
- Weight - Concomitant medications - Adverse event recording Administration of etoposide:
Etoposide dosing will be given. 11.3.1.3 Cycle 1 Day 3 The following assessments will be completed prior to etoposide infusion:
- Vital signs - Weight - Plasma sample for tarextumab PK  
- Concomitant medications
- Adverse event reporting Administration of etoposide: Etoposide dosing will be given.  
- Adverse event recording 11.3.1.4 Cycle 1 Day 8
- Blood sample for biomarker - Plasma sample for tarextumab PK  
- Hematology - Concomitant medications
- Adverse event recording
clinical protocol
11.3.2 cycles 2-6 11.3.2.1 day

The following assessments will be completed prior to study drug infusion (laboratory assessments can be performed up to 3 days prior to Day 1 of Cycles 2-6):
- Targeted physical examination with areas of the body to be examined at the Investigator's discretion
- Vital signs - Weight - ECOG performance status - Hematology - Chemistry - Coagulation - Urinalysis (dip stick is sufficient)
Protocol 59R5-003, Amendment 6 Page 73 of 235 2016 CONFIDENTIAL  
- Electrocardiogram (ECG) including PR interval, RR interval, QRS duration, and QTc interval
- Concomitant medications
- Serum sample for anti-tarextumab antibody on all subjects **(Collect at Cycles 3 and 5 only)** - Blood sample for CTCs **(Collect at Cycles 4 and 5 only)** - Plasma sample for tarextumab PK (**Collect at Cycles 3 and 5 only)** - Tumor assessment with CT (with contrast), or MRI scan of chest, abdomen, and pelvis will be done every 6 weeks+5 days after Day 1 of Cycle 1 (Day 1 of Cycle 3 and every 6 weeks+5 days thereafter). The same method should be used throughout the study to follow the same anatomical location. Bone scan will be only performed at the investigator's discretion if clinically indicated
Administration of study drug, etoposide, and cisplatin or carboplatin: Hematology, BUN, bicarbonate, creatinine, glucose, chloride, potassium, and sodium lab results must be reviewed by the Investigator prior to study drug dosing. Study drug will be administered first, followed by etoposide infusion, and then cisplatin or carboplatin infusion.  
- Adverse event recording The following procedures will be completed after administration of study drug at Cycle 3 only:  
- Plasma samples for tarextumab PK: 5 (±2) minutes after the end of study drug infusion, but prior to EP administration.
11.3.2.2 Day 2 of Cycles 2-6 The following assessments will be completed prior to etoposide infusion:
- Vital signs  
- Weight - Blood sample for biomarker (**Collect at Cycles 2 and 3 only**) - Concomitant medications - Adverse event recording
Administration of etoposide: Etoposide dosing will be given.  
,19(67,*$7,21$/1(:'58* ()
11.3.2.3 Day 3 of Cycles 2-6 The following assessments will be completed prior to etoposide infusion:
- Vital signs - Weight - Plasma sample for tarextumab PK **at Cycles 3 and 5**  
- Concomitant medications - Adverse event reporting
Administration of etoposide: Etoposide dosing will be given. 11.3.2.4 Day 8 of Cycles 2 and 3 Only
- Plasma sample for tarextumab PK **(Collect at Cycle 3 only)**  
- Blood sample for biomarker - Hematology
- Tumor core biopsy (Optional and only if subject has signed the optional tumor core biopsy consent; collect at Cycle 2 only). The site can call the Sponsor's medical monitor to discuss an alternative timepoint if it is not feasible to collect the optional tumor biopsy on Day 8 (±2) of Cycle 2.  
- Concomitant medications  
- Adverse event recording
clinical protocol
11.3.3 after cycle 6 -

After the completion of 6 planned cycles of EP, subjects who do not have disease progression and have not had prophylactic cranial irradiation (PCI) or whole brain radiation (WBRT) prior to study entry and are good candidates for PCI per the Investigators should receive PCI within 8 weeks after the last dose of chemotherapy at a total dose of 25 Gy in 10 fractions. If subjects discontinue EP with treatment-related toxicities prior to completing 6 cycles and are good candidates for PCI per the Investigators, PCI can be initiated at the time that is determined appropriated per the Investigator. Subjects who do not receive PCI within 8 weeks after the last dose of chemotherapy can have PCI later during the study as determined by the Investigator. Study drug (tarextumab or Placebo) administration should continue at every 21-day cycle between the completion of chemotherapy and the initiation of PCI. PCI should not be initiated within 2 weeks of study drug administration and study drug will be held during the PCI treatment period. Subjects will resume study drug alone 14 days after completion of PCI, until disease progression or unacceptable treatment-related toxicities or withdrawal of consent (Appendix A). Subjects will discontinue study treatment if there is evidence of central nervous system (CNS) metastasis.
clinical protocol
11.3.4 subsequent cycles after cycle

After the subject completes the 6 planned cycles of EP, only study drug will be given on Day 1 of subsequent cycles. The first dose of study drug after the completion of prophylactic cranial irradiation (PCI) should be given > 14 days after the last dose of radiation. The following assessments will be completed prior to study drug infusion (laboratory assessments can be done up to 3 days prior to Day 1 of each cycle):
- Targeted physical examination at the Investigator's discretion  
- Vital signs - Weight - ECOG performance status - Hematology - Chemistry - Coagulation - Urinalysis (dip stick is sufficient) - Concomitant medications
- Serum sample for anti-tarextumab antibody on all subjects **(Collect at Cycle 7, 9 and every**
other cycle thereafter, only)
- Plasma sample for tarextumab PK **(collect at Cycle 7, 9 and every other cycle thereafter**
only)
- Tumor assessment with CT (with contrast), or MRI scan of chest, abdomen, pelvis, will be done every 6 weeks +5 days after Day 1 of Cycle 1 (Day 1 of Cycle 7 and every 6 weeks +5 days thereafter). The same method should be used throughout the study to follow the same anatomical location. Bone scan will be only performed at the investigator's discretion if clinically indicated
clinical protocol
administration of study drug

Hematology, BUN, bicarbonate, creatinine, glucose, chloride, potassium, and sodium lab results must be reviewed by the Investigator prior to study drug dosing. Only study drug will be given on day 1 of each cycle after Cycle 4.  
- Adverse event recording
clinical protocol
11.4 treatment termination

Subjects who have agreed to the optional tumor core biopsy in the Informed Consent and have pre and post-treatment optional tumor biopsy collected, will have tumor core biopsy at the time of treatment termination visit, if feasible. The following assessments must be performed approximately 4 weeks after the last dose of study drug, etoposide, or cisplatin or carboplatin, whichever is discontinued last, but prior to the initiation of a new anti-cancer therapy:  
- Physical examination - Vital signs - Weight - ECOG performance status - Hematology - Chemistry - Coagulation
- Urinalysis (dip stick is sufficient)
- Electrocardiogram (ECG) including PR interval, RR interval, QRS duration, and QTc interval
- Serum sample for anti-tarextumab antibody on all subjects  
- Blood sample for biomarker **(unless done within the last 14 days)** - Plasma sample for tarextumab PK from all subjects enrolled.  
- Tumor assessment with CT (with contract) or MRI scan of chest, abdomen, and pelvis for subjects who have not previously demonstrated disease progression within the previous 4 weeks.  
- Concomitant medications
- Adverse event recording
clinical protocol
11.5 follow up

Subjects who are discontinued from study treatment will be followed for survival and any subsequent anti-cancer therapies. Survival follow-up information and subsequent anti-cancer therapies, including systemic therapies, surgery (resection of metastatic disease), and radiation therapy will be collected during telephone calls, through subjects medical records, and/or clinic visits every 3 months until death, loss to follow-up, or study termination by the sponsor. The study staff may use a public information source (e.g., county records) to obtain information about survival status only. Additionally, subjects who discontinue study treatment for any reason other than disease progression will be followed with tumor assessment every 6 weeks/42 days (±5 days) and bone scan every 12 weeks (+/- 5 days) during the Follow-up Period until documented disease progression or initiation of new anti-cancer therapy, whichever is sooner.
clinical protocol
12.0 data quality assurance

Accurate, consistent, and reliable data will be ensured through the use of standard practices and procedures. Site initiation visits will be conducted separately at each clinical site. Clinical Research Associates (CRAs) will monitor the study and verify that the data are accurate. OncoMed Pharmaceuticals, Inc. has contracted with a contract research organization (CRO) to perform the data management of this trial. The data will be captured using a validated EDC system. The medical monitors, CRAs, and site personnel will be trained in the use of the EDC system. The clinical data and the site-specific laboratory data will be entered by site personal into the EDC system. System backups for data stored at OncoMed Pharmaceuticals, Inc. and at all CROs, and records retention for the study data will be consistent with the standard procedures for these organizations.
clinical protocol
13.0 statistical plan 13.1 power

The Phase 1b portion of the trial is a 3+3 dose escalation design. Table 6 shows the probability of declaring a dose as exceeding the MTD for a variety of underlying toxicity rates. For example there is an 83 percent probability to declare a dose with an incidence of dose limiting toxicity of 50 percent as exceeding the MTD. This compares with a probability of 29 percent for a dose with an incidence of dose limiting toxicity of 20 percent.  
| Probability of 1 subject  with Toxicity in first  group of 3 then at least  1 subject with toxicity in  second group of 3   |                                          |       |       |
|-----------------------------------------------------------------------------------------------------------------------------|------------------------------------------|-------|-------|
| Probability of more than  1 out of 3 subjects with  Toxicity in first group of  three                                       | Probability of Stopping  Dose Escalation |       |       |
| Incidence of Toxicity  0.05                                                                                                 | 0.007                                    | 0.019 | 0.027 |
| 0.10                                                                                                                        | 0.028                                    | 0.066 | 0.094 |
| 0.15                                                                                                                        | 0.061                                    | 0.125 | 0.186 |
| 0.20                                                                                                                        | 0.104                                    | 0.187 | 0.291 |
| 0.25                                                                                                                        | 0.156                                    | 0.244 | 0.400 |
| 0.30                                                                                                                        | 0.216                                    | 0.290 | 0.506 |
| 0.35                                                                                                                        | 0.282                                    | 0.322 | 0.604 |
| 0.40                                                                                                                        | 0.352                                    | 0.339 | 0.691 |
| 0.45                                                                                                                        | 0.425                                    | 0.340 | 0.766 |
| 0.50                                                                                                                        | 0.500                                    | 0.328 | 0.828 |
clinical protocol
13.1.2 sample size justification -

At the final analysis we will evaluate the effect of tarextumab on PFS in subjects in the intention to treat population. The final analysis will take place when 91 progression events have been observed or 10 months after the completion of enrollment whichever occurs first.  
Lets denote the treatment effect *in terms of the log of the hazard ratio* by θ1 :
We can write the null hypotheses *for this test in the ITT group of subjects* as.  
1 1 H : 0 θ =
and the alternative as 1 : 0 HA θ <
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The power and type 1 error for the log rank test of this hypothesis is presented in Table 7. .
clinical protocol
table 7 pfs power for

| Analysis 1                                                                                                              | Analysis 2        | Final Analysis   |        |        |
|-------------------------------------------------------------------------------------------------------------------------|-------------------|------------------|--------|--------|
| Total Number of Events                                                                                                  | 61                | 76               | 91     |        |
| Z-Statistic (reject the null) (1)                                                                                       | 3.168             | 2.301            | 1.036  |        |
|                                                                                                                         | p-value (1 sided) | 0.00077          | 0.011  | 0.15   |
| Z statistic (reject the Alt) (2)                                                                                        | -1.773            | -1.486           | -1.079 |        |
|                                                                                                                         | p-value (1 sided) | 0.038            | 0.069  | 0.14   |
| Cumulative Type 1 Error (1-sided)                                                                                       | 8e-04             | 0.0107           | 0.1501 |        |
| Cumulative Power   HR=0.75                                                                                              | 0.0204            | 0.1479           | 0.6318 |        |
|                                                                                                                         | HR=0.67           | 0.0543           | 0.2897 | 0.809  |
|                                                                                                                         | HR=0.65           | 0.0687           | 0.3365 | 0.846  |
|                                                                                                                         | HR=0.60           | 0.1204           | 0.4709 | 0.9194 |
|                                                                                                                         | HR=0.50           | 0.3223           | 0.7647 | 0.9884 |
| Cumulative Prob of Stopping for Harm   Alt                                                                              | 4e-04             | 8e-04            | 0.0018 |        |
|                                                                                                                         | Null              | 0.0381           | 0.0762 | 0.1501 |
|                                                                                                                         | HR=1/0.75=1.33    | 0.258            | 0.4246 | 0.6275 |
|                                                                                                                         | HR=1/0.67=1.49    | 0.4172           | 0.617  | 0.8052 |
|                                                                                                                         | HR=1/0.50=2.0     | 0.8248           | 0.9412 | 0.9877 |
| 1) The boundary for rejecting the null hypothesis for efficacy is obtained from the gamma(-16) alpha spending  function |                   |                  |        |        |  
With 91 events at the final analysis, there is 80 percent power with 0.15 type 1 error to detect a hazard ratio of 0.67. There is a 7.6 percent chance of stopping early for Harm under the null, 42.5 percent chance of stopping early for Harm if the hazard ratio is 1/.75 = 1.33, 61.7 percent chance of stopping early for harm if the hazard ratio is 1/.67 = 1.49, and a 94.1 percent chance of stopping early for harm if the hr = 1/.5 = 2.0. Analyses 1 and 2 will take place at the last two quarterly safety review meeting of the DSMB. The estimated number of events at those times are presented in Table 7. If the number of events differs from what is presented in the table, the efficacy and safety boundaries will be recalculated using the spending functions which are footnoted in Table 7. Survival is a secondary endpoint in this study. An analysis of overall survival will take place at the time of each analysis for PFS as well as at the time that the final analysis of PFS takes place. Further the final analysis of survival will take place when there are 98 events or *6 months after* the final analysis for PFS whichever occurs first. Figure 10 and Table 10 present enrollment, PFS events and Deaths over time. The calculations in Figure 9 and Table 10 take into account Protocol 59R5-003, Amendment 6 Page 80 of 235 2016 CONFIDENTIAL
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non constant hazard as described in Table 8 and 9. The basis for the estimates of non constant hazard are presented in Figure 6- 9 which are Kaplan -Meier (KM) curves for PFS and Survival in (Ref 10, and Ref 14). Regarding enrollment it *was initially* assumed that there is a ramp up time of 5 months with a starting enrollment of 4 subjects per months and that the maximum enrollment rate is 6 subjects per month. *The enrollment in Table 10 and Figure 10 represents* the observed enrollment up to January 2016 and the remaining enrollment is assumed to be 15 subjects per month. The censoring rate *was initially* assumed to be 40 percent of the rate at which events accrue in the control arm and 60 percent of the rate at which events accrue in the tarextumab arm. *When* 79 PFS event accrued in the study*, we observed* 39 censors for a censoring rate of 39/(39*+79)=*33 percent. This information was used to recalibrate the total number of events at the final analysis, the type 1 error and the power.
clinical protocol
table 8 hazards for piece-wise

| Period                                                           | 0-5 months     | 5-7 months      | 7-8 months   | >8 months  0.50   |
|------------------------------------------------------------------|----------------|-----------------|--------------|-------------------|
| (0.125 to 0.0625)  from 8 to 18  months (Noda)                   |                |                 |              |                   |
| Percent Change in  Proportion without  an event  (Change in PFS) | 0.50           | 0.50            | 0.50         |                   |
| (1.00 to 0.50)                                                   | (0.50 to 0.25) | (0.25 to 0.125) | 0.50         |                   |
| (0.125 to 0.0625)  from 8 to 11  months (Hanna)                  |                |                 |              |                   |
| Hazard Control                                                   | 0.1386         | 0.3466          | 0.6931       | 0.0693, 0.2310    |
| Hazard Treatment                                                 | 0.0901         | 0.2253          | 0.4505       | 0.0451, 0.1502    |
| Hazard Ratio                                                     | 0.65           | 0.65            | 0.65         | 0.65              |  
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| Period                                          | 0-9 months     | 9-15 months    | 15-18 months   | >18 months  0.467   |
|-------------------------------------------------|----------------|----------------|----------------|---------------------|
| (.15 to 0.080 from 18 to  24 months Hanna)      |                |                |                |                     |
| Hazard Control                                  | 0.07702        | 0.1155         | 0.1703         | 0.127               |
| Percent Change in  Proportion without  an event | 0.50           | 0.50           | 0.60           |                     |
| (1.00 to 0.50)                                  | (0.50 to 0.25) | (0.25 to 0.10) |                |                     |
| Hazard Treatment                                | 0.05006        | 0.07509        | 0.1107         | 0.0825              |
| Hazard Ratio                                    | 0.65           | 0.65           | 0.65           | 0.65                |  
Table 9: Hazards for Piece-wise Exponential M**odel of Survival** Figure 6: PFS in Subjects Treated with Etoposide plus Cisplatin. from  
  
Noda et al INVESTIGATIONAL NEW DRUG
5.3.4.2 Protocol No. 59R5-003 - Amendment 6 - 22 April 2016 OncoMed Pharmaceuticals, Inc.  
Tarextumab (OMP-59R5)
Figure 7:
PFS in Subjects Treated with Etoposide plus Cisplatin - Hanna  
  
Figure 8:
Survival in Subjects Treated with Etoposide plus Cisplatin(from Noda et al.)  
  
INVESTIGATIONAL NEW DRUG
5.3.4.2 Protocol No. 59R5-003 - Amendment 6 - 22 April 2016 OncoMed Pharmaceuticals, Inc.  
Tarextumab (OMP-59R5)
Figure 9:
Survival in Subjects Treated with Etoposide plus Cisplatin (from Hanna et al.)  
  
Figure 10:
Enrollment, Progressions and Deaths over Time - Control Hazard of Progression of 0.1386 Beyond 9 months  
  
()  
Enrollment, Progressions and Deaths over Time - Control Hazard of Progression of 0.1386 beyond  
  
Table 10:  
  
  
  
| 22 77 85 89 91 105 119 133 134 134 134 134 134 134 134 134 134 134 134 134                     | 5 31 38 43 49 55 62 69 75 80 85 90 94 96 97 98 99 99 100 100   | Total PFS Events2 6 35 42 48 54 61 68 76 82 87 92 98 101 103 104 104 105 105 105 106   | Total Deaths 3 19 23 27 32 37 42 49 55 61 66 72 77 81 86 91 95 99 102 105   | 4 22 27 32 37 42 49 56 63 69 75 81 86 91 96 100 104 108 111 114   |
|------------------------------------------------------------------------------------------------|----------------------------------------------------------------|----------------------------------------------------------------------------------------|-----------------------------------------------------------------------------|-------------------------------------------------------------------|
| Study Time (months) 6 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30  Cum Enrollment | 1 5 6 7 8 9 10 11 12 13 14 15 15 16 16 16 16 16 16 17          | 1 4 5 6 7 8 9 9 10 11 12 12 13 13 13 13 13 13 13 13                                    |                                                                             |                                                                   |  
,19(67,*$7,21$/1(:'58*Total PFS Events 2 and Total Deaths 2 refer to the number of progressions and deaths observed when tarextumab does not prolong progression nor death.  
  
22 April 201 6 CONFIDENTIAL
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We see from *Table 10* that approximately 70 percent of the 98 deaths required for the final analysis of survival will be observed at the time of the final analysis for PFS. Table 11 presents the power to detect a survival benefit for several hazard ratios assuming that type 1 error is controlled at the 0.15 level and *additional analyses* take place at *approximately 50, 67, 83* percent of full information. *These additional analyses will take place at the quarterly DSMB* review meetings. If the actual number of events at the review meetings differs from what is presented in the table, the efficacy and safety boundaries will be recalculated using the spending functions footnoted in Table 11.  
| Analysis 1                                                                                                             | Analysis 2        | Analysis 3   | Final Analysis   |        |        |
|------------------------------------------------------------------------------------------------------------------------|-------------------|--------------|------------------|--------|--------|
| Total Number of Events                                                                                                 | 49                | 66           | 81               | 98     |        |
| Z-Statistic (reject the null)1                                                                                         | 3.889             | 3.174        | 2.333            | 1.036  |        |
|                                                                                                                        | p-value (1-sided) | 0.000050     | 0.00075          | 0.0098 | 0.15   |
| Z statistic (reject the Alt) 2                                                                                         | -2.1              | -1.848       | -1.511           | -1.082 |        |
|                                                                                                                        | p-value (1-sided) | 0.018        | 0.032            | 0.0658 | 0.139  |
| Cumulative Type 1 Error (1-sided)                                                                                      | 1e-04             | 8e-04        | 0.0099           | 0.1501 |        |
| Cumulative Power   HR=0.75                                                                                             | 0.002             | 0.0226       | 0.1499           | 0.6511 |        |
|                                                                                                                        | HR=0.682          | 0.0054       | 0.053            | 0.2711 | 0.8047 |
|                                                                                                                        | HR=0.60           | 0.0178       | 0.1365           | 0.4869 | 0.9324 |
|                                                                                                                        | HR=0.65           | 0.0086       | 0.0777           | 0.3471 | 0.8637 |
|                                                                                                                        | HR=0.50           | 0.0717       | 0.361            | 0.7846 | 0.9918 |
| Cumulative Probability of Stopping                                                                                     |                   |              |                  |        |        |
| for Harm   Alt                                                                                                         | 3e-04             | 5e-04        | 9e-04            | 0.0019 |        |
|                                                                                                                        | Null              | 0.0179       | 0.0381           | 0.0744 | 0.1501 |
|                                                                                                                        | HR=1/0.75 = 1.33  | 0.1372       | 0.266            | 0.4332 | 0.647  |
|                                                                                                                        | HR=1/0.682=1.47   | 0.2235       | 0.4037           | 0.6007 | 0.80   |
|                                                                                                                        | HR=1/0.50 =2.00   | 0.6278       | 0.8426           | 0.9496 | 0.9911 |
| 1 The boundary for rejecting the null hypothesis for efficacy is obtained from the gamma(-16) alpha spending  function |                   |              |                  |        |        |  
With 98 deaths at the final analysis there is 80 percent power with 0.15 type 1 error to detect a hazard ratio of 0.682. There is a 7.4 percent chance of stopping early for Harm under the null, 43.3 percent chance of stopping early for Harm if the hazard ratio is 1/.75 = 1.33, 60.1 percent chance of stopping early for harm if the hazard ratio is 1/.682 = 1.47, and a 95.0 percent chance of stopping early for harm if the hr = 1/.5 = 2.0.  
Protocol 59R5-003, Amendment 6 Page 86 of 235 2016 CONFIDENTIAL
clinical protocol
13.1.3 randomization and blinding

For the purpose of randomizing subjects to treatment, each subject's platinum based therapy as well as the the prior use of whole brain radiation or PCI will be collected at screening. A dynamic randomization system will assign subjects to treatment in a way that balances the assignments to tarextumab + Chemo versus Chemo + placebo alone among all subjects in the trial, among all subjects receiving the same platinum based therapy (Carboplatin or Cisplatin), and among subjects who received as well as those who did not receive prior whole brain radiation or PCI. Investigators, site personnel, subjects, and the sponsor will remain blinded to treatment assignment for the duration of the study until the final analysis of overall survival is completed.
clinical protocol
13.1.4 procedures for unblinding

All requests for urgent safety unblinding require the approval of the Medical Monitor and may be made by calling either the Medical Monitor directly during business hours or the 24-hour randomization support staff after business hours (contact information will be provided in the Study Reference Manual). The randomization support staff will forward the request to the Medical Monitor. Upon OncoMed's approval, the randomization system will provide the site with the study treatment assignment. No treatment cross-over will be permitted in the study.
clinical protocol
13.2 phase 1b

All reported adverse events will be mapped to standard coding terms using the Medical Dictionary for Regulatory Activities (MedDRA), grouped by system organ class and preferred terms and tabulated by dose groups. The incidence of adverse events at each dose will be tabulated by grade and relationship to study drug. Vital signs and Laboratory markers will also be summarized by dose of study drug using mean changes from baseline. Shift tables for lab markers will be provided for each dose of study drug. Tumor response will be presented in a subject listing sorted by dose group. Information included in the listing will be Best tumor response, time to progression or death, best percent decrease in sum of longest diameter (SLD) from baseline, and duration of response. Tumor response in the expansion cohort will also be summarized. Time to Progression or Death and duration of response will be summarized with a Kaplan Meier Curve and related statistics. Best tumor response will be summarized with simple descriptive statistics. The largest percent decrease in SLD will be summarized with a waterfall plot and simple descriptive statistics.
clinical protocol
13.3 phase 2 13.3.1 subject

The Intent-to-Treat (ITT) Population is comprised of all randomized subjects. All baseline characteristics, demographic and efficacy data will be analyzed using the ITT Population. The Per Protocol Population (PP) is comprised of all randomized subjects who received at least one dose of study drug and had at least one post baseline tumor assessment. All efficacy data will be analyzed using the PP population as well as the ITT Population. The Safety Population is comprised of all subjects who receive at least one partial dose of tarextumab or Placebo and who have at least one post-dosing safety evaluation (labs, vital signs or adverse events). All safety endpoints will be summarized using the Safety Population.  
The Pharmacokinetic Population is comprised of all subjects who had at least one follow-up tarextumab blood sample obtained. The Immunogenicity Population is comprised of all subjects who had a baseline and at least one follow-up anti-*tarextumab* sample obtained.
clinical protocol
13.3.2 analysis set

The Analysis set for the Phase 2 portion of the study will include all subjects who were randomized in the Phase 2 portion of the trial to receive either tarextumab or control. The Analysis set will not include data from subjects who were enrolled in the Phase 1b portion of the trial. The data cut for the formal final analysis of the study will take place at the point where 91 progression events have occurred or 10 months after the completion of enrollment, whichever occurs first. Note that the analysis time may be extended beyond 10 months for reasons concerning study conduct (e.g. subjects who are randomized and not treated). This will ensure that the study will have 81 percent power to detect a hazard ratio of 0.67 (improvement in median PFS from 4.8 months to 7.2 months) with an associated total one sided type 1 error of 0.15. The data cut for the final analysis of survival will be 6 months after the data cut for the formal final analysis of the study or when 98 deaths have been observed, whichever occurs first. Once again, the time for the final analysis may be extended beyond 6 months for reasons of study conduct.
clinical protocol
13.4 endpoints 13.4.1 efficacy endpoints

Efficacy endpoints will include Investigator-assessed progression-free survival, continuous variable assessment of tumor length, best response, response rate defined as rate of confirmed complete response (CR) + rate of confirmed partial response (PR), duration of response, sites of progression, Land mark survival at 6, 12, 18 and 24 months and overall survival. Efficacy endpoints will be analyzed using the ITT Population and are described in more detail in the Statistical Methods (Section 13.6).
clinical protocol
13.4.2 safety endpoints

Safety endpoints will include AEs, SAEs, clinical laboratory assessments, and anti-tarextumab antibody testing. Safety endpoints will be analyzed using the Safety Population for both treatment groups. The purpose of these analyses will be to provide a thorough evaluation of potential safety issues.
clinical protocol
adverse events

All reported adverse events will be mapped to standard coding terms using the Medical Dictionary for Regulatory Activities (MedDRA), grouped by system organ class and preferred terms and tabulated by treatment groups. The incidence of adverse events in each treatment group will be tabulated by NCI-CTCAE v 4.0.2 grade and relationship to study drug. Adverse events that led to withdrawal and adverse events that were considered serious will be tabulated separately.
clinical protocol
clinical laboratory assessments and vital

Clinical laboratory data (hematology, chemistry, and urinalysis) and vital signs will be summarized by treatment group using descriptive statistics of the reported values and changes from baseline at the point of each subject's minimum value/change, maximum value /change and the last value/change. In addition, the frequency counts and percentages of subjects shifting from "low," or "normal," at baseline to "high" post baseline or "high" or "normal" at baseline to "low" post baseline for each treatment group will also be provided at the same time points. The high and low post baseline categories will be further classified by NCI-CTCAE grading if available. All laboratory and vital sign data will be presented in listings and special attention will be given to any unexpected abnormal results. ECOG ECOG performance status at baseline and follow-up will be listed by subject for each treatment group. Changes in ECOG performance status scores from baseline will be summarized by treatment group at selected scheduled timepoints using shift tables.
clinical protocol
13.4.3 immunogenicity endpoints

Immunogenicity endpoints will be analyzed using the Immunogenicity Population. The incidence of anti-tarextumab antibody development in each treatment group will be compared with simple proportions. For subjects with a positive result for anti-tarextumab antibody, the incidence of neutralizing capability development will further be summarized by standard quantitative methods. In addition, the impact on safety and efficacy of detectable anti-tarextumab antibodies and neutralizing anti-tarextumab antibodies will be assessed by summarizing PFS and Response rate in the subgroups of subjects with and without these anti tarextumab antibodies. These analyses may not be carried out if the number of subjects with anti59R5 antibodies does not permit a reasonable estimate of PFS and Response rate.
clinical protocol
13.4.4 pharmacokinetic endpoints

For subjects enrolled in the Phase 1b portion of the trial, AUC, clearance, volume of distribution and apparent half life) of tarextumab will be summarized by dose group with descriptive statistics including the mean, variance, median and range. Pharmacokinetic data obtained from the Phase 1b and Phase 2 portions of the study will be pooled with data from the Phase 1a study (Study 59R5-001) to conduct population PK analysis. Population mean and inter-individual variability of the PK parameters will be reported. Individual PK parameter and exposure will be reported.
clinical protocol
13.4.5 exploratory endpoints

Changes from baseline in exploratory pharmacodynamic biomarkers, including Notch pathway related genes and proteins and circulating tumor cells following tarextumab treatment will be summarized with simple descriptive statistics. Tests to compare the changes in these variables between the 59R5 arm and the control arm may be undertaken as well on an informal descriptive basis. Surrogacy of changes in these exploratory biomarkers will be evaluated in models for time to progression and response that include these exploratory variables and the randomized treatment assignment. These models may also account for the level of Notch 3 expression.
clinical protocol
13.5 statistical methods

Other than for the primary efficacy endpoint of PFS, and overall survival, no adjustment will be made for multiplicity. The methods of analyses listed below are described for the intention to treat group of subjects.
clinical protocol
13.5.1 progression-free survival

The primary endpoint PFS, based on the Investigator-assessments of tumor response, is defined as the number of days from randomization until death or disease progression as defined by RECIST criteria for the ITT Population. The Kaplan-Meier method will be used to estimate the proportion of subjects without progression or death overtime 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-value for treatment effect will be generated using a stratified Log-Rank test. The stratification factors will be platinum choice (cisplatin versus carboplatin) and the prior use of whole brain radiation or PCI. . 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 anti-cancer therapy will be censored at the time they start this treatment. Surgical resection of tumor, palliative radiation (prophylactic cranial irradiation, according to standard of care, is permitted for subjects who are without progression following 6 cycles of EP treatment, subjects may have prophylactic cranial irradiation (PCI) or whole brain radiation (WBRT) prior to study entry) and/or a new systemic anti-cancer therapy will be considered non protocol therapy. Initiation of a new intravenous bisphosphonate or denosumab more than 30 days after the first administration of study drug will be also considered non protocol therapy. Formal testing for determining whether tarextumab has an impact of PFS will be carried out as described in *Table 7*. 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 1. PFS will also be summarized for the subset of subjects who received cisplatin and separately for the subset of subjects who received carboplatin.
clinical protocol
continuous variable assessment of tumor

The tumor length will be calculated as the sum of the longest diameters for the target lesions (as defined by RECIST 1.1 criteria). 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, 6 weeks post-baseline, and 12 weeks post-baseline. These summary statistics will also be presented for differences from baseline at 6 and 12 weeks post-baseline for each arm of the study. 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 displayed. An ANCOVA model will be used to test the hypothesis that there is no Protocol 59R5-003, Amendment 6 Page 91 of 235 2016 CONFIDENTIAL
difference between treatment arms with regard to changes from baseline tumor length at scheduled tumor assessments. Choice of platinum therapy (cisplatin versus carboplatin) and prior use of WBRT or PCI 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 t 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 adverse event, the worst possible rank will be assigned. The rate of change in tumor volume at progression (SLD at progression - SLD at nadir)/SLD at nadir will be compared between the two arms of the study. The rate of change in tumor burden has been shown to be predictive of survival (Ref 15, and Ref 16). In addition the rate of change in tumor volume from baseline to the first tumor assessment (SLD first scheduled post baseline tumor assessment - SLD baseline)/(SLD baseline) will be compared between the two arms of the study. The comparison will be made to test the difference in the growth rate in the tarextumab arm versus control arm.
clinical protocol
13.5.2 response rate (best overall

The best overall response is defined as the best Investigator-assessed response recorded from the start of the treatment until disease progression in the following order of importance:  
- Complete Response (CR) - Partial Response (PR) - Stable Disease (SD) - Progressive Disease (PD) - Not Evaluable (NE)
The number and proportion of subjects achieving each of these categories of response will be summarized for each dose group. The best overall response rate is the number of subjects whose best response is either a CR or PR divided by the number of subjects randomized to the respective arms. The confirmed response rate is the number of subjects per treatment arm who have either a confirmed CR or confirmed PR (according to RECIST criteria) divided by the number of subjects randomized to the respective arms. These proportions and their 95% confidence intervals will be displayed. The p-value for equality between treatment arms will be calculated for the two groups using a logistic regression model with treatment, type of platinum based therapy, and prior use of WBRT or PCI as factors in the model. Subjects without any tumor assessments will be counted as a non responder.
clinical protocol
13.5.3 duration of response

The Investigator-assessed duration of response is 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. 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. Subjects who have not experienced death or progression by their last contact will be censored at the time of their last radiographic response assessment. If the number of responses is not sufficient to produce interpretable KM curves, the analysis of duration of response may not be undertaken.
clinical protocol
sites of progression

The sites of progression will be classified according to organ type and compared between the two arms using a chi-square 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.
clinical protocol
13.5.4 overall survival

A comparison of the overall survival for the two groups will be performed. Overall survival is defined as the number of days from randomization until death occurs. 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 intervals for median survival times will also be calculated. A p-value for treatment effect will also be generated using a stratified Cox proportional hazards model. The stratification factors will be type of platinum based therapy and the prior use of whole brain radiation or PCI. Subjects who have not experienced death by their last contact date will be censored at that time and the number and percentage of these subjects will be displayed. Subjects will not be censored for OS if they start non-protocol therapy. If there is a disparity in discontinuation rates between treatment arms, a sensitivity analysis will be performed to assess the impact. Survival will also be summarized for the subset of subjects who received cisplatin and separately for the subset of subjects who received carboplatin.
clinical protocol
13.5.5 landmark survival

The Kaplan Meier estimates of survival at 6, 12, 18 and 24 months will be compared between the two arms using a simple Z test.
clinical protocol
13.5.6 correlation of biomarkers with

The impact of the biomarkers Notch3, Hes1, Hey2, Hey1 and Hes6 on the treatment effect as measured by PFS and OS will be evaluated with a Cox Proportional Hazards regression model with treatment, biomarker and treatment by biomarker interaction included in the model as independent variables. The impact of these biomarkers will also be assessed on the treatment effect for 12 month OS and ORR using a logistic regression model with treatment, biomarker and treatment by biomarker interaction included in the model.
clinical protocol
13.6 demographics and baseline characteristics

Demographic and baseline characteristics will be analyzed using the Intent-to-Treat Population for both treatment arms. Quantitative and/or categorical summaries will be presented for demographics and other baseline characteristics. For continuous variables, data will be summarized by sample size, mean, standard deviation, median, minimum, and maximum. Categorical data will be summarized as frequency counts and percentages.
clinical protocol
13.7 treatment exposure

Treatment exposure will be summarized as duration on treatment and extent of exposure to Cisplatin, Carboplatin, Etoposide, tarextumab, and Placebo by treatment arm. Duration on treatment will be summarized quantitatively by number of doses and duration in days using mean, standard deviation, median, minimum, and maximum. Measures of extent of exposure include the cumulative dose per subject, dose intensity and compliance. Dose intensity is defined as the total dose the subject actually received divided by the total dose the subject would have received had there been no dose delays and no dose reductions. Compliance will be summarized as the number of subjects who had dose(s) withheld or delayed. A table summarizing the number of subjects with 0%, 20%, 40%, 60%, 80%, and 100% compliance will also be presented. The reasons for dose(s) withheld or delayed will also be summarized.
clinical protocol
13.8 termination criteria

Enrollment will terminate when approximately 135 subjects have been randomized. All ongoing subjects will continue to be dosed until disease progression, unacceptable toxicity, subject withdrawal, or the Investigator withdraws subjects from the study.
clinical protocol
13.9 deviation reporting

The following protocol deviations will be recorded and summarized by treatment arm in the final report:  
1. enrollment violations 2. dosing violations 3. concomitant therapy violations 4. continuation of therapy when treatment should have been discontinued
clinical protocol
13.10 data safety monitory board

A Data Safety Monitoring Board (DSMB) will review data on an ongoing basis in Phase 2 portion of the study to ensure subject safety. Specifically, they will review partially blinded demographic, dosing and safety data at the following timepoints: 1) after 10 subjects have been randomized and all subjects have received at least 2 doses of tarextumab or Placebo, 2) after 25 subjects have been randomized and all subjects have received 2 doses of tarextumab or Placebo, and 3) quarterly thereafter. The DSMB will consist of at least two Oncologists and a statistician who are not otherwise participating in the conduct of the trial. A separate unblinded and independent statistician designated by OncoMed will prepare summary tables and listings summarizing results for all subjects.. The rules/details of presentations to the DSMB will be summarized in the DSMB Charter.
clinical protocol
13.11 analysis of pfs and

Two analyses for PFS are planned beyond the DSMB Safety Reviews detailed in Section 13.10. These analyses will take place at the quarterly meetings of the DSMB and be initiated in May 2016. As noted above in Table 7 and Table 11, a gamma(-12)spending function will be used to control the type 1 error for the assessment of efficacy and a gamma(-4) spending function will be used to control the type 1 error for the assessment of harm arising from the multiple analysis over time of PFS and overall survival. The final analysis for pfs will occur when 91 progression events have occurred while the final analysis for OS will occur when 98 deaths have been observed
clinical protocol
13.12 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.
clinical protocol
14.0 ethical considerations

This study will be conducted according to international standards of Good Clinical Practice (ICH guidance E6), all federal, state, and local regulations as well as with the requirements of the appropriate Institutional Review Board or Ethics Committee and any other institutional requirements.
clinical protocol
15.0 investigator requirements 15.1 informed

A sample informed consent form will be provided. OncoMed 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.
clinical protocol
15.2 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 all regulatory requirements and the 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 adverse events. Investigators are required to follow their respective IRB or IEC requirements for the reporting of Serious Adverse Events and written safety reports to the IRB or IEC. Investigators must immediately forward to their IRBs or IECs any updates provided by OncoMed (e.g., Investigator Brochure, safety amendment, etc.)
clinical protocol
15.3 study monitoring

Site visits will be conducted on a regular basis by an authorized OncoMed representative (e.g., Clinical Research Associate [CRA]) to inspect study data, subjects' medical records, and remote data capture (RDC) fields in accordance with current 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 study drug 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.
clinical protocol
15.4 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.
clinical protocol
15.5 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.
clinical protocol
15.6 investigational medicinal product accountability

The tarextumab and Placebo required for completion of this study will be provided by OncoMed or its agent. The recipient will acknowledge receipt of this IMP by completing the Drug Request/ Acknowledgment of Receipt Form and faxing it to OncoMed or its representative in Phase 1b portion of the study and by completing the corresponding information in Interactive Web-based randomization system (IWRS) *in Phase 2 portion of the study.* 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 all used and/or partially used vials. If the site does not have the capacity to destroy IMP, the used/partially used vials should be returned to the drug distribution center for destruction along with a completed Drug Return Form. Sites will destroy all unopened, unused, and expired vials per the site's institutional guidelines after approval by OncoMed or designee. Site may also return the remaining IMP to the drug distribution center along with a completed Drug Return Form. 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.
clinical protocol
15.7 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.  
,19(67,*$7,21$/1(:'58* ()
clinical protocol
15.8 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.
clinical protocol
16.0 references

1. D'Angelo SP, Pietanza MC. The molecular pathogenesis of small cell lung cancer.  
Cancer Biology & Therapy 2010;10 (1):1-10.  
2. Puglisi M, Dolly S, Faria A, Myerson JS, Popat S, O'Brien MER. Treatment options for small cell lung cancer - do we have more choice? British Journal of Cancer 2010;102:629-638.  
3. Clarke MF, Fuller M. Stem Cells and Cancer: Two Faces of Eve. Cell 2006;124:11111115.  
4. Wicha MS, Liu S, Dontu G. Cancer Stem Cells: An Old Idea - A Paradigm Shift. Cancer Research 2006;66:1883-1890.  
5. Bao S, Wu Q, McLendon RE, Hao Y, Shi Q, Hjelmeland AB, et al. Glioma stem cells promote radioresistance by preferential activation of the DNA damage response. Nature 2006; 444:756-760.  
6. Dylla SJ, Beviglia L, Park IK, Chartier C, Raval J, Ngan L, et al. Colorectal Cancer Stem Cells Are Enriched in Xenogeneic Tumors Following Chemotherapy. PloS ONE 2008;3(6):1-13.  
7. Rosen JM, Jordan CT. The Increasing Complexity of the Cancer Stem Cell Paradigm.  
Science 2009;324:1670-1673.  
8. Takebe N, Harris PJ, Warren RQ, Ivy SP. Targeting cancer stem cells by inhibiting Wnt, Notch, and Hedgehog pathways. Nature Clinical Oncology 2011; 8:97-106.  
9. Daniel VC, Marchionni L, Hierman JS, Rhodes JT, Devereux WL, Rudin CM, et al.A
Primary Xenograft Model of Small_Cell Lung Cancer Reveals Irreversible Changes in Gene Expression Imposed by Culture In vitro. Cancer Research 2009;69(8):3364-3373.  
10. Noda K, Nishiwaki Y, Kawahara M, Negoro S, Sugiura T, et al. Irinotecan plus cisplatin compared with etoposide plus cisplatin for extensive small-cell lung cancer. New England Journal of Medicine 2002;346(2): 85-91.  
11. Foster N, Mandrekar S, Schild S, Nelson G, Rowland K, et al. Prognostic Factors Differ by Tumor Stage for Small Cell Lung Cancer. Cancer 2009;115:2721-31.  
12. Oken, M.M., Creech, R.H., Tormey, D.C., Horton, J., Davis, T.E., McFadden, E.T.,
Carbone, P.P.: Toxicity And Response Criteria Of The Eastern Cooperative Oncology Group. Am J Clin Oncol 1982;5:649-655.
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19(67721/1('58

()
13. Eisenhauer EA, Therasse P, Bogaerts J, Schwartz LH, Sargent D, Ford R, et al. New response evaluation criteria in solid tumors: revised RECIST guideline (version 1.1). Eur J Cancer 2009:45:228–47.  
14. Hanna N, Bunn PA Jr., Langer C, Einhorn L, Guthrie T Jr., Beck T, et al. Randomized Phase III Trial Comparing Irinotecan/Cisplatin With Etoposide/Cisplatin in Patients With Previously Untreated Extensive-Stage Disease Small-Cell Lung Cancer; J Clin Oncol 2006;24(13):2038-43.  
15. Claret L, Girard P, Hoff PM, Van Cutsem E, Zuideveld KP, Jorga K, et al. Model-Based Prediction of Phase III Overall Survival in Colorectal Cancer on the Basis of Phase II Tumor Dynamics. J. Clin. Oncol. 27:4103-8 2009.  
16. Claret L, Gupta M, Han K, Joshi A, Sarapa N, He J, et al. Evaluation of Tumor-Size Response Metrics to Predict Overall Survival in Western and Chinese Patients With FirstLine Metastatic Colorectal Cancer. J. Clin. Oncol. 31:2110-14, 2013  
  
22 April 201 6 CONFIDENTIAL
Page 102 of 235 Protocol 59R5-003, Amendment 6  
| Tarextumab (OMP-59R5)                                       | Follow-Upb                                                  | Every 3  months             |                               |                                                      |    |                    |    |    |    |
|-------------------------------------------------------------|-------------------------------------------------------------|-----------------------------|-------------------------------|------------------------------------------------------|----|--------------------|----|----|----|
| IND No. 106826, Serial 0037                                 | Terminationa                                                |                             |                               |                                                      |    |                    |    |    |    |
| Treatment                                                   |                                                             |                             |                               |                                                      |    |                    |    |    |    |
| Cycles 1-6 (every 21 days) > Cycles 7  (every 21 days)      | X                                                           | X                           | X                             | X                                                    | X  | X                  | X  | X  |    |
| SCHEDULE OF ASSESSMENTS FOR SUBJECTS IN PHASE 1B            | Day 1(± 1 day)                                              | X                           | X                             | X                                                    | X  | X                  | X  | X  |    |
| Post Cycle  6 (Cycles 1-3  only)                            |                                                             |                             |                               |                                                      |    |                    |    |    |    |
| Treatment Period                                            | Day 8                                                       | X                           |                               |                                                      |    |                    |    |    |    |
| Day 1  (±1  day) Day 2 Day 3  Day-14  to -1  Day -28  to -1 | X X                                                         |                             |                               |                                                      |    |                    |    |    |    |
| ,19(67,*$7,21$/1(:'58*                                                             | 5.3.4.2 Protocol No. 59R5-003 - Amendment 6 - 22 April 2016 | Xd                          | Xd                            | Xd                                                   | Xd | Xd                 | Xd | Xd |    |
| X                                                           |                                                             |                             |                               |                                                      |    |                    |    |    |    |
| APPENDIX B:                                                 | X                                                           | X                           | X                             | X                                                    | X  | Serum chemistryg X | X  | X  | X  |
| Screening                                                   |                                                             |                             |                               |                                                      |    |                    |    |    |    |
| OncoMed Pharmaceuticals, Inc.                               | X                                                           | X                           | Weight, vital signs,  heighte | Serum pregnancy test  (childbearing potential  only) |    |                    |    |    |    |
| Medical and oncology  history                               | Physical examinationc                                       | Coagulation (PT/INR,  aPTT) |                               |                                                      |    |                    |    |    |    |
| ECOG performance  status                                    | Urinalysis (dip stick  sufficient)                          |                             |                               |                                                      |    |                    |    |    |    |
| Procedure                                                   | Informed Consent                                            | Electrocardiogram           | Hematologyf                   |                                                      |    |                    |    |    |    |  
| Tarextumab (OMP-59R5)                                                 | Follow-Upb                                                                       | Every 3  months   | Every 6 weeksp          |         |
|-----------------------------------------------------------------------|----------------------------------------------------------------------------------|-------------------|-------------------------|---------|
| IND No. 106826, Serial 0037                                           | Terminationa                                                                     |                   |                         |         |
| Treatment                                                             |                                                                                  |                   |                         |         |
| (every 21 days)                                                       |                                                                                  |                   |                         |         |
| APPENDIX B: SCHEDULE OF ASSESSMENTS FOR SUBJECTS IN PHASE 1B (CONT'D) | Xo                                                                               |                   |                         |         |
| Xh                                                                    | Xi                                                                               | Xj                | Xn                      |         |
| Day 1(± 1 day)                                                        |                                                                                  |                   |                         |         |
| > Cycles 7                                                            | Xi                                                                               | Xo                | As clinically indicated |         |
| Treatment Period                                                      | Post Cycle  6                                                                    | (C1/C3)           |                         |         |
| Xh                                                                    | (C1/C2/C3)                                                                       | Xn (C2)           |                         |         |
| (Cycles 1-3  only)                                                    |                                                                                  |                   |                         |         |
| Day 8                                                                 | Xj                                                                               | Xk (C2)           |                         |         |
| Cycles 1-6 (every 21 days)                                            | Day  2 Day 3  (±1 day)  Day 1                                                    |                   |                         |         |
| Day14 to - 1  Day -28  to -1                                                                       | (C1/C3)                                                                          |                   |                         |         |
| Xh                                                                    | (C2/C3)                                                                          |                   |                         |         |
| Xj                                                                    |                                                                                  |                   |                         |         |
| ,19(67,*$7,21$/1(:'58*                                                                       | 5.3.4.2 Protocol No. 59R5-003 - Amendment 6 - 22 April 2016                      | Xh (C1/C3)        | Xi (C1/C4)              | (C3/C5) |
| Xo                                                                    |                                                                                  |                   |                         |         |
| Blood for biomarkersj Xj (C1)                                         | Xk                                                                               | Xl                |                         |         |
| Screening                                                             |                                                                                  |                   |                         |         |
| OncoMed Pharmaceuticals, Inc.                                         | m X  FFPE tissue                                                                 | X                 | X                       | X       |
| Optional tumor biopsyn                                                | Contrast CT, or MRI  (chest, abdomen, and  pelvis), brain MRI/CT  with contrasto |                   |                         |         |
| Hair for biomarkers k                                                 | Blood for pharmacogenomics                                                                                  |                   |                         |         |
| Procedure                                                             | Pharmacokineticsh                                                                | Anti-tarextumabi  | Bone Scan               |         |  
| Tarextumab (OMP-59R5)                                     | Follow-Upb                                                  | Every 3  months                         |    |    |    |    |
|-----------------------------------------------------------|-------------------------------------------------------------|-----------------------------------------|----|----|----|----|
| IND No. 106826, Serial 0037                               | X                                                           | X                                       |    |    |    |    |
| SCHEDULE OF ASSESSMENTS FOR SUBJECTS IN PHASE 1B (CONT'D) | Terminationa                                                |                                         |    |    |    |    |
| Treatment                                                 |                                                             |                                         |    |    |    |    |
| (every 21 days)                                           | X                                                           | X                                       |    |    |    |    |
| Day 1(± 1 day)                                            |                                                             |                                         |    |    |    |    |
| > Cycles 7                                                | X                                                           | X                                       | X  |    |    |    |
| Treatment Period                                          | Post Cycle  6                                               | Xq                                      |    |    |    |    |
| (Cycles 1-3  only)                                        |                                                             |                                         |    |    |    |    |
| Day 8                                                     | X                                                           | X                                       |    |    |    |    |
| Cycles 1-6 (every 21 days)                                | Day  2 Day 3  (±1 day)  Day 1                               |                                         |    |    |    |    |
| Day14 to - 1  Day -28  to -1                                                           | X                                                           | X                                       | X  |    |    |    |
| X                                                         | X                                                           | X                                       |    |    |    |    |
| ,19(67,*$7,21$/1(:'58*                                                           | 5.3.4.2 Protocol No. 59R5-003 - Amendment 6 - 22 April 2016 | X                                       | X  | X  | X  | X  |
| X                                                         |                                                             |                                         |    |    |    |    |
| Screening                                                 |                                                             |                                         |    |    |    |    |
| APPENDIX B:                                               |                                                             |                                         |    |    |    |    |
| OncoMed Pharmaceuticals, Inc.                             | X Concomitant medications                                   | Etoposide administration                |    |    |    |    |
| Subsequent anti-cancer  therapies                         | tarextumab Infusion                                         | Prophylactic cranial  irradiation (PCI) |    |    |    |    |
| Survival Follow-up                                        |                                                             |                                         |    |    |    |    |
| Procedure                                                 | Platinum therapy  administration                            |                                         |    |    |    |    |
| Adverse events                                            |                                                             |                                         |    |    |    |    |  
Protocol 59R5-003, Amendment 6
()
y drug, or etoposide or platinum therapy, whichever is discontinued last, but before the initiation of a new anticancer therapy b. All Subjects will be followed for survival and subsequent anti-cancer therapy information after the treatment termination unless a subject requests to be withdrawn from study survival follow-up. Survival follow-up and subsequent anti-cancer therapy information will be collected during telephone calls, through subjects' medical records, and/or at clinic visit every 3 months until death, loss to follow-up or study termination by the sponsor. c. Full physical examination at screening and treatment termination only. At all other times, targeted physical examination will be done at the Investigator's discretion. d. The assessment does not need to be repeated if it was done within 7 days prior to the first dose e. Height required at screening only. Vital signs and weight: screening, day 1 of each cycle prior to the start of study drug dosing, days 2 and 3 prior to etoposide administration during Cycles 1 through 6 and treatment termination. f. Hematology includes complete blood count (CBC) with differential, hemoglobin (Hgb), and platelet count. The results need to be reviewed by the Investigator prior to each study drug and EP administration. Hematology on Day 1 of each cycle starting from Cycle 2 can be performed up to 3 days prior to Day 1 dosing. g. Full chemistry includes sodium, potassium, chloride, bicarbonate, blood urea nitrogen (BUN), creatinine, glucose, ALT, AST, alkaline phosphatase, total bilirubin, direct bilirubin, lactate dehydrogenase (LDH), total protein, albumin, calcium, phosphorus, and magnesium. Chemistry on Day 1 of each cycle starting from Cycle 2 can be performed up to 3 days prior to Day 1 dosing. h. Plasma samples will be obtained for tarextumab pharmacokinetic analysis at pre-dose and 5 minutes (±2 minutes) after the end of tarextumab infusion and prior to the EP administration on Day 1 of Cycle 1 and Cycle 3, and on Days 3 (pre-dose) and 8 of Cycles 1 and 3, at other times as clinically indicated such as when significant toxicities occur, as well as at treatment termination. On days when tarextumab and etoposide and/or platinum therapy are given together, the plasma sample should be obtained 5 minutes (±2 minutes) after the completion of the infusion of tarextumab, but prior to EP administration. i. Serum samples will be obtained for anti-tarextumab pre-dose on Day 1 of every three cycles starting from Cycle 1, at other times as clinically indicated such as when significant toxicities occur, and at the Treatment Termination visit. j. A pre-dose sample of a total of 19 mL of blood will be drawn on Day 1 of Cycle 1(pre-dose), on Day 2 of Cycles 2 and 3, and on Day 8 of Cycles 1-3 for subjects continuing on tarextumab to evaluate changes in plasma proteins (4 mL) (e.g., EGFR, PLGF, ENA-78, etc.), CTCs (10 mL), and Notch-related gene expression of mRNA (5 mL) as described in Section 10.0. A sample will also be obtained at the time of treatment termination, unless one has been obtained during the prior 14 days. A pre-dose sample of blood will be drawn on Day 1 of Cycle 4 and 5 to explore effects of treatment on CTCs. Instructions for the collection, handling, storage, and shipment are provided in the Study Reference Binder.  
,19(67,*$7,21$/1(:'58* NOTES TO APPENDIX B: a. Approximately 4 weeks after the last stud 22 April 201 6