clinical protocol
untitled h2

| Protocol No.   | 59R5-003                                                                                                                                                                                                                                                                                                                     |
|----------------|------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|
| Title:         | A Phase 1b/2 Study of Tarextumab (OMP-59R5) in Combination with  Etoposide and Platinum Therapy in Subjects with Untreated Extensive  Stage Small Cell Lung Cancer  PINNACLE: Phase 1b/2 INvestigation of anti-Notch Antibody Therapy  with Etoposide and Platinum Therapy in Small Cell Lung Carcinoma  Safety and Efficacy |
| Version:       | 18 December 2012  Amendment 1: 09 May 2013  Amendment 2: 19 August 2013  Amendment 3: 23 October 2013  Amendment 4: 17 April 2014  Amendment 5: 10 September 2014  Amendment 6: 22 April 2016                                                                                                                                |
| IND Number:    | 106826                                                                                                                                                                                                                                                                                                                       |
| Sponsor:       | OncoMed Pharmaceuticals, Inc.  800 Chesapeake  Redwood City, CA 94063  Phone: 650-995-8200                                                                                                                                                                                                                                   |
clinical protocol
confidential

This document contains proprietary and confidential information of OncoMed Pharmaceuticals, Inc. Acceptance of this document constitutes agreement by the recipient that no previously unpublished information contained herein will be published or disclosed without the prior written approval of OncoMed Pharmaceuticals, Inc. with the exception that this document may be disclosed to study personnel under your supervision who need to know the contents for conducting the study and appropriate Institutional Review Boards/Ethics Committees under the condition that the personnel have agreed to keep this information confidential. The foregoing shall not apply to disclosure required by governmental regulations or laws; however, OncoMed Pharmaceuticals, Inc. shall be promptly notified of any such disclosure.  
,19(67,*$7,21$/1(:'58* ()
SPONSOR CONTACTS  
Medical Monitor: Primary:  
  
INVESTIGATOR SIGNATURE PAGE
OncoMed Pharmaceuticals, Inc.  
Protocol No. 59R5-003 Amendment *6: 22 April 2016* I will provide copies of the protocol, any subsequent protocol amendments, and access to all information provided by the Sponsor to the study personnel under my supervision. I will discuss this material with them to ensure that they are fully informed about the investigational drug and the study protocol. I agree to conduct this clinical trial according to the attached protocol. I also agree to conduct this study in compliance with Good Clinical Practice (GCP), 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.  
Principal Investigator Date  
| Printed Name:  Institution:  Address:  Telephone Number:   |
|------------------------------------------------------------|  
SPONSOR SIGNATURE PAGE
OncoMed Pharmaccuticals, Inc.  
Protocol No. 59R5-003 Amendment 6: 22 April 2016 This study protocol has been reviewed and approved by the undersigned person. It is confirmed that the information and guidance given in this protocol complies with the scientific principles, the guideline of Good Clinical Practices, the Declaration of Helsinki in the latest relevant version, and the applicable legal and regulatory requirements.
clinical protocol
synopsis

Title of Study: A Phase 1b/2 Study of Tarextumab in Combination with Etoposide and Platinum Therapy in Subjects with Untreated Extensive Stage Small Cell Lung Cancer INNACLE: Phase 1b/2 INvestigation of anti-Notch Antibody Therapy with Etoposide and Platinum Therapy in Small Cell Lung Carcinoma Safety and Efficacy Study Period: Approximately 36 months **Development Phase:** Phase 1b/2  
Objectives: Primary Objectives:
- To determine the maximum tolerated dose (MTD) of tarextumab when administered on Day 1 of each 21 day cycle along with etoposide 100 mg/m2 on Days 1, 2 and 3, and cisplatin 80 mg/m2 or carboplatin area under the curve (AUC) of 5 mg/mL•min on Day 1 in subjects with untreated extensive stage small cell lung cancer
(Phase 1b portion)
- To determine the improvement in Progression Free Survival (PFS) resulting from the addition of tarextumab to etoposide and platinum therapy (EP) in subjects receiving first-line therapy for extensive stage small cell lung cancer (Phase 2 portion)
Secondary Objectives:
- To determine the pharmacokinetics of tarextumab in combination with EP in subjects receiving first-line therapy for extensive stage small cell lung cancer (Phase 1b and 2 portion)
- To determine the immunogenicity of tarextumab in combination with EP in subjects receiving first-line therapy for extensive stage small cell lung cancer (Phase 1b and 2 portions)
- To estimate the improvement in overall survival (OS), 12 months OS, and the overall response rate (ORR)
resulting from the addition of tarextumab to EP in subjects receiving first-line therapy for extensive stage small cell lung cancer (Phase 2 portion)
- To correlate the treatment effect in PFS and OS, 12 month OS and ORR resulting from the addition of tarextumab to EP in subjects receiving first-line therapy for extensive stage small cell lung cancer in subjects with Notch3, Hes 1, Hey 2, Hey 1 and Hes 6 expression (Phase 2 portion)
- To determine the safety and tolerability of tarextumab in combination with EP in subjects who are receiving first-line therapy for extensive stage small cell lung cancer (Phase 1b portion)
- To compare the safety and tolerability of tarextumab in combination with EP relative to EP alone in all subjects who are receiving first-line therapy for extensive stage small cell lung cancer (Phase 2 portion)
Exploratory Objective:
- To describe the changes in exploratory pharmacodynamic (PD) biomarkers, including Notch pathway related genes and proteins and circulating tumor cells following tarextumab treatment (Phase 1b and 2 portions)
clinical protocol
study design

The study consists of a Phase1b lead-in portion to determine the MTD of tarextumab in combination with EP for 6 cycles followed by treatment with tarextumab alone until unacceptable toxicity or progression of disease. The initial dose escalations of tarextumab will be conducted with etoposide and cisplatin. The dose of tarextumab will not exceed 15 mg/kg. Following the establishment of the highest tolerable dose of tarextumab in combination with etoposide and cisplatin, a cohort of 6 subjects will be treated at this dose in combination with etoposide and carboplatin. Once the safety and tolerability of tarextumab of the highest tolerable dose is confirmed with etoposide and cisplatin/carboplatin, the protocol will explore a Phase 2, multicenter, randomized, placebo-controlled portion comparing the efficacy and safety of tarextumab at this highest tolerable dose in combination with EP for 6 cycles followed by single agent tarextumab relative to EP alone for 6 cycles in subjects receiving first-line therapy for extensive stage small cell lung cancer. However, if a DLT is observed in 2 or more subjects in the cohort of 6 subjects treated with the highest tolerable dose of tarextumab with etoposide and carboplatin, a new cohort of 3 to 6 subjects will be enrolled at the next lower dose level of tarextumab with etoposide and carboplatin. The highest tarextumab dose that is tolerable with both platinum options will be used in Phase 2 portion of the study. For example: if tarextumab at 15 mg/kg is tolerable with etoposide and cisplatin, but not tolerable with etoposide and carboplatin and tarextumab at 12.5 mg/kg is tolerable with etoposide and carboplatin, then tarextumab at 12.5 mg/kg will be the dose used in Phase 2 portion of the study. Subjects may be treated with cisplatin or carboplatin as determined by the Investigator prior to randomization.  
Alteration to the choice of platinum therapy is not permitted once the subject is randomized.  
Etoposide 100 mg/m2 will be administered on Days 1, 2 and 3 along with cisplatin 80 mg/m2 or with carboplatin area under the curve (AUC) of 5mg/mL•min on Day 1 of every 21-day cycle for 6 cycles in Phase 1b. In Phase 2 portion of the study, cisplatin dose will be 75 mg/m2, etoposide and carboplatin dose will the same as the one used in Phase 1b.  
tarextumab or Placebo will be given on Day 1 of every 21-day cycle prior to the administration of EP. Subjects may continue one of the chemotherapy drugs if the other is held or discontinued prior to completing 6 cycles of EP and prior to disease progression. Subjects should continue EP alone for a total of 6 cycles if study drug is held or discontinued prior to the completion of 6 cycles of EP. Subjects may continue study drug if one or both of the chemotherapy drugs is held or discontinued prior to completing 6 cycles of EP and prior to disease progression.  
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.  
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 approximately every 3 months starting from the last study treatment 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) during Follow-up until documented disease progression or initiation of new anti-cancer therapy, whichever is sooner.
clinical protocol
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Study Population and Number of Subjects: Subjects must have previously untreated extensive stage small cell lung cancer proven either by histology or cytology.  
In addition, subjects must have Formalin-Fixed, Paraffin-Embedded (FFPE) tumor tissue, either archived or fresh biopsied for Notch3*, Hes1, Hey2, Hey1 and Hes6* analysis. In the Phase 2 portion, subjects must have measurable disease by RECIST 1.1 criteria in order to be eligible.  
Approximately 30 subjects will be enrolled into Phase 1b portion of the study, the exact number will depend on the number of dose levels assessed and the toxicities observed. For the Phase 2 portion of the trial, approximately 135 subjects will be treated with at least one dose of study drug
(either tarextumab or placebo).
clinical protocol
diagnosis and main criteria for

1. Histologically or cytologically documented extensive stage small cell lung cancer (combined small cell carcinoma is allowed); extensive stage is defined as disease beyond the ipsilateral hemithorax, including malignant pleural or pericardial effusion or hematogenous metastases (contralateral mediastinal and ipsilateral supraclavicular lymphadenopathy are generally classified as limited disease).  
2. Adults of 18 years of age or older. 3. Performance Status (ECOG) of 0 or 1.  
4. FFPE tumor tissue, either fresh core needle biopsied (two fresh cores preferred whenever possible), or archived available for Notch3*, Hes1, Hey2, Hey1 and Hes6* analysis 5. Adequate organ function:
a. Adequate hematologic function (absolute neutrophil count [ANC]  1,500 cells/ȝL; hemoglobin  9 g/dL,
platelets  100,000/ȝL).  
b. Adequate renal function (serum creatinine  1.5 mg/dL or calculated creatinine clearance  60 mL/min using Cockroft Gault formula).  
c. Adequate hepatic function (alanine aminotransferase [ALT]  3 x upper limit of normal [ULN],
ALT may be  5 x ULN if due to liver metastases but cannot be associated with concurrent elevated bilirubin >1.5xULN unless it is approved by the Sponsor's Medical Monitor).  
d. Prothrombin Time (PT)/International Normalized Ration (INR) 1.5 × ULN, activated partial thromboplastin time (aPTT) 1.5 × ULN.  
6. Written consent on an IRB/IEC-approved Informed Consent Form prior to any study-specific evaluation.  
7. For women of child-bearing potential, negative serum pregnancy test at screening and use of physician-approved method of birth control from 30 days prior to the first study drug administration to 30 days following the last study drug administration or the last EP in the study, whichever is discontinued last.  
8. Male subjects must be surgically sterile or must agree to use physician-approved contraception during the study and for 30 days following the last study drug administration or the last EP in the study, whichever is discontinued last.
clinical protocol
additionally for individuals eligible to

9. Subject must have evidence of measurable disease per RECIST 1.1 criteria.
clinical protocol
exclusion criteria

1. Limited stage small cell lung cancer appropriate for radical treatment with chemoradiation. 2. Prior therapy including radiation, chemotherapy or surgery for newly diagnosed extensive stage small cell lung cancer. Exceptions to this exclusion criterion include: 1) prophylactic cranial irradiation or whole brain radiation
(WBRT) prior to the first administration of study drug provided that the subject has stable neurologic condition for at least 2 weeks after the completion of the radiation, adverse event that is related to the radiation has recovered to be  Grade 1, and is not receiving corticosteroid of > 40 mg prednisone daily equivalent dose to control the symptoms, 2) focused radiation for symptomatic relief for isolated bone metastases; 3) bisphosphonate or denosumab therapy for bone metastasis initiated prior to study entry.  
3. Presence of uncontrolled Grade  1 diarrhea within 4 weeks prior to the first study drug administration.  
4. Presence of any serious or uncontrolled illness including, but not limited to: ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris, uncontrolled cardiac arrhythmia, uncontrolled arterial thrombosis, symptomatic pulmonary embolism, and psychiatric illness that would limit compliance with study requirement.  
Diagnosis and Main Criteria for Eligibility: (Cont'd) 5. History of myocardial infarction, acute coronary syndromes (including unstable angina), coronary angioplasty and/or stenting within 6 months prior to the first administration of study drug.  
6. A history of malignancy with the exception of:
a. Adequately treated basal cell carcinoma, squamous cell carcinoma of the skin, or in situ cervical cancer b. Superficial bladder cancer c. Adequately treated stage I cancer from which the subject is currently in remission, or d. Any other cancer from which the subject has been disease-free for  3 years 7. Known human immunodeficiency virus (HIV) infection.  
8. Females who are pregnant or breastfeeding. 9. Concurrent use of therapeutic warfarin (prophylactic low dose of warfarin, i.e., 1 mg daily for port catheter is allowed).  
Additionally, individuals ineligible to participate in Phase 2 portion of the study if : 10. Subjects have relapsed after treatment for limited disease Test Product, Dose, and Mode of Administration Study drug will be either tarextumab or Placebo (Phase 2, only). Study drug will be given intravenously on Day 1 of every 21-day cycle. The subject should not receive two consecutive doses of study drug within 18 days.  
Tarextumab is an IgG2 fully human monoclonal antibody that is directed against the Notch2/3 receptors. Tarextumab is supplied at a concentration of 10 mg/mL in 25mL single-use glass vial filled to 20 mL to deliver at total of 200 mg per vial. Tarextumab vials must be stored at 2°C–8°C. DO NOT FREEZE. DO NOT SHAKE.  
Please refer to the Pharmacy Manual for the details on tarextumab preparation and administration. Placebo is a formulation of 50mM Histidine, 100mM Sodium Chloride, 45mM Sucrose and 0.01% (v/v) Polysorbate-20, pH 6.0. Placebo will be administered in the same manner as tarextumab. Please refer to the Pharmacy Manual for details regarding Placebo preparation and administration.  
Etoposide will be administered by IV infusion at a dose of 100 mg/m2 over 30 to 60 minutes on Days 1, 2 and 3 of each 21-day treatment cycle for 6 cycles in accordance with institutional standard of care. The subject should not receive two Day 1 consecutive doses of etoposide within 18 days. A one day window will be allowed for each consecutive day of etoposide dosing (e.g. Day 2 and 3 dosing may occur on Day 3 and 4, or Day 3 and 5). Cisplatin or carboplatin will be the choice of platinum therapy. Initially, all subjects in Phase 1b will receive cisplatin until the MTD/highest tolerable dose is determined with tarextumab in combination with etoposide and cisplatin. After that, a cohort of 6 subjects will be enrolled to receive tarextumab at the MTD/highest tolerable dose with etoposide and carboplatin. Subjects in Phase 2 will receive cisplatin or carboplatin as determined by the Investigator prior to randomization.  
Cisplatin will be administered by IV infusion at a dose of 80 mg/m2 over 30 minutes to 2 hours on Day 1 of each 21day treatment cycle for 6 cycles in accordance with institutional standard of care in Phase 1b and at a dose of 75 mg/m2 in Phase 2 portion of the study. The subject should not receive two consecutive doses of cisplatin within 18 days.  
Carboplatin will be administered by IV infusion at AUC of 5 mg/mL•min over 15 minutes or longer on Day 1 of each 21-day treatment cycle for 6 cycles in accordance with institutional standard of care. The subject should not receive two consecutive doses of carboplatin within 18 days.  
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. Subjects may continue one of the chemotherapy drugs if the other is held or discontinued prior to completing 6 cycles of EP and prior to disease progression. For subjects who have study drug held or discontinued for tolerability reasons, EP chemotherapy should continue to the completion of 6 cycles. Subjects may continue study drug if one or both of the chemotherapy drugs is held or discontinued prior to completing 6 cycles of EP and prior to disease progression.
clinical protocol
duration of treatment

In the absence of unacceptable study drug treatment-related toxicity or disease progression, subjects may receive study treatment for up to 1 year at the discretion of the Investigator and beyond 1 year with the agreement of the Investigator and the Sponsor.
clinical protocol
safety evaluation

Safety will be assessed by adverse event monitoring (including attribution of adverse events and serious adverse events), physical examination, vital signs, clinical laboratory testing and anti-tarextumab testing on an ongoing basis as outlined in the Schedule of Assessments.
clinical protocol
efficacy evaluation

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

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 infusion on Day 1 of Cycles 1 and 3, on Days 3 and 8 of Cycles 1 and 3, at other times as clinically indicated such as when significant toxicities occur as well as at the time of treatment termination, as outlined in the Schedule of Assessments (APPENDIX B). 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 starting from Cycle 5 prior to study drug administration 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.  
Biomarker Evaluation: Samples will be obtained for biomarker evaluations as outlined in the Schedule of Assessments (APPENDIX B and APPENDIX C).  
Notch3, *Hes1, Hey2, Hey1, and Hes6* expression levels (e.g., protein and/or RNA) will be assessed in FFPE tumor specimens to correlate the treatment effect in *relation to these gene expressions*. The expression level of additional proteins and genes may be evaluated and correlated with clinical benefit. Additionally, DNA testing may be done on subjects who consent to have the optional DNA testing on FFPE tumor specimens collected. Exploratory pharmacodynamics assays to confirm target engagement will include assessments of hair follicles (Phase 1b portion only), plasma proteins, and blood mRNA. Circulating tumor cells (CTCs) will also be monitored to explore the effects of treatment on CTCs. In addition, a pharmacogenomic blood sample will be collected on Day 1 of Cycle 1 prior to dosing from subjects who give informed consent to assess Notch target- or pathway-related genes.  
Optional tumor biopsies will be obtained to assess tumor biomarkers before and during tarextumab treatment and at the time of progression in subjects who are consented to provide pre- and post-treatment tumor biopsies, provided it is feasible.  
,19(67,*$7,21$/1(:'58* ()  
| 1.0                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                 | TABLE OF CONTENTS   |
|-----------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|---------------------|
| SPONSOR CONTACTS 2 INVESTIGATOR SIGNATURE PAGE 3 SPONSOR SIGNATURE PAGE 4 SYNOPSIS 5 1.0 TABLE OF CONTENTS 10 LIST OF TABLES 14 LIST OF FIGURES 15 LIST OF APPENDICES 15 2.0 LIST OF ABBREVIATIONS 16 3.0 BACKGROUND 19 3.1 Investigational Medicinal Product 19 3.2 Disease Background 19 3.3 Nonclinical Data 19 3.4 Clinical Background 23 3.5 Dose Rationale 27 3.6 Study Conduct 28 3.7 Subject Population 28 4.0 STUDY OBJECTIVES AND ENDPOINTS 29 4.1 Study Objectives 29 5.0 OVERALL STUDY DESIGN AND PLAN DESCRIPTION 30 5.1 Phase 1b Portion 31 5.2 Dose Limiting Toxicity 32 5.3 Dose Escalation Plan 32 5.4 Maximum Tolerated Dose 33 5.4.1 Follow-Up 34 5.5 Phase 2 Portion 35 5.5.1 Blinded Treatment Phase 35 5.5.2 Follow-up 36 6.0 SELECTION OF STUDY POPULATION 36 6.1 Inclusion Criteria 36 6.2 Exclusion Criteria 37 6.3 Removal of Subjects from Study Treatment 39 6.4 Subject Identification and Replacement of Subjects 40 7.0 TREATMENT OF SUBJECTS 40 7.1 Study Drug (tarextumab or Placebo) 41 Protocol 59R5-003, Amendment 6 Page 10 of 235 22 April 2016  CONFIDENTIAL |                     |
clinical protocol
investigational new drug

IND No. 106826, Serial 0037  
| 5.3.4.2 Protocol No. 59R5-003 - Amendment 6 - 22 April 2016                                                               |                                                                                                                               |                                                                                                                     |
|---------------------------------------------------------------------------------------------------------------------------|-------------------------------------------------------------------------------------------------------------------------------|---------------------------------------------------------------------------------------------------------------------|
| OncoMed Pharmaceuticals, Inc.                                                                                             | Tarextumab (OMP-59R5)                                                                                                         |                                                                                                                     |
| Study Drug Administration .........................................................................41                     |                                                                                                                               |                                                                                                                     |
| 7.1.1                                                                                                                     |                                                                                                                               |                                                                                                                     |
| 7.1.2                                                                                                                     | Study Drug Description ..............................................................................42                       |                                                                                                                     |
| Study Drug Packaging ................................................................................42                   |                                                                                                                               |                                                                                                                     |
| 7.1.3                                                                                                                     |                                                                                                                               |                                                                                                                     |
| 7.1.4                                                                                                                     | Study Drug Ordering, Storage, and Accountability .................................42                                          |                                                                                                                     |
| 7.1.5                                                                                                                     | Study Drug Preparation                                                                                                        |                                                                                                                     |
| 7.2                                                                                                                       | E                                                                                                                             |                                                                                                                     |
| 7.2.1                                                                                                                     | Administration ..............................................................................................42               |                                                                                                                     |
| 7.2.2                                                                                                                     | Description .........................................................................................................43       |                                                                                                                     |
| 7.2.3                                                                                                                     | Storage ...............................................................................................................43     |                                                                                                                     |
| 7.2.4                                                                                                                     | Packaging ............................................................................................................43      |                                                                                                                     |
| 7.3                                                                                                                       | CC                                                                                                                            |                                                                                                                     |
| Administration ................................................................................................43         |                                                                                                                               |                                                                                                                     |
| 7.3.1                                                                                                                     |                                                                                                                               |                                                                                                                     |
| 7.3.2                                                                                                                     | Description .........................................................................................................43       |                                                                                                                     |
| 7.3.3                                                                                                                     | Storage ...............................................................................................................43     |                                                                                                                     |
| 7.3.4                                                                                                                     | Packaging ............................................................................................................43      |                                                                                                                     |
| Carboplatin                                                                                                               |                                                                                                                               |                                                                                                                     |
| 7.4                                                                                                                       | 7.4.1                                                                                                                         | Administration ..................................................................................................44 |
| 7.4.2                                                                                                                     | Description ..........................................................................................................44      |                                                                                                                     |
| 7.4.3                                                                                                                     | Storage ...................................................................................................................44 |                                                                                                                     |
| Packaging .............................................................................................................44 |                                                                                                                               |                                                                                                                     |
| 7.4.4                                                                                                                     |                                                                                                                               |                                                                                                                     |
| 7.5                                                                                                                       | Dose Modifications or Delay for Treatment-Related Toxicities .............................44                                  |                                                                                                                     |
| 7.5.1                                                                                                                     | Infusion Reaction Management ..........................................................................54                     |                                                                                                                     |
| 7.6                                                                                                                       | Anti-Emetics, Anti-diarrhea and Hematopoietic Supportive Care .........................54                                     |                                                                                                                     |
| 7.7                                                                                                                       | Concomitant and Prohibited Therapy .                                                                                          |                                                                                                                     |
| 7.8                                                                                                                       | Treatment Compliance                                                                                                          |                                                                                                                     |
| 8.0                                                                                                                       | SAFETY ASSESSMENTS .                                                                                                          |                                                                                                                     |
| Adverse Events Definitions and Reporting Procedures                                                                       |                                                                                                                               |                                                                                                                     |
| 8.1                                                                                                                       | Definition of Adverse Event .......................................................................................56         |                                                                                                                     |
| 8.1.1                                                                                                                     |                                                                                                                               |                                                                                                                     |
| 8.1.2                                                                                                                     | Adverse Event -Causality rating .......................................................................56                     |                                                                                                                     |
| 8.1.3                                                                                                                     | Definition of Serious Adverse Event ..............................................................57                          |                                                                                                                     |
| Disease Progression and Death                                                                                             |                                                                                                                               |                                                                                                                     |
| 8.1.3.1                                                                                                                   |                                                                                                                               |                                                                                                                     |
| 8.1.4                                                                                                                     | Serious Adverse Event Reporting Procedures ...........................................57                                      |                                                                                                                     |
| 8.2                                                                                                                       | Clinical Laboratory Assessments                                                                                               |                                                                                                                     |
| 8.2.1                                                                                                                     | Hematology .                                                                                                                  |                                                                                                                     |
| 8.2.2                                                                                                                     | C Chemistry                                                                                                                   |                                                                                                                     |
| 8.2.3                                                                                                                     | Urinalysis .                                                                                                                  |                                                                                                                     |
| Protocol 59R5-003, Amendment 6                                                                                            | Page 11 of 235                                                                                                                | 2 April 2016                                                                                                        |
| CONFIDENTIAL                                                                                                              |                                                                                                                               |                                                                                                                     |  
| 5.3.4.2 Protocol No. 59R5-003 - Amendment 6 - 22 April 2016                                            |                                                                                                                                                |              |
|--------------------------------------------------------------------------------------------------------|------------------------------------------------------------------------------------------------------------------------------------------------|--------------|
| OncoMed Pharmaceuticals, Inc.                                                                          | Tarextumab (OMP-59R5)                                                                                                                          |              |
|                                                                                                        |                                                                                                                                                |              |
| 8.3                                                                                                    | Vital Signs and Other Physical Findings ....................................................................................59                 |              |
| 8.4                                                                                                    | CC                                                                                                                                             |              |
| Immunogenicity Assessments                                                                             |                                                                                                                                                |              |
| 8.5                                                                                                    | Pharmacokinetic Assessments ................................................................................................................59 |              |
| 8.6                                                                                                    |                                                                                                                                                |              |
| 9.0                                                                                                    | EFFICACY ASSESSMENTS ...........................................................................................................60             |              |
| 10.0                                                                                                   | BIOMARKERS AND EXPLORATORY ASSESSMENTS ..........................................60                                                            |              |
| 1.0                                                                                                    | STUDY VISIT SCHEDULE AND ASSESSMENTS ............................................................61                                            |              |
| Screening                                                                                              |                                                                                                                                                |              |
| 11.1                                                                                                   |                                                                                                                                                |              |
| 11.2                                                                                                   | Treatment Visits - Phase 1b .............................................................................................63                    |              |
| 11.2.1                                                                                                 | Cycle 1 ............................................................................................................................64         |              |
| Cycle 1 Day 1                                                                                          |                                                                                                                                                |              |
| 11.2.1.1                                                                                               | Cycle 1 Day 2                                                                                                                                  |              |
| 11.2.1.2                                                                                               |                                                                                                                                                |              |
| 11.2.1.3                                                                                               | Cycle 1 Day 3..............................................................................................................65                  |              |
| 11.2.1.4                                                                                               | Cycle 1 Day 8...................................................................................................................66             |              |
| Cycles 2-6 .                                                                                           |                                                                                                                                                |              |
| 11.2.2                                                                                                 | Day 1 (± 1 day) of Cycles 2-6                                                                                                                  |              |
| 11.2.2.1                                                                                               |                                                                                                                                                |              |
| 11.2.2.2                                                                                               | Day 2 of Cycles 2-6 ..........................................................................................67                               |              |
| 11.2.2.3                                                                                               | Day 3 of Cycles 2-6 .........................................................................................68                                |              |
| Day 8 of Cycles 2 and 3 Only ......................................................................68  |                                                                                                                                                |              |
| 11.2.2.4                                                                                               | After Cycle 6 of etoposide and cisplatin/carboplatin with                                                                                      |              |
| 11.2.3                                                                                                 | tarextumab                                                                                                                                     |              |
| 11.2.4                                                                                                 | Cycle 7 and every cycle thereafter .....................................................................69                                     |              |
| 11.2.4.1                                                                                               | Day 1 (± 1 day) of Cycle 7 and every cycle thereafter ..................69                                                                     |              |
| 11.3                                                                                                   | Treatment Visits - Phase 2 ................................................................................................70                  |              |
| 11.3.1                                                                                                 | Cycle 1 ...........................................................................................................................71          |              |
| 11.3.1.1                                                                                               | Cycle 1 Day 1                                                                                                                                  |              |
| Cycle 1 Day 2                                                                                          |                                                                                                                                                |              |
| 11.3.1.2                                                                                               | Cycle 1 Day 3.........................................................................................................73                       |              |
| 11.3.1.3                                                                                               |                                                                                                                                                |              |
| 11.3.1.4                                                                                               | Cycle 1 Day 8........................................................................................................73                        |              |
| Cycles 2-6 .                                                                                           |                                                                                                                                                |              |
| 11.3.2                                                                                                 | Day 1 (± 1 day) of Cycles 2-6                                                                                                                  |              |
| 11.3.2.1                                                                                               |                                                                                                                                                |              |
| 11.3.2.2                                                                                               | Day 2 of Cycles 2-6 ........................................................................................74                                 |              |
| 11.3.2.3                                                                                               | Day 3 of Cycles 2-6 ..........................................................................................75                               |              |
| Day 8 of Cycles 2 and 3 Only                                                                           |                                                                                                                                                |              |
| 11.3.2.4                                                                                               |                                                                                                                                                |              |
| 11.3.3                                                                                                 | After Cycle 6 - Planned EP Treatment cycles                                                                                                    |              |
| Subsequent Cycles After Cycle 6.....................................................................76 |                                                                                                                                                |              |
| 11.3.4                                                                                                 |                                                                                                                                                |              |
| Protocol 59R5-003, Amendment 6                                                                         | Page 12 of 235                                                                                                                                 | 2 April 2016 |  
CONFIDENTIAL
INVESTIGATIONAL NEW DRUG  
| 5.3.4.2 Protocol No. 59R5-003 - Amendment 6 - 22 April 2016                                                                                 |                                                                                                                                                         |              |
|---------------------------------------------------------------------------------------------------------------------------------------------|---------------------------------------------------------------------------------------------------------------------------------------------------------|--------------|
| OncoMed Pharmaceuticals, Inc.                                                                                                               | Tarextumab (OMP-59R5)                                                                                                                                   |              |
| 11.3.4.1                                                                                                                                    | Day 1 (± 1 day) of Subsequent Cycles After Completion of                                                                                                |              |
| Planned EP Cycles ..................................................................................................76                      |                                                                                                                                                         |              |
| T Treatment Termination ..............................................................................................................77    |                                                                                                                                                         |              |
| 1.4                                                                                                                                         | Follow up                                                                                                                                               |              |
| 11.5                                                                                                                                        |                                                                                                                                                         |              |
| 12.0                                                                                                                                        | DATA QUALITY ASSURANCE ...................................................................................................78                            |              |
| 13.0                                                                                                                                        | STATISTICAL PLAN                                                                                                                                        |              |
| 13.1                                                                                                                                        | Power and Sample Size                                                                                                                                   |              |
| Phase 1b ................................................................................................................................79 |                                                                                                                                                         |              |
| 13.1.1                                                                                                                                      |                                                                                                                                                         |              |
| 13.1.2                                                                                                                                      | Sample Size Justification - Phase 2                                                                                                                     |              |
| 13.1.3                                                                                                                                      | Randomization and Blinding ...........................................................................87                                                |              |
| 13.1.4                                                                                                                                      | Procedures for Unblinding ...................................................................................87                                         |              |
| 13.2                                                                                                                                        | Phase 1b                                                                                                                                                |              |
| 13.3                                                                                                                                        | Phase 2 .............................................................................................................................................88 |              |
| 13.3.1                                                                                                                                      | Subject Populations for Analysis ........................................................................88                                             |              |
| Analysis Set...........................................................................................................88                   |                                                                                                                                                         |              |
| 13.3.2                                                                                                                                      |                                                                                                                                                         |              |
| 13.4                                                                                                                                        | Endpoints                                                                                                                                               |              |
| 13.4.1                                                                                                                                      | Efficacy Endpoints .................................................................................................88                                  |              |
| 13.4.2                                                                                                                                      | Safety Endpoints .......................................................................................................89                              |              |
| 13.4.3                                                                                                                                      | Immunogenicity Endpoints ...........................................................................90                                                  |              |
| 13.4.4                                                                                                                                      | Pharmacokinetic Endpoints                                                                                                                               |              |
| 13.4.5                                                                                                                                      | Exploratory Endpoints ..................................................................................90                                              |              |
| 13.5                                                                                                                                        | Statistical Methods                                                                                                                                     |              |
| Progression-Free Survival ...............................................................................91                                 |                                                                                                                                                         |              |
| 13.5.1                                                                                                                                      |                                                                                                                                                         |              |
| 13.5.2                                                                                                                                      | Response Rate (Best Overall Response) .....................................................92                                                           |              |
| 13.5.3                                                                                                                                      | Duration of Response                                                                                                                                    |              |
| 13.5.4                                                                                                                                      | OVERALL SURVIVAL                                                                                                                                        |              |
| LANDMARK SURVIVAL                                                                                                                           |                                                                                                                                                         |              |
| 13.5.5                                                                                                                                      | Correlation of Biomarkers with Efficiacy Endpoints ..............................94                                                                     |              |
| 13.5.6                                                                                                                                      |                                                                                                                                                         |              |
| 13.6                                                                                                                                        | Demographics and Baseline Characteristics ................................................................94                                            |              |
| 13.7                                                                                                                                        | T Treatment Exposure                                                                                                                                    |              |
| Termination Criteria                                                                                                                        |                                                                                                                                                         |              |
| 13.8                                                                                                                                        | Deviation Reporting                                                                                                                                     |              |
| 13.9                                                                                                                                        |                                                                                                                                                         |              |
| 13.10                                                                                                                                       | Data Safety Monitory Board                                                                                                                              |              |
| 13.11                                                                                                                                       | Analysis of PFS and OS Prior to the Final Analysis ..................................................95                                                 |              |
| DIRECT ACCESS TO SOURCE DATA/DOCUMENTATION ................................95                                                               |                                                                                                                                                         |              |
| 13.12                                                                                                                                       | ETHICAL CONSIDERATIONS                                                                                                                                  |              |
| 14.0                                                                                                                                        |                                                                                                                                                         |              |
| Protocol 59R5-003, Amendment 6                                                                                                              | Page 13 of 235                                                                                                                                          | 2 April 2016 |  
| 5.3.4.2 Protocol No. 59R5-003 - Amendment 6 - 22 April 2016 OncoMed Pharmaceuticals, Inc.   | Tarextumab (OMP-59R5)                                                                                                                                                                                                                                                                                                            |
|---------------------------------------------------------------------------------------------|----------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|
| 15.0                                                                                        | INVESTIGATOR REQUIREMENTS 96 15.1 Informed Consent 96 15.2 Institutional Review Board/Ethics Committee Approval 96 15.3 Study Monitoring 97 15.4 Auditing Procedures 97 15.5 Data Collection 97 15.6 Investigational Medicinal Product Accountability 98 15.7 Disclosure of Data and Publication 98 15.8 Retention of Records 99 |
| 16.0                                                                                        | REFERENCES 100                                                                                                                                                                                                                                                                                                                   |  
Table 1: Summary of the Activity of Tarextumab in SCLC Xenografts .................20 Table 2: Study 59R5-001: Worse Grade Treatment Related Diarrhea  
(N=34/42) ...................................................................................................24  
Table 3: Study 59R5-001: Grade 3 Treatment Related Adverse Events by Body  
System (N=39) ...........................................................................................25  
Table 4: Maximum Tolerated Dose Determination and Cohort Expansion ............33 Table 5: Suggested Guidelines for Study Drug and Etoposide-Platinum Therapy  
Dose Modification and Delay ....................................................................46  
Table 6: Power to Declare a Dose as Exceeding the MTD for Various Incidence  
Rates ...........................................................................................................79  
Table 7: *PFS: Power for H1* ....................................................................................80 Table 8: Hazards for Piece-Wise Exponential Model of Progression Free  
Survival ......................................................................................................81  
Table 9: Hazards for Piece-wise Exponential Model of Survival ............................82 Table 10: Enrollment, Progressions and Deaths over Time - Control Hazard of  
Progression of 0.1386 beyond 9 months ....................................................85  
Table 11: *Power for OS*..............................................................................................86  
,19(67,*$7,21$/1(:'58*  
| Table 1:   | Summary of the Activity of Tarextumab in SCLC Xenografts 20                                                 |
|------------|-------------------------------------------------------------------------------------------------------------|
| Table 2:   | Study 59R5-001: Worse Grade Treatment Related Diarrhea  (N=34/42) 24                                        |
| Table 3:   | Study 59R5-001: Grade 3 Treatment Related Adverse Events by Body  System (N=39) 25                          |
| Table 4:   | Maximum Tolerated Dose Determination and Cohort Expansion 33                                                |
| Table 5:   | Suggested Guidelines for Study Drug and Etoposide-Platinum Therapy  Dose Modification and Delay 46          |
| Table 6:   | Power to Declare a Dose as Exceeding the MTD for Various Incidence  Rates 79                                |
| Table 7:   | PFS: Power for H1 80                                                                                        |
| Table 8:   | Hazards for Piece-Wise Exponential Model of Progression Free  Survival 81                                   |
| Table 9:   | Hazards for Piece-wise Exponential Model of Survival 82                                                     |
| Table 10:  | Enrollment, Progressions and Deaths over Time - Control Hazard of  Progression of 0.1386 beyond 9 months 85 |
| Table 11:  | Power for OS 86                                                                                             |
|            | LIST OF TABLES                                                                                              |  
| APPENDIX A:                   | STUDY SCHEMA 102                                                                                             |
|-------------------------------|--------------------------------------------------------------------------------------------------------------|
| APPENDIX B:                   | SCHEDULE OF ASSESSMENTS FOR SUBJECTS IN PHASE 1B 103                                                         |
| APPENDIX C                    | SCHEDULE OF ASSESSMENTS FOR SUBJECTS IN PHASE 2 108                                                          |
| APPENDIX D:                   | ECOG PERFORMANCE STATUS CRITERIA 113                                                                         |
| APPENDIX E:                   | RECIST CRITERIA 1.1 114                                                                                      |
| APPENDIX F:                   | SAMPLE INFORMED CONSENT - Phase 1b 120                                                                       |
| APPENDIX G:                   | SAMPLE INFORMED CONSENT - Phase 2 143                                                                        |
| APPENDIX H:                   | SAMPLE PHARMACOGENOMICS/DNA INFORMED CONSENT ..166                                                           |
| APPENDIX I:                   | PROTOCOL AMENDMENT SUMMARY OF CHANGES 171                                                                    |
| AMENDMENT 1:                  | 09 MAY 2013 171                                                                                              |
| AMENDMENT 2:                  | 19 AUGUST 2013 197                                                                                           |
| AMENDMENT 3:                  | 23 OCTOBER 2013 218                                                                                          |
| AMENDMENT 4:                  | 17 APRIL 2014 231                                                                                            |
| AMENDMENT 5:                  | 10 SEPTEMBER 2014 233                                                                                        |
| AMENDMENT 6:                  | 22 APRIL 2016 235                                                                                            |
| OncoMed Pharmaceuticals, Inc. | Tarextumab (OMP-59R5)                                                                                        |
| LIST OF FIGURES               |                                                                                                              |
| Figure 1:                     | Activity of Tarextumab in Lu68 SCLC Tumor Recurrence Model 21                                                |
| Figure 2:                     | Activity of Tarextumab in 87 SCLC Tumor Recurrence Model in  Combination with Carboplatin plus Irinotecan 22 |
| Figure 3:                     | Tarextumab Inhibits Growth of Lu40 SCLC Tumors in Combination  with Taxol 22                                 |
| Figure 4:                     | Tarextumab Inhibits Growth of Lu61 SCLC Tumors 23                                                            |
| Figure 5:                     | Notch Genes and Overall Survival 27                                                                          |
| Figure 6:                     | PFS in Subjects Treated with Etoposide plus Cisplatin. from Noda et al..82                                   |
| Figure 7:                     | PFS in Subjects Treated with Etoposide plus Cisplatin - Hanna 83                                             |
| Figure 8:                     | Survival in Subjects Treated with Etoposide plus Cisplatin(from Noda  et al.) 83                             |
| Figure 9:                     | Survival in Subjects Treated with Etoposide plus Cisplatin (from  Hanna et al.) 84                           |
| Figure 10:                    | Enrollment, Progressions and Deaths over Time - Control Hazard of  Progression of 0.1386 Beyond 9 months 84  |
|                               | LIST OF APPENDICES                                                                                           |  
,19(67,*$7,21$/1(:'58* ()  
| 2.0                  | LIST OF ABBREVIATIONS                                                   |
|----------------------|-------------------------------------------------------------------------|
| Abbreviation or Term | Definition/Explanation                                                  |
| aPTT                 | activated partial thromboplastin time                                   |
| AE                   | adverse event                                                           |
| ALT (SGPT)           | alanine aminotransferase (serum glutamic pyruvic transaminase)          |
| ANC                  | absolute neutrophil count                                               |
| AST (SGOT)           | aspartate aminotransferase (serum glutamic oxaloacetic transaminase)    |
| AUC                  | area under the curve                                                    |
| BP                   | blood pressure                                                          |
| BUN                  | blood urea nitrogen                                                     |
| CBC                  | complete blood count                                                    |
| CR                   | complete response                                                       |
| CRA                  | clinical research associate                                             |
| CRF                  | case report form                                                        |
| CT                   | computed tomography (scan)                                              |
| CTC                  | circulating tumor cell                                                  |
| CTCAE                | common toxicity criteria for adverse events (National Cancer Institute) |
| D5W                  | 5% dextrose in water                                                    |
| dL                   | deciliter(s)                                                            |
| DLT                  | dose-limiting toxicity                                                  |
| DSMB                 | data safety monitoring board                                            |
| ECG                  | electrocardiogram                                                       |
| ECOG                 | eastern cooperative oncology group                                      |
| eCRF                 | electronic case report form                                             |
| EDC                  | electronic data capture                                                 |
| EP                   | etoposide and platinum therapy (cisplatin or carboplatin)               |
| FACS                 | fluorescent-activated cell sorting                                      |
| FFPE                 | formalin-fixed, paraffin-embedded                                       |
| GI                   | gastrointestinal                                                        |
| GCP                  | good clinical practice                                                  |
| HIPAA                | health insurance portability and accountability act OF 1996             |
| IEC                  | independent ethics committee                                            |  
,19(67,*$7,21$/1(:'58*  
| 5.3.4.2 Protocol No. 59R5-003 - Amendment 6 - 22 April 2016 OncoMed Pharmaceuticals, Inc.   | Tarextumab (OMP-59R5)                              |
|---------------------------------------------------------------------------------------------|----------------------------------------------------|
| Abbreviation or Term                                                                        | Definition/Explanation                             |
| IMP                                                                                         | investigational medicinal product                  |
| INR                                                                                         | international normalized ration                    |
| IRB                                                                                         | institutional review board                         |
| ITT                                                                                         | intent-to-treat (population)                       |
| L                                                                                           | liter(s)                                           |
| LFT(s)                                                                                      | liver function test(s)                             |
| IV                                                                                          | Intravenous                                        |
| IWRS                                                                                        | Interactive Web-based randomization system         |
| Kg                                                                                          | kilogram(s)                                        |
| Kaplan-Meier                                                                                | KM                                                 |
| LD                                                                                          | longest diameter (of a lesion), or limited disease |
| LDH                                                                                         | lactic dehydrogenase                               |
| MedDRA                                                                                      | medical dictionary for regulatory activities       |
| Mg                                                                                          | milligram(s)                                       |
| Min                                                                                         | minute(s)                                          |
| mL                                                                                          | milliliter(s)                                      |
| MRI                                                                                         | magnetic resonance imaging                         |
| MTD                                                                                         | maximum tolerated dose                             |
| NCI                                                                                         | national cancer institute                          |
| NE                                                                                          | not evaluable                                      |
| NOAEL                                                                                       | no observed adverse effect level                   |
| ORR                                                                                         | overall response rate                              |
| OS                                                                                          | overall survival                                   |
| PCI                                                                                         | prophylactic cranial irradiation                   |
| PD                                                                                          | progressive disease or pharmacodynamic             |
| PK                                                                                          | pharmacokinetics                                   |
| PFS                                                                                         | progression free survival                          |
| PR                                                                                          | partial response                                   |
| PVC                                                                                         | polyvinyl chloride                                 |
| RECIST                                                                                      | response evaluation criteria in solid tumors       |
| SAE                                                                                         | serious adverse event                              |  
,19(67,*$7,21$/1(:'58*  
| 5.3.4.2 Protocol No. 59R5-003 - Amendment 6 - 22 April 2016 OncoMed Pharmaceuticals, Inc.   | Tarextumab (OMP-59R5)         |
|---------------------------------------------------------------------------------------------|-------------------------------|
| Abbreviation or Term                                                                        | Definition/Explanation        |
| SCLC                                                                                        | small cell lung cancer        |
| SD                                                                                          | stable disease                |
| SLD                                                                                         | sum of longest diameter       |
| ULN                                                                                         | upper limit of normal         |
| US                                                                                          | Ultrasound                    |
| WBRT                                                                                        | whole brain radiation therapy |
clinical protocol
3.0 background 3.1 investigational medicinal

Investigational Medicinal Product is either tarextumab or Placebo.  
Tarextumab is a fully human IgG2 monoclonal antibody that inhibits the function of both Notch2 and Notch3 receptors. Tarextumab is supplied at a concentration of 10 mg/mL in 25-mL singleuse glass vial filled to 20 mL to deliver at total of 200 mg per vial. Tarextumab vials must be stored at 2°C–8°C. DO NOT FREEZE. DO NOT SHAKE. Placebo is a formulation of 50mM Histidine, 100mM Sodium Chloride, 45mM Sucrose and 0.01% (v/v) Polysorbate-20, pH 6.0. Placebo will be handled the same way as tarextumab.
clinical protocol
3.2 disease background

Small cell lung cancer (SCLC) comprises ~ 15% of the total cases of lung cancer in the US (Ref 1) and Europe. At the time of diagnosis, approximately 30% of patients with SCLC will have tumors confined to the hemithorax of origin, the mediastinum, or the supraclavicular lymph nodes. These patients are designated as having limited-stage disease (LD) while patients with tumors that have spread beyond the supraclavicular areas are said to have extensive-stage disease (ED). SCLC is more responsive to chemotherapy and radiation therapy than other cell types of lung cancer; however, a cure is difficult to achieve because SCLC has a greater tendency to be widely disseminated by the time of diagnosis. Chemotherapy is the main treatment for EDSCLC. Combination therapy with EP is considered the standard first line regimen and results in a high response rate (60-70%), but tumor recurrence after therapy is very common and the five year survival rate is only ~ 5% (Ref 2). Development of new and effective therapies for this disease has been lacking, and consequently, there is a significant need to develop novel approaches for the treatment of SCLC.
clinical protocol
3.3 nonclinical data

Many current cancer treatments, while producing an initial reduction in tumor burden, have not resulted in a long-term benefit. A possible explanation for this observation is the presence of cancer stem cells (Ref 3, Ref 4), which represent a small percentage of the tumor, but are the most tumorigenic component driving growth and metastasis and are more resistant to traditional cytotoxic therapy, including both radiotherapy (Ref 5) and chemotherapy (Ref 6), than the remaining bulk of the tumor. Like normal stem cells, cancer stem cells may be characterized by three properties: self-renewal, the capacity to develop into multiple lineages, and the ability to proliferate extensively (Ref 7). Cancer stem cells (CSCs) have been most extensively studied in hematologic malignancy, but have now also been identified in many solid tumors, including breast, colon, lung, head and neck, glioblastoma, and pancreatic cancers. CSCs rely on the activation of developmental pathways including the Notch pathway and several new therapies, including tarextumab, are being developed to target these pathways (Ref 8).
clinical protocol
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()
SCLC is characterized by expression of Notch receptors and Notch target genes indicating that the pathway is likely to be activated in this disease. OncoMed Pharmaceuticals has established a collection of patient derived xenografts, including several from small cell lung cancer patients, that retain much of the cellular heterogeneity of the patient's tumor and which enable the preclinical study of potential therapeutics in models that better represent the clinical setting than traditional xenografts from cell lines that have passaged in tissue culture (Ref 9). We have found that these xenograft models express various levels of Notch1, Notch2 or Notch3 as shown by immunohistochemistry. In addition, we have also shown elevated expression of various Notch target genes in SCLC including PBX1, HEYL, HEY2, and HES6 (data not shown). Additionally, we have tested the effects of anti-Notch2/3 (tarextumab) in eight SCLC patient derived models and tarextumab was found to be active in seven of these models (Table 1)  
| SCLC Tumor                                                                                                  | Efficacy   |
|-------------------------------------------------------------------------------------------------------------|------------|
| Lu40                                                                                                        | +          |
| Lu61                                                                                                        | +          |
| Lu65                                                                                                        | +          |
| Lu66                                                                                                        | +          |
| Lu67                                                                                                        | -          |
| Lu68                                                                                                        | +          |
| Lu87                                                                                                        | +          |
| Lu90                                                                                                        | +          |
| SCLC patient derived xenografts were tested with tarextumab in combination with chemotherapeutic treatment. |            |  
SCLC patient derived xenografts were tested with tarextumab in combination with chemotherapeutic treatment. A "+" indicates a reduction in tumor volume by tarextumab plus chemotherapy (p < 0.05) relative to the group treated with chemotherapy alone. The asterisk indicates that tarextumab also exhibited single agent activity in Lu61.  
We also tested the activity of tarextumab in SCLC in a tumor recurrence experiment that was meant to recapitulate some of the clinical features of the response of SCLC to chemotherapeutic treatment. Our initial tumor recurrence experiment was carried out in OMP-Lu68 tumors, a patient derived SCLC tumor which expresses Notch3 and Notch2, the targets of tarextumab. The experiment had two treatments phases - an "induction phase" where tumor bearing mice were treated with a high dose of chemotherapy with or without tarextumab and a "maintenance phase" where either tarextumab or control antibody treatments were continued. Established Lu68 lung tumors were treated with cisplatin or cisplatin plus tarextumab and it was observed that coadministration of tarextumab with cisplatin led to an increased rate of tumor regression relative to cisplatin alone (Figure 1). Continued treatment with tarextumab during the maintenance phase significantly delayed the rate of tumor recurrence (Figure1).  
()
A similar experiment was carried on the Lu87 SCLC xenograft model. In this case we used carboplatin plus irinotecan as the chemotherapeutic regimen. We found that tarextumab treatment led to a significant delay in tumor regrowth after the initial response to chemotherapeutic treatment Figure 2. The design of these pre-clinical tumor recurrence experiments was intended to model the PINNACLE trial design - combination of tarextumab plus chemotherapy followed by tarextumab only in the maintenance phase. Irinotecan was chosen as a chemotherapeutic agent for these pre-clinical studies because both irinotecan and etoposide are topoisomerase inhibitors and irinotecan is much better tolerated in mice than etoposide. Similarly, we have found that carboplatin is generally better tolerated than cisplatin in our pre-clinical studies. These data in Lu87 establish that tarextumab can be efficacious in combination with chemotherapeutic regimens that include carboplatin. Additional studies in several other SCLC tumors also showed that tarextumab was efficacious in combination with carboplatin (data not shown). In addition to these tumor recurrence experiments, we also found that tarextumab inhibited tumor growth in combination with Taxol in Lu40 SCLC tumors (Figure 3) and as a single agent in Lu61 SCLC tumors (Figure 4).
clinical protocol
figure 1 activity of tarextumab

,19(67,*$7,21$/1(:'58* ()
Figure 2: Activity of Tarextumab in 87 SCLC Tumor Recurrence Model in Combination with Carboplatin plus Irinotecan  
  
Legend: Lu87 tumor cells were implanted in Nod-Scid mice and allowed to grow until the average tumor volume was ~ 180 mm3. Tumor bearing mice were randomized into two groups and treated with either carboplatin and irinoecan plus control antibody or carboplatin and irinotecan plus tarextumab. After three weeks, the carboplatin and irinotecan treatments were discontinued and the antibody treatment schedule was maintained. Tarextumab was dosed at 40 mg/kg every two weeks. Carboplatin and irinotecan were dosed at 20 mg/kg once per week for the first two week and 10 mg/kg once per week for the third dose. There were 8 animals per in control group and seven animals in the 59R5. The mean + SEM for each group is shown.  
Figure 3: Tarextumab Inhibits Growth of Lu40 SCLC Tumors in Combination with Taxol  
  
Legend: Lu40 tumor cells were implanted in Nod-Scid mice and allowed to grow until the average tumor volume was ~ 150 mm3. Tumor bearing mice were randomized into four groups (n = 10 per group) and treated with either Control Ab, tarextumab, Taxol, or the combination of tarextumab and Taxol. Tarextumab was dosed at 40 mg/kg every two weeks and Taxol was dosed at 10 mg/kg once per week. Tumor measurements were taken on the indicated days and the mean + SEM for each group is shown.  
Figure 4: Tarextumab Inhibits Growth of Lu61 SCLC Tumors
clinical protocol
summary

Collectively, our data show that inhibiting Notch signaling with tarextumab results in anti-tumor activity in several SCLC xenografts. Importantly, tarextumab treatment can increase response to chemotherapy treatment and delay tumor re-growth after initial tumor shrinkage in response to chemotherapy. Given the urgent need for new therapeutic options for treatment of SCLC, we plan to explore the utility of this antibody in clinical testing in SCLC in combination with chemotherapy.
clinical protocol
3.4 clinical background

The first-in-human clinical trial of tarextumab (Study 59R5-001) began with a single-agent multiple dose escalation study in subjects with solid tumors. Subjects were treated in escalating dose cohorts of 0.5, 1, 2.5, and 5 mg/kg administered IV weekly. Additionally, escalating dose cohorts of 5, 7.5, and 10mg/kg administered IV every other week, and 7.5mg/kg every three weeks were tested as well. As of April 25, 2013, a total of forty-two subjects have been treated in Study 59R5-001: three at 0.5 mg/kg weekly, three at 1 mg/kg weekly, six at 2.5 mg/kg weekly, nine at 5 mg/kg weekly, six at 5 mg/kg every other week, six at 7.5mg/kg every other week, three at 10 mg/kg every other week, and six at 7.5mg/kg every three weeks.
clinical protocol
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()
Two DLTs occurred in two of nine subjects treated at 5 mg/kg weekly: one Grade 3 hypokalemia secondary to Grade 3 diarrhea in one subject and one Grade 3 diarrhea in another subject, which led to the MTD for weekly dosing schedule to be 2.5 mg/kg. No DLTs occurred in 6 subjects treated at 7.5 mg/kg every three weeks that led to the MTD for every three week schedule to be 7.5 mg/kg. Two DLTs both Grade 3 diarrhea, occurred in two of three subjects treated with a single dose of tarextumab at 10 mg/kg every other week and no DLTs occurred in 6 subjects treated at 7.5 mg/kg every other week, which led to the MTD for every other week schedule to be 7.5 mg/kg every other week. Toxicities observed to date have been mostly Grades 1 and 2, and were manageable with supportive care and/or interruption or dose reduction of tarextumab. There were no AEs of a Grade 4 severity reported. AEs with a severity of Grade 3 were uncommon and have been primarily diarrhea. Diarrhea has been the most common adverse event, occurring in 81% (34 of 42) of subjects treated on the study regardless of schedule, which was expected based on the observance of diarrhea in the cynomolgus monkey toxicology study. Diarrhea was observed at 2.5 mg/kg weekly and above dose cohorts, and was dose dependent. Table 2 below tabulates the incidence and worse severity of diarrhea occurred while receiving tarextumab among dose levels according NCI-CTCAE criteria v4.02.  
| Diarrhea   | 0.5 mg/kg            |                        |                      |                       |                        |                         |                         |    |
|------------|----------------------|------------------------|----------------------|-----------------------|------------------------|-------------------------|-------------------------|----|
| Grade      | QW                   |                        |                      |                       |                        |                         |                         |    |
| (n=2/3)    | 1 mg/kg  QW  (n=0/3) | 2.5 mg/kg  QW  (n=6/6) | 5 mg/kg  QW  (n=8/9) | 5 mg/kg  QoW  (n=4/6) | 10 mg/kg  QoW  (n=3/3) | 7.5 mg/kg  Q3W  (n=5/6) | 7.5 mg/kg  QoW  (n=6/6) |    |
| 1          | 1                    | -                      | 3                    | 4                     | 3                      | -                       | 4                       | 3  |
| 2          | 1                    | -                      | 3                    | 2                     | -                      | -                       | 1                       | 3  |
| 3          | -                    | -                      | -                    | 2                     | 1                      | 3                       | -                       |    |  
Additional common treatment-related adverse events included (as of November 17, 2012 data cutoff with 39 subjects treated) fatigue (30.8%), nausea (28.2%), decreased appetite (17.9%), vomiting (15.4%), increased alanine transaminase (ALT) (10.3%), hypokalemia (15.4 and dizziness (10.3%). Table 2 and Table 3 summarize all treatment related CTC Grade 3 adverse events that occurred in Study 59R5-001 by body system as of November 17, 2012; there were no Grade 4 or 5 events on study.  
()
Table 3: Study 59R5-001: Grade 3 Treatment Related Adverse Events by Body System (N=39)  
| Body System                                                               | Preferred Term     | Number of Subjects   |
|---------------------------------------------------------------------------|--------------------|----------------------|
| Gastrointestinal Disorders                                                | Diarrhea           | 6 (15.4%)            |
| Blood and Lymphatic System Disorders                                      | Anemia             | 2 (5.1%)             |
| Alanine Aminotransferase  Increased  Aspartate Aminotransferase  Increase | 1 (2.6%)  1 (2.6%) |                      |
| Investigations                                                            |                    |                      |
| Metabolism and Nutrition Disorders                                        | Hypokalaemia       | 2 (5.1%)             |
| General Disorders and Administration Site  Conditions                     | Fatigue            | 1 (2.6%)             |  
No RECIST complete or partial responses have been noted on this Phase 1 study. However, six subjects have had RECIST stable disease (SD) lasting greater than 56 days (ranging from 61 days to 165 days, all of them have come off the study). As of November 17, *2015*, twenty *seven* subjects have been treated in the current study (Study 59R5-003): three, three, six, three and *six* each at 5 mg/kg, 7.5 mg/kg, 10 mg/kg, 12.5 mg/kg and 15 mg/kg dose cohorts respectively with etoposide and cisplatin; one DLT of Grade 3 nausea was reported from a subject at 10 mg/kg dose cohort that lasted more than 48 hours despite daily IV fluids and antiemetics. The dose cohort of 10 mg/kg was expanded to enroll a total of 6 subjects. 15 mg/kg of tarextumab was the highest dose tested in Phase 1b and was selected for the Phase 2 portion of the study. To establish the safety and tolerability of this selected dose, tarextumab 15 mg/kg was administered in combination with etoposide and cisplatin to a cohort of 6 subjects. An additional 6 subjects were treated with tarextumab 15 mg/kg in combination with etoposide and carboplatin. As of April 19, 2016 a total of 119 subjects have been treated in Study 59R5-003 Phase 2 portion. 4 of these subjects have been treated with tarextumab 15 mg/kg or placebo in combination with etoposide and cisplatin and 115 subjects have been treated with tarextumab 15 mg/kg or placebo in combination with etoposide and carboplatin.  
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Tarextumab has been studied in a Phase 1b/2 study in combination with nab-paclitaxel and gemcitabine in subjects with previously untreated stage IV pancreatic cancer (Study 59R5-002, ALPINE). The study was initially conducted in combination with gemcitabine alone and was amended to incorporate nab-paclitaxel into the chemotherapy backbone in response to the changes in standard of care in this disease population. As of *November 17, 2015,* forty subjects have been treated in Phase 1b of Study 59R5-002: five and four at 2.5 mg/kg and 5.0 mg/kg respectively every other week in combination with gemcitabine at 1000 mg/m2 on Days 1, 8 and 15 of every 28 day cycle, four, six, six, three and twelve at 5 mg/kg, 7.5 mg/kg, 10 mg/kg, 12.5 mg/kg and 15 mg/kg respectively every other week in combination with nab-paclitaxel at 125 mg/m2 and gemcitabine at 1000 mg/m2 on Days 1, 8 and 15 of every 28 day cycle. No DLTs have been reported in the first 35 subjects. Dose escalation stopped at tarextumab 15 mg/kg as the highest dose tested in Phase 1b portion of the study. Tarextumab 15 mg/kg dose cohort was then expanded with 5 additional subjects treated, one of which had Grade 3 diarrhea that lasted for 5 days during the first cycle. Overall, tarextumab in combination with nab-paclitaxel and gemcitabine continued to be well tolerated up to 15 mg/kg. 15 mg/kg has been selected as the Phase 2 dose in ALPINE study. As of November 17, 2015, 177 subjects have been randomized with 172 subjects treated in Phase 2 portion of Alpine study. To date, tarextumab has been well tolerated up to 15 mg/kg. Among the 356 subjects treated through 17 November 2015, 23 (6.5%) subjects discontinued tarextumab/placebo treatment due to AEs, regardless of relationship. Toxicities observed to date have been mostly Grades 1 and 2, and manageable with supportive care and/or interruption or dose reduction of tarextumab. The most common (occurring in *25% of subjects) treatment emergent events are diarrhea (62.6%),* nausea (49.2%), thrombocytopenia (45.2%), neutropenia (26.7%), anemia (48%), vomiting (31.5%), fatigue (57.0%) and decreased appetite (28.7%). The most common (occurring in 25% of subjects) treatment related events are diarrhea (53.1%), fatigue (41.6%), thrombocytopenia (26.7%) and nausea (27.2%). Adverse events with a severity of Grade 3 that were considered related were uncommon and have been primarily diarrhea (9.6%), anemia (12.1%), thrombocytopenia (10.1%), neutropenia (7.6%) and fatigue (7.6%). Please refer to the updated Investigator Brochure for more details.
clinical protocol
exploratory phase 1b biomarker data

Exploratory biomarker data from the phase1b portion of the PINNACLE study shows a trend of improved outcome in patients with high Notch target genes i.e. Hes1, Hey2, Hey1 and Hes6 in the 12.5 mg/kg and 15 mg/kg cohorts. Figure 5: *Notch Genes and Overall Survival*  
  
Legend: Notch genes and overall survival. Expression of Notch3 gene levels and Notch target genes (Hes1, Hey2, Hey1, Hes6) was measured in FFPE tissues from 19 patients in the Phase1b portion of the trial. Biomarker high vs. low was set at a 50th percentile. Red lines include patients in the 5, 7.5, and 10 mg/kg cohorts and blue lines indicate patient in the 12.5 and 15 mg/kg cohorts.
clinical protocol
3.5 dose rationale

Treatment with EP is the standard of care for subjects with untreated extended stage small cell lung cancer. The most common AE of tarextumab is diarrhea, whereas cytopenia and nephrotoxicity (with cisplatin) are the most common adverse event with EP administration. Therefore, the most common AEs of tarextumab and EP do not overlap, providing the justification for investigating this combination in the study. The initial dose escalations of tarextumab will be conducted with etoposide and cisplatin. Subjects enrolled in this study will receive a starting dose of 5 mg/kg of tarextumab once every three weeks, which is one dose below the MTD of 7.5 mg/kg every three weeks in Study 59R5-001. Dose escalation will be 2.5 mg/kg per increment and will not exceed an tarextumab dose of 15 mg/kg. 15 mg/kg is twice of the single agent MTD of 7.5 mg/kg every three weeks established in Study 59R5-001 and pharmacodynamics modulation of the notch pathway was seen at 1 mg/kg above in tumor biopsies and surrogate tissues in Study 59R5-001, and at 7.5 mg/kg above in hair follicles in Study 59R5-002(Investigator Brochure Edition 04 dated January 15, 2014). Following the establishment of the highest tolerable dose of tarextumab in combination with etoposide and cisplatin, a cohort of 6 subjects will be treated at this highest tolerable dose in combination with etoposide and carboplatin. Once the safety and tolerability of tarextumab at this dose is confirmed with etoposide and cisplatin/carboplatin, the protocol will explore a Phase 2, multicenter, randomized, placebo-controlled portion comparing the efficacy and safety of tarextumab at the highest tolerable dose in combination with EP for 6 cycles followed by single agent tarextumab relative to EP alone for 6 cycles in subjects receiving first-line therapy for extensive stage small cell lung cancer. However, if a DLT is observed in 2 or more subjects in the cohort of 6 subjects treated with the highest tolerable dose of tarextumab with etoposide and carboplatin, a new cohort of 3 to 6 subjects will be enrolled at the next lower dose level of tarextumab with etoposide and carboplatin. The highest tarextumab dose that is tolerable with both platinum options will be used in Phase 2 portion of the study. For example: if tarextumab at 15 mg/kg is tolerable with etoposide and cisplatin, but not tolerable with etoposide and carboplatin and tarextumab at 12.5 mg/kg is tolerable with etoposide and carboplatin, then tarextumab at 12.5 mg/kg will be the dose used in Phase 2 portion of the study. In Phase 2 portion of the study, Subjects may be treated with cisplatin or carboplatin as determined by the Investigator prior to randomization. Alteration to the choice of platinum therapy is not permitted once the subject is randomized. Etoposide will be administered by IV infusion at a dose of 100 mg/m2 on Days 1, 2, and 3 of every 21-day cycle. Cisplatin will be administered by IV infusion at a dose of 80 mg/m2 in Phase 1b and 75 mg/m2 in Phase 2 portion of the study or carboplatin at AUC of 5 mg/mL•min on Day 1 of every 21-day cycle. This is the dose regimen for etoposide and platinum therapy commonly used in first line treatment for extensive stage small cell lung cancer. tarextumab has an estimated apparent half-life of 2 to 3 days at 7.5 mg/kg in Study 59R5-001, subjects will not receive PCI within 2 weeks of study drug administration and will not receive tarextumab during the radiation to alleviate any potential interaction between the study drug and the radiation. Therefore, risks and potential benefits of participation have been appropriately mitigated for this patient population.
clinical protocol
3.6 study conduct

This study will be conducted in compliance with the protocol approved by the Institutional Review Board (IRB) or Independent Ethics Committee (IEC), and in accordance with Good Clinical Practice (GCP) standards and all applicable regulatory requirements. No deviation from the protocol will be implemented without the prior review and approval of the IRB/IEC except where it may be necessary to eliminate an immediate hazard to a research subject. In such a case, the deviation will be reported to the IRB or IEC as soon as possible.
clinical protocol
3.7 subject population

Subjects must be at least 18 years of age, have adequate organ and marrow function, have an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1, have untreated extensive stage small cell lung cancer, and FFPE tumor tissue, either archived or fresh core needle biopsied for Notch3*, Hes1, Hey2, Hey1 and Hes6* analysis. Additionally for the Phase 2 portion of the study, subjects must have evidence of measurable disease by RECIST 1.1 criteria.
clinical protocol
4.0 study objectives and endpoints

Primary Objectives:  
- To determine the maximum tolerated dose (MTD) of tarextumab when administered on Day 1 of each 21 day cycle along with etoposide 100 mg/m2 on Days 1, 2 and 3 and cisplatin 80 mg/m2 or carboplatin AUC of 5 mg/mL•min on Day 1 in subjects with untreated extensive stage small cell lung cancer (Phase 1b portion)
- To determine the improvement in Progression Free Survival (PFS) resulting from the addition of tarextumab to etoposide and platinum therapy (EP) in subjects receiving first-line therapy for extensive stage small cell lung cancer (Phase 2 portion)
Secondary Objectives:  
- To determine the pharmacokinetics of tarextumab in combination with EP in subjects receiving first-line therapy for extensive stage small cell lung cancer (Phase 1b and 2 portions)
- To determine the immunogenicity of tarextumab in combination with EP in subjects receiving first-line therapy for extensive stage small cell lung cancer (Phase 1b and 2 portions)
- To estimate the improvement in overall survival (OS), 12 months OS, and the overall response rate (ORR) resulting from the addition of tarextumab to EP in subjects receiving first-line therapy for extensive stage small cell lung cancer (Phase 2 portion)
- To correlate the treatment effect in PFS, OS, 12 month OS and the ORR resulting from the addition of tarextumab to EP in subjects with Notch 3, Hey2, Hes1, Hey1 and Hes6 expression (Phase 2 portion)
- To determine the safety and tolerability of tarextumab in combination with EP in subjects who are receiving first-line therapy for extensive stage small cell lung cancer (Phase 1b portion)
- To compare the safety and tolerability of tarextumab in combination with EP relative to EP
alone in all subjects who are receiving first-line therapy for extensive stage small cell lung cancer with Phase 2 portion)
Exploratory Objective:  
- To describe the changes in exploratory pharmacodynamic (PD) biomarkers, including Notch pathway related genes and proteins and circulating tumor cells following tarextumab treatment. (Phase 1b and 2 portions)
clinical protocol
5.0 overall study design and

The study consists of a Phase1b lead-in portion to determine the MTD of tarextumab in combination with EP for 6 cycles followed by treatment with tarextumab alone until unacceptable toxicity or progression of disease. The initial dose escalations of tarextumab will be conducted with etoposide and cisplatin. The dose of tarextumab will not exceed 15 mg/kg.  
Following the establishment of the highest tolerable dose of tarextumab in combination with etoposide and cisplatin, a cohort of 6 subjects will be treated at this dose in combination with etoposide and carboplatin. Once the safety and tolerability of tarextumab at this dose is also confirmed with etoposide and carboplatin, the protocol will explore a Phase 2, multicenter, randomized, Placebo-controlled portion comparing the efficacy and safety of tarextumab at the highest tolerable dose in combination with EP for 6 cycles followed by single agent tarextumab relative to EP alone for 6 cycles in subjects receiving first-line therapy for extensive stage small cell lung cancer. However, if a DLT is observed in 2 or more subjects in the cohort of 6 subjects treated with the highest tolerable dose of tarextumab with etoposide and carboplatin, a new cohort of 3 to 6 subjects will be enrolled at the next lower dose level of tarextumab with etoposide and carboplatin. The highest tarextumab dose that is tolerable with both platinum options will be used in Phase 2 portion of the study. In Phase 2 portion of the study, Subjects may be treated with cisplatin or carboplatin as determined by the Investigator prior to randomization. Alteration to the choice of platinum therapy is not permitted once the subject is randomized.  
Etoposide 100 mg/m2 will be administered on Days 1, 2 and 3 along with cisplatin 80 mg/m2 for Phase 1 b and 75 mg/m2 for Phase 2 portion of the study or carboplatin at AUC of 5 mg/mL•min on Day 1 of every 21-day cycle for 6 cycles, tarextumab or Placebo will be given on Day 1 of every 21-day cycle prior to the administration of EP. Subjects may continue one of the chemotherapy drugs if the other is held or discontinued prior to completing 6 cycles of EP and prior to disease progression. Subjects should continue EP alone for a total of 6 cycles if tarextumab is held or discontinued prior to the completion of 6 cycles of EP. Subjects may continue study drug if one or both of the chemotherapy drugs is held or discontinued prior to completing 6 cycles of EP and prior to disease progression.
clinical protocol
5.1 phase 1b portion

The Phase 1b portion is to determine the MTD of tarextumab in combination with etoposide and cisplatin/carboplatin in subjects with previously untreated extensive stage small cell lung cancer. Initially, cohorts of 3 to 6 subjects with previously untreated extensive stage small cell lung cancer will be enrolled sequentially into successively higher tarextumab dose level in combination with etoposide 100 mg/m2 on Days 1, 2 and 3 and cisplatin 80 mg/m2 on Day 1 of every 21-day cycle for 6 cycles. The starting dose of OMP59R5 is 5 mg/kg. Dose escalation will be 2.5 mg/kg per increment and will not exceed an tarextumab dose of 15 mg/kg. Subjects at each dose level will be treated and observed for DLT through the end of the first cycle (21 days). Each subject will participate in only 1 cohort. Once the highest tolerable dose is determined with tarextumab in combination with etoposide and cisplatin, a cohort of 6 subjects will be treated at this dose with etoposide and carboplatin to confirm the safety and tolerability of this dose with etoposide and carboplatin. Carboplatin will be given at AUC of 5 mg/mL•min on Day 1 of every 21- day cycle for 6 cycles in combination with etoposide 100 mg/m2 on Days 1, 2, and 3. If a DLT is observed in 2 or more subjects in the cohort of 6 subjects treated with the highest tolerable dose of tarextumab with etoposide and carboplatin, a new cohort of 3 to 6 subjects will be enrolled at the next lower dose level of tarextumab with etoposide and carboplatin. Subjects may continue one of the chemotherapy drugs if the other is held or discontinued prior to completing 6 cycles of EP and prior to disease progression. For subjects who have tarextumab held or discontinued for tolerability reasons, EP chemotherapy should continue to the completion of 6 cycles. Subjects may continue study drug if one or both of the chemotherapy drugs is held or discontinued prior to completing 6 cycles of EP and prior to disease progression. After the completion of 6 cycles of EP, subjects who do not have disease progression and have not had prophylactic cranial irradiation (PCI) or whole brain radiation (WBRT) prior to study entry and are good candidates for PCI per the Investigators should receive PCI within 8 weeks after the last dose of chemotherapy at a total dose of 25 Gy in 10 fractions. Subjects who do not receive PCI within 8 weeks after the last dose of chemotherapy can have PCI later during the study as determined by the Investigator. Tarextumab administration should continue at every 21-day cycle between the completion of chemotherapy and the initiation of PCI. PCI should not be initiated within 2 weeks of study drug administration and study drug will be held during the PCI treatment period. Subjects will resume tarextumab alone 14 days after completion of PCI, until disease progression or unacceptable treatment-related toxicities or withdrawal of consent (Appendix A). Subjects will discontinue study treatment if there is evidence of central nervous system (CNS) metastasis. Approximately 30 subjects will be enrolled into Phase 1b portion of the study, the exact number will depend on the number of dose levels assessed and the toxicities observed.
clinical protocol
5.2 dose limiting toxicity

Adverse events will be graded according to the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI-CTCAE) version 4.02 (see Study Reference Binder). Doselimiting- toxicity (DLT) is defined as either of the following tarextumab treatment-related toxicities occurring within the first 21 days (Cycle 1):  
-  Grade 3 non-hematologic toxicity except for Grade 3 electrolyte disturbances that respond to correction within 24 hours, or Grade 3 rash, diarrhea, nausea, vomiting, and mucositis that responds to standard medical supportive care within 48 hours;
- Grade 3 thrombocytopenia associated with Grade 2 hemorrhage or any Grade 4 thrombocytopenia;
- Grade 4 neutropenia lasting >7 days
- Grade 3 or 4 neutropenia of any duration associated with fever ≥ 38.3°C (101°F);
- Grade 4 anemia;
- Any clinically significant toxicity that occurs during the first 21 days or beyond Day 21 that in the judgment of the Investigators and Sponsor is dose-limiting.
clinical protocol
5.3 dose escalation plan

Initially, cohorts of 3 to 6 evaluable subjects with previously untreated extensive stage small cell lung cancer will be enrolled sequentially into successively higher tarextumab dose level in combination with etoposide 100 mg/m2 on Days 1, 2 and 3, and cisplatin 80 mg/m2 on Day 1 of every 21-day cycle for 6 cycles. Subjects at each dose level will be treated and observed for DLT through the end of the first cycle (21 days) to be considered evaluable for DLT determination. Each subject will participate in only 1 cohort. The starting dose of tarextumab is 5 mg/kg on Day 1 of each 21-day cycle. The subsequent dose level will be increased in 2.5 mg/kg increments (i.e., 7.5 mg/kg, 10 mg/kg, etc) until the MTD is reached but will not exceed an tarextumab dose of 15 mg/kg. Dose escalation will only proceed if no DLT is observed in a cohort of at least 3 subjects after discussion and agreement between the participating Investigators and Sponsor's Medical Monitor. If a DLT is observed in only 1 subject in a cohort of 3 subjects, an additional 3 subjects may be enrolled up to a total of 6 subjects at this dose level. Dose escalation will then proceed only if no more than 1 subject in the cohort of six subjects has experienced a DLT during the first cycle of treatment and after discussion and agreement between the participating Investigators and Sponsor's Medical Monitor.
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If a DLT is observed in 2 or more subjects in a cohort of 3 or 6 subjects, an additional 3 subjects will be enrolled for a total of 6 subjects at the previous lower dose level, if only 3 subjects were treated at that lower dose level. The Investigators and Sponsor, after their safety review, may elect to study a dose level that is intermediate to the current dose level and the next lower dose level previously studied, e.g. 6 mg/kg as an intermediate dose between 5 mg/kg and 7.5mg/kg. The level of dose de-escalation and a decision to go to an intermediate dose level will be determined after discussion between the participating Investigators and Sponsor's Medical Monitor prior to dose escalation. If a DLT is observed in 2 or more subjects in a cohort of 3 to 6 subjects treated with the starting dose of 5 mg/kg, a new cohort of 3 to 6 subjects will be enrolled at either 2.5 mg/kg or an intermediate dose level between 2.5 mg/kg and 5 mg/kg. Table 4 below provides a summary of the dose escalation decision rules for determination of the MTD.
clinical protocol
5.4 maximum tolerated dose

The MTD is defined as the highest dose level of tarextumab at which no more than 1 out of 6 subjects experiences DLT during the first cycle (21 days) of therapy with etoposide and cisplatin. Dose escalation will not continue beyond 15 mg/kg of tarextumab. Table 4 provides a summary of the dose escalation decision rules for determination of the MTD.
clinical protocol
table 4 maximum tolerated dose

| Number of Subjects per Cohort With  a DLT During Cycle 1 (Days 1 to 21)                | Dose Escalation Decision Rule                                                                                                                                                                                                                                                                                                                                                                                                                                                  |
|----------------------------------------------------------------------------------------|--------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|
| 0 out of 3                                                                             | Enter at least 3 subjects at the next dose level.                                                                                                                                                                                                                                                                                                                                                                                                                              |
| 1 out of 3                                                                             | Enter up to 3 more subjects at this dose level.  If none of the 3 additional subjects has a DLT, proceed to the  next dose level.  If 1 or more of the 3 additional subjects has a DLT, then dose  escalation will be stopped, and the MTD will have been  exceeded. Up to 3 additional subjects may be entered at a lower  dose level if only 3 subjects were treated previously at that dose  or a new cohort of 3 subjects at an intermediate dose level may  be evaluated. |
| ≥2                                                                                     | Dose escalation will be stopped, and the MTD will have been  exceeded. Up to 3 additional subjects may be entered at a lower  dose level if only 3 subjects were treated previously at that dose  or a new cohort of 3 subjects at an intermediate dose level may  be evaluated.                                                                                                                                                                                               |
| ≤1 out of 6 at the highest dose                                                        | This is generally the MTD.                                                                                                                                                                                                                                                                                                                                                                                                                                                     |
| evaluated.  Abbreviations: DLT = dose limiting toxicity; MTD = maximum tolerated dose. |                                                                                                                                                                                                                                                                                                                                                                                                                                                                                |  
All participating sites are required to send in DLT Notification Forms within 24 hours of learning of the event. Participating investigators and the Sponsor's Medical Monitor will review study drug-related toxicities from the current dose before escalating to the next dose.  
Once the highest tolerable dose is determined with tarextumab in combination with etoposide and cisplatin with 15 mg/kg as the highest dose of tarextumab being tested, a cohort of 6 subjects will be treated at this dose with etoposide and carboplatin (AUC 5 mg/mL•min on on Day 1 of every 21-day cycle for 6 cycles) to confirm the safety and tolerability of this dose with etoposide and carboplatin before commencing the Phase 2 portion of the study. However, if a DLT is observed in 2 or more subjects in the cohort of 6 subjects treated with the highest tolerable dose of tarextumab with etoposide and carboplatin, a new cohort of 3 to 6 subjects will be enrolled at the next lower dose level of tarextumab with etoposide and carboplatin. The highest tarextumab dose that is tolerable with both platinum options will be used in Phase 2 portion of the study. For example: if tarextumab at 15 mg/kg is tolerable with etoposide and cisplatin, but not tolerable with etoposide and carboplatin and tarextumab at 12.5 mg/kg is tolerable with etoposide and carboplatin, then tarextumab at 12.5 mg/kg will be the dose used in Phase 2 portion of the study.
clinical protocol
5.4.1 follow-up

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. Additionally, subjects who are discontinued from study treatment will be followed for survival and any subsequent anti-cancer therapies. Survival follow-up information and subsequent anticancer 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 starting from the last study treatment 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.
clinical protocol
5.5 phase 2 portion

Phase 2 portion may commence after the safety and tolerability of the highest tolerable dose of OMP 59R5 has been confirmed in both cohorts of subjects with etoposide and cisplatin/carboplatin during Phase 1b. The highest tarextumab dose that is tolerable with both platinum options will be used in the Phase 2 portion of the study. For example: if tarextumab at 15 mg/kg is tolerable with etoposide and cisplatin, but not tolerable with etoposide and carboplatin and tarextumab at 12.5 mg/kg is tolerable with etoposide and carboplatin, then tarextumab at 12.5 mg/kg will be the dose used in Phase 2 portion of the study. The Phase 2 portion includes a blinded treatment phase and follow-up phase. It is a multicenter, randomized, placebo-controlled portion evaluating the efficacy and safety of tarextumab in combination with etoposide and platinum therapy in subjects with previously untreated extensive stage small cell lung cancer. Subjects may be treated with cisplatin or carboplatin as determined by the Investigator prior to randomization. Alteration to the choice of platinum therapy is not permitted once the subject is randomized. Approximately 135 evaluable subjects will be enrolled to the Phase 2 portion of the study. Evaluable subjects are those who received at least one dose of study drug (either tarextumab or Placebo).
clinical protocol
5.5.1 blinded treatment phase

Subjects who qualify for enrollment into the Phase 2 portion of the study will be randomized in a 1:1 ratio to receive study treatment of EP with Placebo or EP with tarextumab. The randomization will be balanced on the choice of platinum therapy (cisplatin versus carboplatin) and the prior use of whole brain radiation or prophylactic cranial irradiation). Alteration to the choice of platinum therapy is not permitted once the subject is randomized. Treatment for each subject will begin on Study Day 1 (the first dosing day). Etoposide 100 mg/m2 will be given on Days 1, 2 and 3 and cisplatin 75 mg/m2 or carboplatin AUC of 5 mg/mL•min will be given on Day 1 of every 21-day cycle for 6 cycles. Subjects may remain in the Blinded Treatment Phase to continue one of the chemotherapy drugs if the other is held or discontinued prior to completing 6 cycles of EP and prior to disease progression. For subjects who have study drug held or discontinued for tolerability reasons, EP chemotherapy should continue to the completion of 6 cycles. Subjects may continue study drug if one or both of the chemotherapy drugs is held or discontinued prior to completing 6 cycles of EP and prior to disease progression.
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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 (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
5.5.2 follow-up

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. Additionally, 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 starting from the last study treatment 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.
clinical protocol
6.0 selection of study population

Subjects must meet all of the following criteria to be eligible for the study:  
1. Histologically or cytologically documented extensive stage small cell lung cancer (combined small cell carcinoma is allowed); extensive stage is defined as disease beyond the ipsilateral hemithorax, including malignant pleural or pericardial effusion or hematogenous metastases (contralateral mediastinal and ipsilateral supraclavicular lymphadenopathy are generally classified as limited disease).  
2. Adults of 18 years of age or older. 3. Performance Status (ECOG) of 0 or 1. 4. FFPE tumor tissue, either fresh core needle biopsied (two fresh cores preferred whenever possible), or archived available for Notch3, *Hes1, Hey2, Hey1 and Hes6* analysis.  
5. Adequate organ function:
a. Adequate hematologic function (absolute neutrophil count [ANC]  1,500 cells/ȝL;
hemoglobin  9 g/dL, platelets  100,000/ȝL).  
b. Adequate renal function (serum creatinine  1.5 mg/dL or calculated creatinine clearance 60 mL/min using Cockroft Gault formula).  
c. Adequate hepatic function (alanine aminotransferase [ALT]  3 x upper limit of normal
[ULN], ALT may be  5 x ULN if due to liver metastases but cannot be associated with concurrent elevated bilirubin > 1.5xULN unless it is approved by the Sponsor's Medical Monitor).  
d. Prothrombin Time (PT)/International Normalized Ration (INR)  1.5 × ULN, activated partial thromboplastin time (aPTT)  1.5 × ULN.  
6. Written consent on an IRB/IEC-approved Informed Consent Form prior to any study-specific evaluation.  
7. For women of child-bearing potential, negative serum pregnancy test at screening and use of physician-approved method of birth control from 30 days prior to the first study drug administration to 30 days following the last study drug administration or the last EP in the study, whichever is discontinued last.  
8. Male subjects must be surgically sterile or must agree to use physician-approved contraception during the study and for 30 days following the last study drug administration or the last EP in the study, whichever is discontinued last.
clinical protocol
additionally for individuals eligible to

9. Subject must have evidence of measurable disease per RECIST 1.1 criteria.
clinical protocol
6.2 exclusion criteria

Subjects who meet any of the following criteria will not be eligible for participation in the study:  
1. Limited stage small cell lung cancer appropriate for radical treatment with chemoradiation.
2. Prior therapy including radiation, chemotherapy or surgery for newly diagnosed extensive stage small cell lung cancer. Exceptions to this exclusion criterion include: 1) prophylactic cranial irradiation or whole brain radiation (WBRT) prior to the first administration of study drug provided that the subject has stable neurologic condition for at least 2 weeks after the completion of the radiation, adverse event that is related to the radiation has recovered to be Grade 1, and is not requiring corticosteroid of > 40 mg prednisone daily equivalent dose to control the symptoms, 2) focused radiation for symptomatic relief for isolated bone metastases; 3) bisphosphonate or denosumab therapy for bone metastasis initiated prior to study entry.  
3. Presence of uncontrolled Grade  1 diarrhea within 4 weeks prior to the first study drug administration.  
4. Presence of any serious or uncontrolled illness including, but not limited to: ongoing or active infection, symptomatic congestive heart failure unstable angina pectoris, uncontrolled cardiac arrhythmia, uncontrolled arterial thrombosis, symptomatic pulmonary embolism, and psychiatric illness that would limit compliance with study requirement.  
5. History of myocardial infarction, acute coronary syndromes (including unstable angina),
coronary angioplasty and/or stenting within 6 months prior to the first administration of study drug.  
6. A history of malignancy with the exception of:
a. Adequately treated basal cell carcinoma, squamous cell carcinoma of the skin, or in situ cervical cancer b. Superficial bladder cancer
c. Adequately treated stage I cancer from which the subject is currently in remission, or  
d. Any other cancer from which the subject has been disease-free for  3 years 7. Known human immunodeficiency virus (HIV) infection. 8. Females who are pregnant or breastfeeding. 9. Concurrent use of therapeutic warfarin (prophylactic low dose of warfarin, i.e., 1 mg daily for port catheter is allowed)
clinical protocol
6.3 removal of subjects from

Each subject has the right to withdraw from the study at any time without prejudice to further treatment. The Investigator must withdraw from the study any subjects who request to be withdrawn. A subject's participation in the study may be discontinued at any time at the discretion of the Investigator and in accordance with his/her clinical judgment. When possible, tests and evaluations listed for the treatment termination visit should be carried out approximately 4 weeks after the last administration of tarextumab or Placebo, etoposide, or platinum therapy, whichever is discontinued last, but before the initiation of new anti-cancer therapy. The sponsor must be notified of all subjects' withdrawals as soon as possible. The sponsor also reserves the right to discontinue participation by an individual Investigator or site for poor enrollment or noncompliance. If a subject fails to return for scheduled visits, a documented effort must be made to determine the reason. If the subject cannot be reached by telephone after 2 attempts, a certified letter should be send to the subjects requesting contact with the Investigator. This information should be recorded in the study records. Prior to enrollment into the study, the Investigator or designee must explain to each subject, that the subject's protected health information obtained during the study may be shared with the study sponsor, regulatory agencies, and IRB/EC in order to analyze and evaluate study results. It is the Investigator's responsibility to obtain written permission to use protected health information per country-specific regulations. If permission to use protected health information is withdrawn, it is the Investigator's responsibility to obtain a written request, to ensure that no further data will be collected from the subject and the subject will be removed from the study. Subjects may terminate study treatment due to:  
- Disease progression - Initiation of new anti-cancer therapy including 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 etoposide and cisplatin 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.  
- Initiation of a new intravenous bisphosphonate or denosumab more than 30 days after the first administration of study drug
- Development of toxicity that, in the Investigator's judgment, precludes further study participation
- Significant protocol violations or noncompliance on the part of the subject or Investigator - Discontinuation is in the subject's best interest and/or in the judgment of the Investigator - Lost to follow-up - Pregnancy
clinical protocol
6.4 subject identification and replacement

Each subject will be assigned a unique subject identifier. This unique identifier will be on all electronic case report form (eCRF) pages. In Phase 1b, subjects who withdraw from the study prior to completing Day 21 of Cycle 1 for reasons other than study drug-related toxicities will be replaced. In Phase 2, subjects who are randomized, but not dosed, will not be replaced. However, enrollment in the study will continue until 135 subjects are randomized and treated.
clinical protocol
7.0 treatment of subjects

Subjects will be given study drug in combination with EP. Study drug will be tarextumab in the Phase 1b portion, and either tarextumab or Placebo in the Phase 2 portion. Study drug will be administered by IV infusion on Day 1 of every 21-day cycle.  
The subject should not take two consecutive doses of study drug within 18 days.  
Etoposide will be administered by IV infusion at a dose of 100 mg/m2 over 30 to 60 minutes on Days 1, 2 and 3 of each 21-day treatment cycle for 6 cycles in accordance with institutional standard of care. The subject should not receive two Day 1 consecutive doses of etoposide within 18 days. A one day window will be allowed for each consecutive day of etoposide dosing (e.g. Day 2 and 3 dosing may occur on Day 3 and 4, or Day 3 and 5). Cisplatin or carboplatin will be the choice of platinum therapy. Initially, all subjects in Phase 1b will receive cisplatin until the MTD/highest tolerable dose is determined with tarextumab in combination with etoposide and cisplatin. After that, a cohort of 6 subjects will be enrolled to receive tarextumab at the MTD/highest tolerable dose with etoposide and carboplatin. Subjects in Phase 2 will receive cisplatin or carboplatin as determined by the Investigator prior to randomization.  
Cisplatin will be administered by IV infusion at a dose of 80 mg/m2 over 30 minutes to 2 hours on Days 1 of each 21-day treatment cycle for 6 cycles in accordance with institutional standard of care in Phase 1b and at 75 mg/m2 in Phase 2 portion of the study. The subject should not receive two cisplatin doses within 18 days. Carboplatin will be administered by IV infusion at a dose of AUC of 5 mg/mL•min over 15 minutes or longer on Days 1 of each 21-day treatment cycle for 6 cycles in accordance with institutional standard of care. The subject should not receive two carboplatin doses within 18 days.  
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On days when study drug is given together with etoposide and cisplatin/carboplatin, study drug should be given prior to etoposide and cisplatin/carboplatin administration. Subjects may continue one of the chemotherapy drugs if the other is held or discontinued prior to completing 6 cycles of EP and prior to disease progression. If tarextumab held or discontinued, subjects will continue to receive etoposide on days 1, 2, and 3, and platinum therapy on day 1 of each 21-day cycle for a total of 6 cycles. Subjects may continue study drug if one or both of the chemotherapy drugs is held or discontinued prior to completing 6 cycles of EP and prior to disease progression. 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 (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. The baseline weight should be used to calculate the total dose (mg) of the study drug, etoposide, and cisplatin throughout the study, unless the weight changes by >10%, in which case the current weight should be used to calculate the dose.  
In the absence of subjects meeting any of the withdrawal criteria (see Section 6.3), they may receive study treatment for up to 1 year at the discretion of the Investigator and beyond 1 year with the agreement of the Investigator and the Sponsor.
clinical protocol
7.1 study drug (tarextumab or

Please refer to the Pharmacy Manual for the details on tarextumab or Placebo preparation and administration.
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There is no provision for intra-subject dose escalation of study drug. Weight-based doses will not be recalculated unless there is a weight change 10%. Carboplatin dose needs to be recalculated in subjects who have  10% weight change from baseline. If a semipermanent peripheral or central line is used to administer the drug, the catheter should be flushed per institutional standard procedures prior to and at the end of each infusion and the line should NOT be used for blood draws when there is a post-dose PK sampling. 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.
clinical protocol
7.1.2 study drug description

Tarextumab is an IgG2 fully human monoclonal antibody that is directed against the Notch2/3 receptors.  
Tarextumab is a clear to opalescent, colorless to slightly yellow liquid and is supplied at a concentration of 10 mg/mL in 25-mL single-use glass vial filled to 20 mL to deliver at total of 200 mg per vial. Placebo is a clear to slightly opalescent, colorless to slightly yellow liquid formulation of 50mM Histidine, 100mM Sodium Chloride, 45mM Sucrose and 0.01% (v/v) Polysorbate-20, pH 6.0.
clinical protocol
7.1.3 study drug packaging

Labeling of the study drug vials and cartons will comply with all applicable regulations.
clinical protocol
7.1.4 study drug ordering storage

The instructions for drug ordering are provided in the Pharmacy Binder. The study drug vials must be stored at 2°C–8°C. DO NOT FREEZE. DO NOT SHAKE. An accurate study drug accountability log must be maintained and kept up to date at all times.
clinical protocol
7.1.5 study drug preparation

Please refer to the Pharmacy Manual for details on study drug preparation. Any unused portion left in a vial may not be used for another subject, as the product contains no preservative (i.e., they are single-use vials).
clinical protocol
7.2 etoposide 7.2.1 administration

Etoposide must be administered after the administration of the study drug, and prior to cisplatin on Day 1. Etoposide should be administered by IV infusion at a dose of 100 mg/m2 over 30 to 60 minutes on Days 1, 2, and 3 of every 21-day cycle.
clinical protocol
7.2.2 description

Etoposide (also commonly known as VP-16) is a semisynthetic derivative of podophyllotoxin used in the treatment of certain neoplastic diseases. The chemical name for etoposide is 4'-Demethylepipodophyllotoxin 9-[4,6-O-(R)-ethylidene-ȕ-D-glucopyranoside], 4'-(dihydrogen phosphate).
clinical protocol
7.2.3 storage

Etoposide should be stored in a controlled setting according to the instructions of the package insert.
clinical protocol
7.3 cisplatin 7.3.1 administration

Cisplatin must be administered after the administration of the study drug and etoposide on Day 1.  
Cisplatin should be administered by IV infusion at a dose of 80 mg/m2 over 30 minutes to 2 hours on Day 1 of every 21-day cycle for Phase 1b and 75 mg/m2 for Phase 2 portion of the study.
clinical protocol
7.3.2 description

Cisplatin is a platinum containing anti-cancer drug used mainly in solid malignancies. The chemical name for cisplatin is (SP-4-2)-diamminedichloridoplatinum.
clinical protocol
7.3.3 storage

Cisplatin must be stored at 15°C–25°C (59°F–77°F) in a controlled setting. Do not refrigerate. Protect the contents from light.
clinical protocol
7.4 carboplatin 7.4.1 administration

Carboplatin must be administered after the administration of the study drug and etoposide on Day 1. Carboplatin should be administered by IV infusion at a dose of AUC of 5 mg/mL•min over 15 minutes or longer on Day 1 of every 21-day cycle per package insert. Using Calvert formula for carboplatin dosing, the total carboplatin is calculated in mg, total dose (mg) = target AUC of 5 x (GFR+25).
clinical protocol
7.4.2 description

Carboplatin is a platinum containing anti-cancer drug used mainly in solid malignancies. The chemical name for Carboplatin is platinum, diammine[1,1-cyclobutanedicarboxylato(2-)-O,O']-, (SP-4-2).
clinical protocol
7.4.3 storage

Carboplatin must be stored at 15°C–30°C (59°F–86°F) in a controlled setting. Do not refrigerate. Protect unopened vials from light. Solutions for infusion should be discarded 8 hours after preparation.