b. secondary data collection n/a
exclusion criteria

Pregnant or breastfeeding, or expecting to conceive or father children within the 1.  
projected duration of the trial, starting with the pre-screening or screening visit through 23 weeks (female) or 31 weeks (male) after the last dose of study drug.  
Treatment with any investigational agent within 28 days prior to registration for protocol therapy. 3. History of psychiatric illness or social situations that would limit compliance with study requirements.  Has a history or current evidence of any condition, therapy, or laboratory abnormality that might confound the results of the trial, interfere with the subject's participation for the full duration of the trial, or is not in the best interest of the subject to participate, in the opinion of the treating investigator.  
4. Known active, untreated central nervous system (CNS) metastases and/or carcinomatous meningitis except for patients with ≤ 3 small (< 0.6 cm) asymptomatic brain lesions where treatment is not indicated. Patients with neurological symptoms must undergo a head computed tomography (CT) scan or brain magnetic resonance imaging (MRI) to exclude brain metastasis. Patients whose brain metastases have been treated may participate provided they show radiographic stability (defined as 2 brain images obtained after treatment to the brain metastases at least 4 weeks apart and show no evidence of intracranial progression)  
  
  
Atezolizumab and with Metastatic NSCLC  
  
5. Known history of human immunodeficiency virus (HIV) or active hepatitis B (by surface antigen expression or polymerase chain reaction [PCR]) or active hepatitis C (by PCR) infection.  
Diagnosis of immunodeficiency or is receiving systemic steroid therapy (>10 mg daily 6.  
prednisone equivalent) or any other form of immunosuppressive therapy within 7 days prior to study registration.  
7.  
Has active autoimmune disease that has required systemic treatment in the past 2 years
(i.e., with use of disease modifying agents, corticosteroids, or immunosuppressive drugs) or a documented history of clinically severe autoimmune disease, or a syndrome that requires systemic steroids or immunosuppressive agents. Vitiligo, alopecia, hypothyroidism only requiring hormone replacement, psoriasis not requiring systemic treatment, celiac disease controlled by diet alone or conditions not expected to recur in the absence of an external trigger are permitted.  
8. Documented history of a cerebral vascular event (stroke or transient ischemic attack), unstable angina, myocardial infarction, or cardiac symptoms consistent with New York Heart Association (NYHA) Class III–IV within 6 months prior to their first dose of study drugs. 9.   Prior malignancies (except non-melanoma skin cancers, and the following in situ cancers: bladder, gastric, colon, endometrial, cervical/dysplasia, melanoma, or breast) unless a complete remission was achieved at least 1 year prior to study entry.  
10. Any active grade 3 or higher viral, bacterial, or fungal infection within 2 weeks of the first dose of the study drugs. Routine antimicrobial prophylaxis is permitted.  
1. Active diverticulitis 12. History of idiopathic pulmonary fibrosis, pneumonitis (including drug-induced), organizing pneumonia (i.e., bronchiolitis obliterans, cryptogenic organizing pneumonia, etc.), or evidence of active pneumonitis on screening chest CT scan. History of radiation pneumonitis in the radiation field (fibrosis) is permitted.
b. secondary data collection n/a
4.2 secondary subjects n/a 4.3

A. Total Number of Subjects We plan to enroll 15 patients on the study. Approximately 25-30 patients will be screened for enrollment.  
B. Total Number of Subjects If Multicenter Study N/A
C. Feasibility The patients will be enrolled over a period of one year. More than 50 patients meeting the eligibility criteria are treated at the Rutgers Cancer Institute every year.  
  
  
DO NOT
4.4 Consent Procedures A. Consent Process
b. secondary data collection n/a
location of consent process

Ongoing Consent
.  
N/A
Individual Roles for Researchers Involved in Consent Consent will be obtained by the study personnel (the treating physician and the research nurse)
Consent Discussion Duration
.  
30-60 minutes Coercion or Undue Influence
.  
Both the treating physician and research nurse will explain to the subject that participation in study is completely voluntary and subject can withdraw consent at any time. The informed consent document may not include any exculpatory language through which the subject or representative is made to waive any of the subject's legal rights or releases, or appears to release the investigator, the sponsor or the institution from liability for negligence.  
Subject Understanding
.  
Subject will be provided a copy of the signed consent and encouraged to ask questions about the consent. The information given to the patient, or the representative, shall be in a language understandable to the subject or representative.
b. secondary data collection n/a
b. waiver or alteration of

N/A
C.  Documentation of Consent Documenting Consent The subject's signed and dated informed consent must be obtained before conducting any procedure specifically for the study. The site investigator must store the original, signed informed consent form. A copy of the signed informed consent form must be given to the subject.  
.  
Waiver of Documentation Of Consent (i.e., will not obtain subject's signature)
N/A
4.5 Special Consent/Populations A.  Minors-Subjects Who Are Not Yet Adults N/A
B.  Wards of the State N/A
C.  Non-English-Speaking Subjects Process for Non-English-Speaking Subjects 59 DO NOT  
  
  
If subjects who do not speak English will be enrolled, a phone translator will be used  
  
to discuss the study as well as the consent in detail. A translator will also be used at each study visit during the physical examination and adverse event assessment.  
Short Form Consent for Non-English Speakers A consent short form for non-English speakers will be used.  
.  
D.  Adults Unable to Consent / Cognitively Impaired Adults (for interventional studies)
N/A
4.6 Economic Burden and/or Compensation for Subjects A. Expenses Costs for all research related testing such as required biopsy on the study will be covered by the study.  
B.  Compensation/Incentives No compensation for participating in the study will be provided to the study subjects.  
C.  Compensation Documentation N/A
4.7 Risks of Harm/Potential for Benefits to Subjects A.  Description of Risks of Harm to Subjects Reasonably Foreseeable Risks of Harm
.  
The study drug may have side effects that may be expected or unexpected. The expected side effects are discussed in the consent. All adverse events will be reported timely according to institutional guidelines.  
Risk of Harm from an Intervention on a Subject with an Existing Condition
.  
N/A
Other Foreseeable Risks of Harm
.  
There is a slight risk of loss of confidentiality of subject information.  
Observation and Sensitive Information
.  
N/A
B.  Procedures which Risk Harm to Embryo, Fetus, and/or Pregnant Subjects N/A
C.  Risks of Harm to Non-Subjects N/A
N/A
.  
D.  Assessment of Social Behavior Considerations E.   Minimizing Risks of Harm Certificate of Confidentiality N/A
Provisions to Protect the Privacy Interests of Subjects
.  
All records identifying the subjects will be kept confidential and, to the extent permitted by the applicable laws and/or regulations, will not be made publicly available. Information collected will be maintained on secure, password protected  
  
60  
  
DO NOT  
  
electronic systems. Paper files that contain personal information will be kept in locked and secure locations only accessible to the study site personnel. Subjects will be informed in writing that some organizations including the sponsor-investigator and his/her research associates. Celldex. IRB, or government agencies, like the FDA.  
may inspect their medical records to verify the information collected, and that all personal information made available for inspection will be handled in strictest confidence and in accordance with local data protection laws. If the results of the study are published, the subjects' identity will remain confidential.  
F.  Potential Benefits to Subjects Subjects may or may not derive clinical benefit from the study therapy depending on the response of their tumor to the study treatment.
b. secondary data collection n/a
5.0 special considerations

5.1 Health Insurance Portability and Accountability Act (HIPAA)
Personal identifiers will not be used for reporting results or shared with anyone other than the study personnel.  
5.2 Family Educational Rights and Privacy Act (FERPA)
N/A
5.3 NJ Access to Medical Research Act (Surrogate Consent)
N/A
5.4 General Data Protection Regulation (GDPR)
N/A
5.5 Code of Federal Regulations Title 45 Part 46 (Vulnerable Populations)
N/A
b. secondary data collection n/a
6.0 data management plan 6.1

Objective Response Rate (ORR): ORR to protocol treatment will be evaluated by irRECIST, and the best overall response will be classified as complete response (CR), partial response (PR), stable disease, progressive disease (PD), and not evaluable (NE).  
ORR is defined as the proportion of patients with a best overall response of CR or PR, divided by the number of assigned patients. CT scans at baseline and during the study will be reviewed by study investigators to determine objective response, date of response and progression.  
Progression-free Survival (PFS)
PFS is time from randomization to the first documented tumor progression, or death due to any cause whichever occurred first. PFS time of any living patient with no documented progression, or any patient starting other cytotoxic and/or cytostatic therapies, will be  
  
61  
  
  
  
censored at the date of last evaluable disease assessment on-study. PFS time of patients with no evaluable disease assessment on-study will be censored at randomization. The logrank test will be used to analyze PFS for comparison of treatment effects, i.e., the only covariate that will be used is the treatment arm. Distributions of PFS times will be estimated using the Kaplan- Meier product-limit method. The median PFS times with two-sided 95%
CIs will be estimated for each treatment group. For the definition of disease progression, refer to irRECIST version.
b. secondary data collection n/a
6.2 data security

All records identifying the subjects will be kept confidential and, to the extent permitted by the applicable laws and/or regulations, will not be made publicly available. Information collected will be maintained on secure, password protected electronic systems. Paper files that contain personal information will be kept in locked and secure locations only accessible to the study site personnel. Subjects will be informed in writing that some organizations including the sponsor-investigator and his/her research associates, Celldex, IRB, or government agencies, like the FDA, may inspect their medical records to verify the information collected, and that all personal information made available for inspection will be handled in strictest confidence and in accordance with local data protection laws.  
A research chart (i.e., shadow chart) is maintained at OHRS for each patient enrolled.  
Copies of significant study source documents will be maintained in the research chart. Examples of source document copies that will be maintained in the research chart include: signed informed consent form, documents that verify eligibility and treatment and documents that verify Grade 3-4 adverse events and response. This information will be updated on a prospective basis and will be confidentially maintained at the Cancer Institute of New Jersey, OHRS on the 5th floor in a locked cabinet. Only the key personnel delegated on the delegation of authority log are permitted to access these charts. All users of this system will complete user training, as required or appropriate per regulations.
b. secondary data collection n/a
6.3 data and safety monitoring

Monitoring of this study will occur in accordance with the Cancer Institute of New Jersey's NCI approved Data and Safety Monitoring Plan (DSMP).  The DSMP is enacted in part by the Human Research Oversight Committee (HROC). HROC is an established group within the Office of Human Research Services, and it is responsible for oversight of all therapeutic and non-therapeutic clinical trials conducted by RCINJ and it meets regularly to review deviations. HROC will serve as the Data Safety Monitoring Board (DSMB) for this clinical trial. All unexpected and serious adverse events will be reported to the DSMB
(as well as each institutional IRB and study sponsor) according to the reporting requirements and per the Rutgers University DSMP. An "initiation audit" will be conducted at the Subsequent audits will occur on an annual basis prior to annual IRB continuing review, if the findings from the initiation audit were satisfactory.  
More frequent audits of patient data and study conduct will occur if necessary.  Prior audit findings and/or situations that may arise during the course of the study will determine the need for more frequent auditing.  All audit findings will be Version Number: v6 MAR 23 RESERVED FOR IRB STAMP
Review Board.  
B.  Data/Safety Monitoring Board Details HROC will serve as the Data Safety Monitoring Board (DSMB) for this clinical trial.  
6.4 Reporting Results A.  Individual Subjects' Results Study results from research tests will not be shared with the study subjects.  
B.  Aggregate Results Aggregate research results will not be shared with study subjects.  
C.  Professional Reporting The policies and procedures of legal department (see: Investigator's Handbook) will govern publication of the trial.  It is expected that the results of this trial will be submitted for publication in a timely manner following the conclusion.  
any abstract or manuscript.  
D.  Clinical Trials Registration, Results Reporting and Consent Posting The trial will be registered on www.clinicaltrials.gov . A copy of the IRB-approved informed consent document and written justification for any changes made to the informed consent for this protocol must be on file at the patients are enrolled.  
6.5 Secondary Use of the Data Samples will be stored by the biorepository and data from these samples may be used for future research.  
7.0 Research Repositories - Specimens and/or Data All Samples for future research will be banked at the Biospecimen Repository. The biorepository supports transdisciplinary and translational research through costeffective, quality controlled biospecimen procurement and processing and cancer focused clinical trial support. The Biorepository follows best practices as dictated by the College of American Pathologists (CAP) guidelines.  
8.0 Approvals/Authorizations Approval will be obtained from Scientific Review Board (SRB) at and
b. secondary data collection n/a
9.0 bibliography

1.  
Jemal, A., et al., Global cancer statistics. CA Cancer J Clin, 2011. 61(2): p. 69-90.  
63 RESERVED FOR IRB STAMP
DO NOT  
  
2.  
w. 4.  
5.  
6.  
7.  
8.  
9.  
10.  
1.  
12. 13. 14.  
15.  
16.  
17.  
18.  
19.  
Siegel, R.L., K.D. Miller, and A. Jemal, Cancer statistics, 2015. CA Cancer J Clin, 2015. 65(1): p. 529.  
Gulley, J., et al., Avelumab (MSB0010718C), an anti-PD-L1 antibody, in advanced NSCLC patients: A phase 1b, open-label expansion trial in patients progressing after platinum-based chemotherapy. Journal of Clinical Oncology, 2015 ASCO Annual Meeting, Vol 33, No 15_suppl (May 20 Supplement), 2015: 8034. Aisner, D.L. and C.B. Marshall, Molecular pathology of non-small cell lung cancer: a practical guide. Am J Clin Pathol, 2012. 138(3): p. 332-46.  
Schiller, J.H., et al., Comparison of four chemotherapy regimens for advanced non-small-cell lung cancer. N Engl J Med, 2002. 346(2): p. 92-8.  
Kelly, K., et al., Randomized phase III trial of paclitaxel plus carboplatin versus vinorelbine plus cisplatin in the treatment of patients with advanced non--small-cell lung cancer: a Southwest Oncology Group trial. J Clin Oncol, 2001. 19(13): p. 3210-8. Weiss, J.M. and T.E. Stinchcombe, Second-Line Therapy for Advanced NSCLC. Oncologist, 2013.  
18(8): p. 947-53.  
Garon, E.B., et al., Ramucirumab plus docetaxel versus placebo plus docetaxel for second-line treatment of stage IV non-small-cell lung cancer after disease progression on platinum-based therapy (REVEL): a multicentre, double-blind, randomised phase 3 trial. Lancet, 2014. 384(9944):
p. 665-73. Rizvi, N.A., et al., Cancer immunology. Mutational landscape determines sensitivity to PD-1 blockade in non-small cell lung cancer. Science, 2015. 348(6230): p. 124-8.  
Rittmeyer, A., et al., Atezolizumab versus docetaxel in patients with previously treated nonsmall-cell lung cancer (OAK): a phase 3, open-label, multicentre randomised controlled trial.  
Lancet, 2017. 389(10066): p. 255-265.  
Dong, H.Y., A. Shahsafaei, and D.M. Dorfman, CD148 and CD27 are expressed in B cell lymphomas derived from both memory and naive B cells. Leuk Lymphoma, 2002. 43(9): p. 18558.  
Trentin, L., et al., B lymphocytes from patients with chronic lymphoproliferative disorders are equipped with different costimulatory molecules. Cancer Res, 1997. 57(21): p. 4940-7.  
Molica, S., et al., CD27 in B-cell chronic lymphocytic leukemia. Cellular expression, serum release and correlation with other soluble molecules belonging to nerve growth factor receptors (NGFr) superfamily. Haematologica, 1998. 83(5): p. 398-402.  
van Oers, M.H., et al., Expression and release of CD27 in human B-cell malignancies. Blood, 1993.  
82(11): p. 3430-6.  
Murase, S., et al., Increased levels of CSF soluble CD27 in patients with primary central nervous system lymphoma. Cancer Lett, 1998. 132(1-2): p. 181-6.  
Ranheim, E.A., M.J. Cantwell, and T.J. Kipps, Expression of CD27 and its ligand, CD70, on chronic lymphocytic leukemia B cells. Blood, 1995. 85(12): p. 3556-65. Shao, H., et al., Minimal residual disease detection by flow cytometry in adult T-cell leukemia/lymphoma. Am J Clin Pathol, 2010. 133(4): p. 592-601.  
Tang, C., et al., Combining radiation and immunotherapy: a new systemic therapy for solid tumors? Cancer Immunol Res, 2014. 2(9): p. 831-8.  
Dewan, M.Z., et al., Fractionated but not single-dose radiotherapy induces an immune-mediated abscopal effect when combined with anti-CTLA-4 antibody. Clin Cancer Res, 2009. 15(17): p. 5379-88.  
RESERVED FOR IRB STAMP
b. secondary data collection n/a
version number v6 mar 23

20. 21.  
2. 23. 24.  
25. 26. 27. 28. 29. 30. 31.  
32.  
3. 34.  
35.  
Golden, E.B., et al., An abscopal response to radiation and ipilimumab in a patient with metastatic non-small cell lung cancer. Cancer Immunol Res, 2013. 1(6): p. 365-72.  
Deng, L., et al., Irradiation and anti-PD-L1 treatment synergistically promote antitumor immunity in mice. J Clin Invest, 2014. 124(2): p. 687-95. Butts, C., et al., Tecemotide (L-BLP25) versus placebo after chemoradiotherapy for stage III nonsmall-cell lung cancer (START): a randomised, double-blind, phase 3 trial. Lancet Oncol, 2014.  
15(1): p. 59-68.  
Sharabi, A.B., et al., Stereotactic Radiation Therapy Augments Antigen-Specific PD-1-Mediated Antitumor Immune Responses via Cross-Presentation of Tumor Antigen. Cancer Immunol Res, 2015. 3(4): p. 345-55.  
Zeng, J., et al., Anti-PD-1 blockade and stereotactic radiation produce long-term survival in mice with intracranial gliomas. Int J Radiat Oncol Biol Phys, 2013. 86(2): p. 343-9.  
Luke, J.J., et al., Safety and Clinical Activity of Pembrolizumab and Multisite Stereotactic Body Radiotherapy in Patients With Advanced Solid Tumors. J Clin Oncol, 2018: p. JCO2017762229.  
Messenheimer, D.J., et al., Timing of PD-1 Blockade Is Critical to Effective Combination Immunotherapy with Anti-OX40. Clin Cancer Res, 2017. 23(20): p. 6165-6177.  
Salama, J.K., et al., An initial report of a radiation dose-escalation trial in patients with one to five sites of metastatic disease. Clin Cancer Res, 2008. 14(16): p. 5255-9.  
Al-Hallaq, H.A., et al., Rationale of technical requirements for NRG-BR001: The first NCI-
sponsored trial of SBRT for the treatment of multiple metastases. Pract Radiat Oncol, 2016. 6(6): p. e291-e298. Dovedi, S.J., et al., Acquired resistance to fractionated radiotherapy can be overcome by concurrent PD-L1 blockade. Cancer Res, 2014. 74(19): p. 5458-68.  
Taube, J.M., et al., Association of PD-1, PD-1 ligands, and other features of the tumor immune microenvironment with response to anti-PD-1 therapy. Clin Cancer Res, 2014. 20(19): p. 5064-74.  
Herbst, R.S., et al., Predictive correlates of response to the anti-PD-L1 antibody MPDL3280A in cancer patients. Nature, 2014. 515(7528): p. 563-7.  
Le, D.T., et al., PD-1 Blockade in Tumors with Mismatch-Repair Deficiency. N Engl J Med, 2015.  
372(26): p. 2509-20.  
Sharabi, A.B., et al., Radiation and checkpoint blockade immunotherapy: radiosensitisation and potential mechanisms of synergy. Lancet Oncol, 2015. 16(13): p. e498-509. Lim, S.H., et al., Effect of neoadjuvant chemoradiation on tumor-infiltrating/associated lymphocytes in locally advanced rectal cancers. Anticancer Res, 2014. 34(11): p. 6505-13.  
Wolchok, J.D., et al., Guidelines for the evaluation of immune therapy activity in solid tumors: immune-related response criteria. Clin Cancer Res, 2009. 15(23): p. 7412-20.
b. secondary data collection n/a
appendix a performance status criteria

| ECOG Performance Status Scale   |
|---------------------------------|
| Descriptions                    |  
  
| 65   |
|------|  
| DO NOT   |
|----------|  
  
  
| Normal activity.  Fully active, able to carry on all pre-   |                                                      |
|-------------------------------------------------------------|------------------------------------------------------|
| 0                                                           | disease performance without restriction.             |
| Symptoms, but ambulatory.  Restricted in physically         |                                                      |
| strenuous activity, but ambulatory and able to carry        |                                                      |
| out work of a light or sedentary nature (e.g., light        |                                                      |
| housework, office work).                                    |                                                      |
| In bed <50% of the time.  Ambulatory and capable            |                                                      |
| 2                                                           | of all self-care, but unable to carry out any work   |
| activities.  Up and about more than 50% of waking           |                                                      |
| hours.                                                      |                                                      |
| In bed >50% of the time.  Capable of only limited           |                                                      |
| 3                                                           | self-care, confined to bed or chair more than 50% of |
| waking hours.                                               |                                                      |
| 100% bedridden.  Completely disabled.  Cannot               |                                                      |
| 4                                                           | carry on any self-care.  Totally confined to bed or  |
| chair.                                                      |                                                      |
| Dead.                                                       |                                                      |  
Atezolizumab and with Metastatic NSCLC