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Immune response in patients with recurrent or metastatic non-small cell lung cancer and performance status of 2 treated with a combination of pembrolizumab and low dose weekly carboplatin/paclitaxel Comprehensive Cancer Center of Wake Forest University (CCCWFU)
CCCWFU \# 62415 Principal **Investigator:** W. Jeff Petty, MD
Section on Hematology and Oncology Wake Forest School of Medicine Co-Investigators: Pierre L. Triozzi, MD
Section on Hematology and Oncology Wake Forest School of Medicine Jimmy Ruiz, M.D.  
Section on Hematology and Oncology Wake Forest School of Medicine Thomas W. Lycan, Jr., D.O. Section on Hematology and Oncology Wake Forest School of Medicine Travis L. Dotson, M.D.  
Pulmonary and Critical Care Wake Forest School of Medicine Christina Bellinger, M.D. Pulmonary and Critical Care Wake Forest School of Medicine Stefan Grant, MD, JD Section on Hematology and Oncology Wake Forest School of Medicine Tamjeed Ahmed, M.D. Section on Hematology and Oncology Wake Forest School of Medicine Immune response in patients with recurrent or metastatic non-small cell lung cancer and performance status of 2 treated with a combination of pembrolizumab and low dose weekly carboplatin/paclitaxel Comprehensive Cancer Center of Wake Forest University (CCCWFU)
CCCWFU \# 62415  
| Biostatistician:                | Ralph B. D'Agostino Jr., PhD  Wake Forest School of Medicine Biostatistical Sciences - Biostatistics                                     |
|---------------------------------|------------------------------------------------------------------------------------------------------------------------------------------|
| Study Coordinator:              | Sharon Averill, RN Comprehensive Cancer Center of Wake Forest University                                                                 |
| Data Manager Contact:           | Amy Hughes Comprehensive Cancer Center of Wake Forest University                                                                         |
| Regulatory Contact:             | Emmanuel Vazquez Comprehensive Cancer Center of Wake Forest University                                                                   |
| Protocol Editor (original):     | Mac Robinson, PhD Comprehensive Cancer Center of Wake Forest University                                                                  |
| Participating Institution:      | CCCWFU                                                                                                                                   |
| Version Date:                   | 03/11/2020 07/17/19 01/28/19 07/20/18 06/20/18 09/15/17 06/01/17 04/10/17 03/22/17 01/24/17 11/30/16 10/18/16 08/24/16 06/13/16 04/28/16 |
| Amended: 3/12/2021 Confidential |                                                                                                                                          |  
Immune response in patients with recurrent or metastatic non-small cell lung cancer and performance status of 2 treated with a combination of pembrolizumab and low dose weekly carboplatin/paclitaxel Comprehensive Cancer Center of Wake Forest University (CCCWFU)
CCWFU \# 62415  
| Contents                                                                                         |                                                                                                                                                      |
|--------------------------------------------------------------------------------------------------|------------------------------------------------------------------------------------------------------------------------------------------------------|
| SCHEMA                                                                                           |                                                                                                                                                      |
| 1.1                                                                                              | Introduction and Background ...................................................................................................................6     |
| Recurrent or metastatic non-small cell lung cancer and performance status of 2 ............... 6 |                                                                                                                                                      |
| 1.2                                                                                              |                                                                                                                                                      |
| 1.3                                                                                              | Immunotherapies                                                                                                                                      |
| 1.3.1                                                                                            | Immunotherapies alone                                                                                                                                |
| 1.3.2                                                                                            | Immunotherapies in combination                                                                                                                       |
| 1.4                                                                                              | Study Rationale                                                                                                                                      |
| 2.1                                                                                              | O Objectives .                                                                                                                                       |
| 2.2                                                                                              | Primary Objectives                                                                                                                                   |
| 2.3                                                                                              | Secondary Objectives                                                                                                                                 |
| 3.1                                                                                              | Patient Selection                                                                                                                                    |
| 3.2                                                                                              | Inclusion Criteria .                                                                                                                                 |
| 3.3                                                                                              | Exclusion Criteria .                                                                                                                                 |
| 3.4                                                                                              | Inclusion of Women and Minorities                                                                                                                    |
| 4.1                                                                                              | Registration Procedures                                                                                                                              |
| Study Outcomes and Study Measures                                                                |                                                                                                                                                      |
| 5.1                                                                                              |                                                                                                                                                      |
| 5.2                                                                                              | Primary Outcomes .                                                                                                                                   |
| 5.3                                                                                              | Secondary Outcomes                                                                                                                                   |
| 6.1                                                                                              | T Treatment Plan                                                                                                                                     |
| 6.2                                                                                              | Study-Related Activities .                                                                                                                           |
| 6.3                                                                                              | Treatment Administration                                                                                                                             |
| 6.3.2                                                                                            | Paclitaxel treatment .                                                                                                                               |
| 6.3.3                                                                                            | Carboplatin treatment                                                                                                                                |
| 6.4                                                                                              | General Concomitant Medication and Supportive Care Guidelines ........................................ 18                                            |
| 6.5                                                                                              | D DURATION OF THE RAPY                                                                                                                               |
| 6.6                                                                                              | D DURATION OF FOLLOW UP                                                                                                                              |
| 7.1                                                                                              | Dosing Delays/Dose Modifications                                                                                                                     |
| 7.2                                                                                              | Pembrolizumab dose modifications for immune-related adverse events ...............................20                                                 |
| 7.3                                                                                              | Pembrolizumab dose modifications for non-immune-related adverse events ...................27                                                         |
| 7.5                                                                                              | Paclitaxel and carboplatin dose modifications                                                                                                        |
| 8.1                                                                                              | Measurement of Effect                                                                                                                                |
| 8.2                                                                                              | Antitumor Effect .                                                                                                                                   |
| 8.2.1                                                                                            | DEFINITIONS                                                                                                                                          |
| 8.2.2                                                                                            | Methods for Evaluation of Measurable Disease                                                                                                         |
| 8.2.3                                                                                            | Response Criteria - irRECIST ............................................................................................................30          |
| 8.2.4                                                                                            | Assessment for efficacy .................................................................................................................32          |
| 8.2.5                                                                                            | Survival Outcomes ................................................................................................................................32 |
| 9.1                                                                                              | Adverse Events List and Reporting Requirements .............................................................................32                       |
| 9.2                                                                                              | Adverse Event Lists                                                                                                                                  |
| 9.3                                                                                              | Adverse Event Characteristics                                                                                                                        |
| 9.4                                                                                              | DSMC SAE Reporting Requirements                                                                                                                      |
| 9.5                                                                                              | WFUHS IRB AE Reporting Requirements                                                                                                                  |
| 9.6                                                                                              | Sponsor Reporting Requirements .....................................................................................................34               |
| Protocol Version Date 03/12/2021                                                                 | Page 3 of 83                                                                                                                                         |  
Immune response in patients with recurrent or metastatic non-small cell lung cancer and  
| performance status of 2 treated with a combination of pembrolizumab and low dose weekly                                                                            |                                                                                                                                                                 |
|--------------------------------------------------------------------------------------------------------------------------------------------------------------------|-----------------------------------------------------------------------------------------------------------------------------------------------------------------|
| carboplatin/paclitaxel                                                                                                                                             |                                                                                                                                                                 |
| Comprehensive Cancer Center of Wake Forest University (CCCWFU)                                                                                                     |                                                                                                                                                                 |
| CCWFU # 62415                                                                                                                                                      |                                                                                                                                                                 |
| 9.5.2                                                                                                                                                              | Events of Clinical Interest ................................................................................................................35                  |
| 9.5.3                                                                                                                                                              | Sponsor Responsibility for Reporting Adverse Events ...............................................................36                                           |
| 10.1                                                                                                                                                               | Pharmaceutical Information                                                                                                                                      |
| 10.2                                                                                                                                                               | Pharmaceutical Accountability ..............................................................................................................36                  |
| 10.3                                                                                                                                                               | KEYTRUDA (pembrolizumab)                                                                                                                                        |
| 10.4                                                                                                                                                               | Taxol (paclitaxel) ..........................................................................................................................................38 |
| 10.5                                                                                                                                                               | Carboplatin                                                                                                                                                     |
| 11.1                                                                                                                                                               | Correlative Studies                                                                                                                                             |
| 11.2                                                                                                                                                               | T TUMOR CORRELATIVE STUDIES                                                                                                                                     |
| Blood Correlative Studies .....................................................................................................................41                  |                                                                                                                                                                 |
| 11.3                                                                                                                                                               |                                                                                                                                                                 |
| 1.4                                                                                                                                                                | Quality of Life Correlative Studies ................................................................................................43                          |
| 12.0  Data Management                                                                                                                                              |                                                                                                                                                                 |
| 13.2                                                                                                                                                               | Power, sample size, and accrual rate ...................................................................................................44                      |
| 13.3                                                                                                                                                               | Analysis of Primary Objective                                                                                                                                   |
| 13.4                                                                                                                                                               | Analysis of Secondary Objectives .................................................................................................45                            |
| Interim Analysis Plan                                                                                                                                              |                                                                                                                                                                 |
| 13.5                                                                                                                                                               |                                                                                                                                                                 |
| References .....................................................................................................................................................47 |                                                                                                                                                                 |
| Appendix A - Protocol Registration Form .................................................................................................49                        |                                                                                                                                                                 |
| Appendix C - Race & Ethnicity Verification Form                                                                                                                    |                                                                                                                                                                 |
| Appendix D - Mandatory DSMC SAE Reporting Guidelines .......................................................................56                                     |                                                                                                                                                                 |
| Screen Shots:                                                                                                                                                      |                                                                                                                                                                 |
| Appendix E - Tumor Response Worksheet .................................................................................................63                          |                                                                                                                                                                 |
| Appendix G - Study Data Collection Form ......................................................................................................68                   |                                                                                                                                                                 |
| Appendix H - Follow-up Form                                                                                                                                        |                                                                                                                                                                 |
| Appendix I - EORTC QLQ-C30 English .                                                                                                                               |                                                                                                                                                                 |
| Appendix J - EORTC QLQ-LC13 English                                                                                                                                |                                                                                                                                                                 |
| Appendix K - EORTC QLQ-C30 Spanish .                                                                                                                               |                                                                                                                                                                 |
| Appendix M - Tumor Correlative Studies Form (Pre-Study) ......................................................................77                                   |                                                                                                                                                                 |
| Appendix N - Blood Correlative Studies Form                                                                                                                        |                                                                                                                                                                 |
| Cellular regulators                                                                                                                                                |                                                                                                                                                                 |
| SOLUBLE REGULATORS                                                                                                                                                 |                                                                                                                                                                 |
| Appendix O - Adverse Event Log                                                                                                                                     |                                                                                                                                                                 |
| Appendix P - Pembrolizumab Guidance Document ....................................................................................80                                |                                                                                                                                                                 |
| Appendix Q - ECOG Performance Status                                                                                                                               |                                                                                                                                                                 |
| Appendix R: Response Criteria                                                                                                                                      |                                                                                                                                                                 |  
Immune response in patients with recurrent or metastatic non-small cell lung cancer and performance status of 2 treated with a combination of pembrolizumab and low dose weekly carboplatin/paclitaxel Comprehensive Cancer Center of Wake Forest University (CCCWFU)
CCCWFU \# 62415
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schema

Cohort 1: Pembrolizumab alone Cohort 2: Pembrolizumab in combination
- Tumor reassessment at week 8 then q12 weeks
- QOL survey q12 weeks
Immune response in patients with recurrent or metastatic non-small cell lung cancer and performance status of 2 treated with a combination of pembrolizumab and low dose weekly carboplatin/paclitaxel Comprehensive Cancer Center of Wake Forest University (CCCWFU)
CCCWFU \# 62415
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1.1 introduction and background 1.2

Lung cancer is the leading cause of cancer-related death worldwide. Most patients with advanced non-small cell lung cancer (NSCLC) are candidates for chemotherapy, and first-line platinum-based combination chemotherapy is associated with an overall response rate of 30%, median progression-free survival of 4 months, and median overall survival of 8–11 months for patients with good performance status (PS).  
1 The strongest predictor of survival in patients with advanced NSCLC is PS (Appendix Q).  
2 It measures the impactof tumor symptoms, together with other preexisting medical problems and comorbidities, on a patient's ability to function daily and for self-care. Although combination chemotherapy has been shown to be beneficial for patients with good PS, PS 0 or 1, there is still debate about its efficacy for patients with a PS of 2, patients who are ambulatory, capable of all self-care, up and about more than 50% of waking hours, but unable to carry out any work.1,3 PS 2patients account for up to 30% of patients with advanced NSCLC, and no treatment is widely accepted as standard.4 Toxicity is the major concern when prescribing chemotherapy in PS 2 patients, but data are conflicting.5 It was recently shown that in patients with stage IV NSCLC receiving palliative chemotherapy, the median progression free survival was 1.5 to 2.5 months with a median overall survival between 2 to 4 months.6 These results were not affected by patient age.  
Interestingly, patients with PS 2 that need to discontinue chemotherapy afterfirst dose due to severe toxicity have a median survival of 2.5 months and a one year survival of only 5%.7 The overall response rate (RR) on this specific patient population seems to be within the single digits (0 to 10%).  
8 In addition topoor response and survival outcomes, many palliative treatments may cause substantial toxicity. In summary, metastatic NSCLC with PS 2 represents a population with a large unmet need for new treatment options in the palliative setting.  
9
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1.3 immunotherapies

The importance of intact immune surveillance in controlling outgrowth of neoplastic transformation has been known for decades. Accumulating evidence shows a correlation between tumor-infiltrating lymphocytes (TILs) in cancer tissue and favorable prognosis in various malignancies. In particular, the presence of CD8+ T-cells and the ratio of CD8+ effector T-cells / FoxP3+ regulatory T-cells seems to correlate with improved prognosis and long-term survival in many solid tumors. The PD-1 receptor-ligand interaction is a major pathway hijacked by tumors to suppress immune control. The normal function of PD-1, expressed on the cell surface of activated T-cells under healthy conditions, is to down-modulate unwanted or excessive immune responses, including autoimmune reactions.  
Immune response in patients with recurrent or metastatic non-small cell lung cancer and performance status of 2 treated with a combination of pembrolizumab and low dose weekly carboplatin/paclitaxel Comprehensive Cancer Center of Wake Forest University (CCCWFU)
CCCWFU \# 62415 PD-1 (encoded by the gene Pdcd1) is an Ig superfamily member related to CD28 and CTLA-4 which has been shown to negatively regulate antigen receptor signaling upon engagement of its ligands (PD-L1 and/or PD L2). The structure of murine PD-1 has been resolved. PD-1 and family members are type I transmembrane glycoproteins containing an Ig Variable-type (V-type) domain responsible for ligand binding and a cytoplasmic tail which is responsible for the binding of signaling molecules. The cytoplasmic tail of PD-1 contains 2 tyrosinebased signaling motifs, an immunoreceptor tyrosine-based inhibition motif (ITIM)
and an immunoreceptor tyrosine-based switch motif (ITSM). Following T-cell stimulation, PD 1 recruits the tyrosine phosphatases SHP-1 and SHP-2 to the ITSM motif within its cytoplasmic tail, leading to the dephosphorylation of effector molecules such as CD3ζ, PKCθ and ZAP70 which are involved in the CD3 T-cell signaling cascade. The mechanism by which PD-1 down modulates T-cell responses is similar to, but distinct from that of CTLA-4 as both molecules regulate an overlapping set of signaling proteins. PD-1 was shown to be expressed on activated lymphocytes including peripheral CD4+ and CD8+ Tcells, B-cells, T regs and Natural Killer cells. Expression has also been shown during thymic development on CD4-CD8- (double negative) T-cells as well as subsets of macrophages and dendritic cells. The ligands for PD-1 (PD-L1 and PD-L2) are constitutively expressed or can be induced in a variety of cell types, including non-hematopoietic tissues as well as in various tumors. Both ligands are type I transmembrane receptors containing both IgV- and IgC-like domains in the extracellular region and contain short cytoplasmic regions with no known signaling motifs. Binding of either PD-1 ligand to PD-1 inhibits T-cell activation triggered through the T-cell receptor. PD-L1 is expressed at low levels on various non-hematopoietic tissues, most notably on vascular endothelium, whereas PD-L2 protein is only detectably expressed on antigen-presenting cells found in lymphoid tissue or chronic inflammatory environments. PD-L2 is thought to control immune T-cell activation in lymphoid organs, whereas PD-L1 serves to dampen unwarranted T-cell function in peripheral tissues.  
Although healthy organs express little (if any) PD-L1, a variety of cancers were demonstrated to express abundant levels of this T-cell inhibitor. PD-1 has been suggested to regulate tumor-specific T-cell expansion in subjects with melanoma. This suggests that the PD-1/PD-L1 pathway plays a critical role in tumor immune evasion and should be considered as an attractive target for therapeutic intervention.  
Pembrolizumab is a potent and highly selective humanized monoclonal antibody
(mAb) of the IgG4/kappa isotype designed to directly block the interaction between PD-1 and its ligands, PD-L1 and PD-L2. KeytrudaTM (pembrolizumab)
has recently been approved in the United Stated for the treatment of patients with unresectable or metastatic melanoma and disease progression following ipilumumab and, if BRAF V600 mutation positive, a BRAF inhibitor. As of August, 2016, Keytruda TM has been approved for the treatment of Head and Neck Cancer, and most recently, as of October 2016, for the treatment of NonSmall Cell Lung Cancer.  
Immune response in patients with recurrent or metastatic non-small cell lung cancer and performance status of 2 treated with a combination of pembrolizumab and low dose weekly carboplatin/paclitaxel Comprehensive Cancer Center of Wake Forest University (CCCWFU)
CCCWFU \# 62415
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1.3.1 immunotherapies alone

Programmed cell death protein 1, also known as PD-1, is a 288 amino acid cell surface protein molecule. PD-1 has two ligands, PD-L1 and PDL2, which are members of the B7 family. Several lines of evidence suggest that PD-1 and its ligands negatively regulate immune responses. Different studies have shown that the cancer microenvironment manipulates the PD-L1/PD-1 pathway and that the induction of PD-L1 expression on tumor cells leads to the inhibition of immune responses against cancer, permitting cancer progression and metastasis.10 In a murine mechanistic experiment, it was shown that the induction of PD-L1 in melanoma microenvironment is mediated by IFN-y produced by the T
cells that are antigen experienced and therefore express PD-1.11 In tumor cells, PD-L1 expression may range from 45 to 50% in NSCLC
biopsies, irrespective of histology.12 The evidence that PD-L1 is commonly up-regulated in NSCLC and that PD-1 is expressed on the majority of tumor infiltrating lymphocytes, represented the rationale forthe development of monoclonal antibodies against PD-L1 or PD-1, and several agents are currently under investigation.12,13 It has been shown recently, that the anti PD-1 monoclonal antibody nivolumab improves overall survival compared to single agent docetaxel in patients with metastatic NSCLC progressed to platinum-based chemotherapy and squamous histology. It is important to note that only patients with good performance status were allowed to participate in this trial; thus there is no data on the toxicity/efficacy profile of PD-1 check point inhibitors in patients with metastatic lung cancer and poor PS. The overall response rate to the PD-1 inhibitors nivolumab and pembrolizumab in patients with metastatic NSCLC (all comers) is 15 to 20%.14 The KEYNOTE-001 study that assessed the efficacy and safety of pembrolizumab in patients with advanced NSCLC showed that among all the patients, the objective response rate was 19.4%, and the median duration of response was 12.5 months.23 The ORR in patients with PS 2 is not known but expected to be lower. Clearly new strategies are needed to improve the RR of patients with metastatic NSCLC and poor PS to the immune checkpoints inhibitors.
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1.3.2 immunotherapies in combination

Immune suppression mediated by myeloid derived suppressor cells
(MDSC) and regulatory T (Treg) cells characterizes patients with advanced NSCLC and poor PS. Increases in these immune suppressor cells are also correlated with poor response to chemotherapy. Inhibiting PD-1 receptor/ligand interactions can abrogate the suppressive effects of MDSC and Treg cells but only partially.  
15 Several studies have shown that low-dose chemotherapy with taxanes and platinum compounds, alone Immune response in patients with recurrent or metastatic non-small cell lung cancer and performance status of 2 treated with a combination of pembrolizumab and low dose weekly carboplatin/paclitaxel Comprehensive Cancer Center of Wake Forest University (CCCWFU)
CCCWFU \# 62415 and in combination, can reduce MDSC and Treg cells and modify the tumor microenvironment to promote immunogenic tumor death.16-18 Lowdose carboplatin and paclitaxel have been shown to enhance the antitumor activity of anti-PD-1 antibody in mouse models of ovarian and lung cancer.19 There is evidence that reductions in MDSC and Treg cells are involved.20 That antitumor immune responses can be promoted clinically with this approach was suggested by the observation that disease control was associated with increases in interferon-γ and interleukin-2 in patients with refractory ovarian cancer treated with lowdose carboplatin and paclitaxel.17 We have examined the combination of weekly low-dose carboplatin and paclitaxel in combination with the anti-EGFR antibody, cetuximab, and have observed remarkable tumor responses and excellent tolerability in patient with advanced head and neck cancer and a PS of 2 (data not published). The ability of taxanes and platinum compounds in noncytotoxic doses to block the immune-suppressive potential of MDSC and Treg cells represents a new therapeutic strategy for enhancing the efficacy of concomitant anti-PD-1 immunotherapy with pembrolizumab in lung cancer patients.19 The effects of pembrolizumab, alone or in combination with chemotherapy, on immune regulatory mechanisms in cancer patients with a poor PS, in general, and in patients with the highly immune-suppressive NSCLC, in specific, are not known. A clinical trial will be performed to examine these mechanisms. This trial may lead to improved therapy for patients with NSCLC as well as other advanced cancers with a poor PS. It may also lead to biomarkers of response as well as suggest specific interventions that can be applied to improve antitumor immunologic activity.
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1.4 study rationale

There remains a significant unmet medical need for additional treatment options for patients with recurrent or metastatic NSCLC and PS of 2. Chang et al., demonstrated on a mice model of ovarian cancer that with the use of dose-dense cisplatin+paclitaxel there is an increase immune response based on an increase number of IFN-γ-secreting CD14+F4/80+ macrophage and subsequent D8+IFN-γ+tumor-infiltrating lymphocytes.(17) We have examined a similar dose dense regimen based on the combination of low dose weekly carboplatin and paclitaxel in combination with the anti-EGFR antibody, cetuximab, and have observed remarkable tumor responses and excellent tolerability in patient with advanced head and neck small cell carcinoma (HNSCC) and poor PS. At our institution, we treated 20 patients with this regimen of weekly cetuximab and carboplatin AUC of 1 and paclitaxel 25 mg m2. Twelve patients experienced partial response
(60%). The median survival was 8 months for the entire cohort and 12 months for the responders (data not published). This preliminary data with a different monoclonal antibody combined with low-dose chemotherapy on a similar tumor model, encouraged us to move forward with the study of the same chemotherapy Immune response in patients with recurrent or metastatic non-small cell lung cancer and performance status of 2 treated with a combination of pembrolizumab and low dose weekly carboplatin/paclitaxel Comprehensive Cancer Center of Wake Forest University (CCCWFU)
CCCWFU \# 62415 combination and the monoclonal antibody pembrolizumab on patient with NSCLC.  
Based upon the available non-clinical and clinical safety data, the limited survival benefit provided by the currently available treatment options to patients, the limited life expectancy due to malignant disease, and the strength of the scientific hypotheses under evaluation, the treatment proposed for evaluation in this study may have the potential to provide meaningful clinical benefit with a manageable safety and tolerability profile by generating higher rate and durable clinical responses, thereby improving quality of life (QOL) and potentially extending survival. Therefore, the investigation of the immune-modulatory effects of the combination of pembrolizumab with low dose carboplatin and paclitaxel in this patient population is acceptable and the benefit/risk assessment for this study is favorable per the proposed study design.
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2.1 objectives 2.2 primary objectives

2.2.1 Determine the immune effects of single agent pembrolizumab and pembrolizumab combined with low-dose carboplatin and paclitaxel 2.2.2 Estimate the treatment response to single agent pembrolizumab and pembrolizumab combined with low-dose carboplatin and paclitaxel
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2.3 secondary objectives

2.3.1 Determine the toxicity and tolerability of pembrolizumab and pembrolizumab combined with low-dose carboplatin and paclitaxel 2.3.2 Assess QOL in patients receiving single agent pembrolizumab and pembrolizumab combined with carboplatin and paclitaxel 2.3.3 Assess the association between immune response and clinical response
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3.1 patient selection 3.2 inclusion

3.2.1 Patients must have histologically or cytologically confirmed NSCLC that is advanced/metastatic (stage IIIb/IV) or recurrent (progression after surgery or radiation or chemo-radiation treatment for loco-regional disease). Patients with epidermal growth factor (EGFR) mutation, anaplastic lymphoma kinase Immune response in patients with recurrent or metastatic non-small cell lung cancer and performance status of 2 treated with a combination of pembrolizumab and low dose weekly carboplatin/paclitaxel Comprehensive Cancer Center of Wake Forest University (CCCWFU)
CCCWFU \# 62415
(ALK) gene rearrangement or ROS1 translocation must have received an approved EGFR, ALK, or ROS1-directed therapy and have signs of disease progression prior to receiving pembrolizumab.  
3.2.2 Patients must be willing to provide tissue from a newly obtained core or excisional biopsy of a tumor lesion. Newly-obtained is defined as a specimen obtained up to 12 weeks (84 days) prior to date of signing consent.
Subjects for whom newly-obtained samples cannot be provided (e.g.  
inaccessible or subject safety concern) may submit an archived specimen
(up to 3 years) *only* upon agreement from the Sponsor. At least 4 mm of tumor tissue will be needed for PD-L1 staining.  
3.2.3 Patients who have received zero (0) to two (2) previous lines of systemic chemotherapy and are *not currently* receiving chemotherapy treatment
(within 2 weeks of randomization).  
3.2.4 At least one measurable lesion as defined by RECIST v1.1 on screening computed tomography (CT) or magnetic resonance imaging (MRI)
3.2.5 Age >18 years.
3.2.6 ECOG performance status of 2.  
3.2.7 Patients must have normal organ and marrow function as defined below:  
| -           | white blood cell count    | > 2,500 cells/mcL                                                          |
|-------------|---------------------------|----------------------------------------------------------------------------|
| -           | absolute neutrophil count | >1,500/mcL                                                                 |
| -           | platelets                 | >100,000/mcL                                                               |
| -           | hemoglobin                | ≥ 9 g/dL                                                                   |
| -           | total bilirubin           | ≤ 2.0 x upper limit of normal (ULN)                                        |
| -           | AST(SGOT)/ALT(SGPT)       | < 2.5 x ULN Or ≤ 5 x ULN in presence of liver  metastases                  |
| -           | creatinine                | within normal institutional limits                                         |
| OR          |                           |                                                                            |
| -           | creatinine clearance      | > 50 mL/min for patients with creatinine levels above institutional normal |
| - potassium | ≥ lower limit of normal   |                                                                            |  
3.2.8 Women of child-bearing potential and men must agree to use adequate contraception (hormonal or barrier method of birth control; abstinence) for the duration of study participation and for 4 weeks after the final administration of study drugs. Should a woman become pregnant or suspect she is pregnant while participating in this study, she should inform her treating physician immediately.  
Immune response in patients with recurrent or metastatic non-small cell lung cancer and performance status of 2 treated with a combination of pembrolizumab and low dose weekly carboplatin/paclitaxel Comprehensive Cancer Center of Wake Forest University (CCCWFU)
CCCWFU \# 62415 3.2.9 Ability to understand and the willingness to sign an IRB-approved informed consent document.
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3.3 exclusion criteria

3.3.1 Known active (untreated) central nervous system (CNS) metastases that require steroids. Subjects with CNS metastases who have completed a course of therapy would be eligible for the study provided they are clinically stable for at least 2 weeks before study entry, defined as:
- No evidence of new or enlarging CNS metastasis or new neurological symptoms attributable to CNS metastases.  
- Asymptomatic and receiving either no or stable doses of anticonvulsants and total doses of corticosteroids equivalent to 10 mg of prednisone or less.  
3.3.2 Current or previous other malignancy within 2 years of study entry, except cured basal or squamous cell skin cancer, superficial bladder cancer, prostate intraepithelial neoplasm, carcinoma in situ of the cervix, or other noninvasive or indolent malignancy without sponsor approval.  
3.3.3 History of previous exposure to an anti PD1/PD-L1 agent 3.3.4 Patients receiving any other investigational agents and or more than two different chemotherapy regimens for treatment of metastatic disease.  
3.3.5 Has had prior chemotherapy, targeted small molecule therapy, or radiation therapy within 2 weeks prior to study Day 1 or who has not recovered (i.e., ≤ Grade 1 or at baseline) from adverse events due to a previously administered agent.  
- Note: Subjects with ≤ Grade 2 neuropathy are an exception to this criterion and may qualify for the study.  
- Note: If subject received major surgery, they must have recovered adequately from the toxicity and/or complications from the intervention prior to starting therapy.
3.3.6 History of allergic reactions attributed to compounds of similar chemical or biologic composition to pembrolizumab, paclitaxel or carboplatin.  
3.3.7 Current uncontrolled cardiac disease such as angina or myocardial infarction, congestive heart failure including New York Heart Association functional classification of 3, or arrhythmia requiring treatment.  
3.3.8 History of pneumonitis or active lung infection.  
3.3.9 Chronic or current active infectious disease requiring systemic antibiotics, antifungals, or antivirals.  
Immune response in patients with recurrent or metastatic non-small cell lung cancer and performance status of 2 treated with a combination of pembrolizumab and low dose weekly carboplatin/paclitaxel Comprehensive Cancer Center of Wake Forest University (CCCWFU)
CCCWFU \# 62415 3.3.10 Patients receiving chronic steroids and or immunosuppression.  
3.3.11 Known HIV infection, Hepatitis B virus (HBV) or hepatitis C virus (HCV)
viremia or at risk for HBV reactivation. HBV DNA and testing for HCV RNA must be undetectable. At risk for HBV reactivation is defined as hepatitis B surface antigen positive or anti-hepatitis B core antibody positive.  
3.3.12 History of autoimmune disease(s).  
3.3.13 Psychiatric illness/social situations that would limit compliance with study requirements.  
3.3.14 Any other condition or circumstance that could interfere with adherence to the study's procedures or requirements, or otherwise compromise the study's objectives such as history of, or any evidence of active, non-infectious pneumonitis.  
3.3.15 Has an active infection requiring systemic therapy. 3.3.16 Pregnant women are excluded from this study because of the potential for teratogenic or abortifacient effects. Because there is an unknown but potential risk for adverse events in nursing infants, breastfeeding should be discontinued prior to study entry.
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3.4 inclusion of women and

Men and women of all races and ethnicities who meet the above-described eligibility criteria are eligible to participate in this study.  
The study consent form will also be provided in Spanish for Spanish-speaking participants. Based on CCCWFU population estimates, we expect approximately 40% of participants to be women. Translating this to our sample size estimate of 40, we plan to enroll at least 16 women. We do not expect the percentage of Hispanic/Latino or racial minority lung cancer patients to be higher than the percentage of Hispanic or racial minority new cancer patients seen at CCCWFU
(1.7% and 14.4%, respectively); similar to the percentage of newly diagnosed cancer patients, we plan to enroll at least 14% (5) racial minority patients. While we do not expect higher percentages than that of Hispanic/Latino newly diagnosed cancer patients (1.7%), we plan to enroll at least one Hispanic/Latino patient.
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4.1 registration procedures

All patients entered on any CCCWFU trial, whether treatment, companion, or cancer control trial, **must** be registered with the CCCWFU Protocol Registrar or entered into ORISScreening Immune response in patients with recurrent or metastatic non-small cell lung cancer and performance status of 2 treated with a combination of pembrolizumab and low dose weekly carboplatin/paclitaxel Comprehensive Cancer Center of Wake Forest University (CCCWFU)
CCCWFU \# 62415 Log within 24 hours of Informed Consent. Patients **must** be registered prior to the initiation of treatment.  
You must perform the following steps in order to ensure prompt registration of your patient:  
1. Complete the Eligibility Checklist (Appendix B) 2. Complete the Protocol Registration Form (Appendix A)
3. Alert the Cancer Center registrar by phone, *and then* send the signed Informed Consent Form, Eligibility Checklist and Protocol Registration Form to the registrar, either by fax or e-mail.
Contact Information:
Protocol Registrar PHONE (336) 713-6767 Protocol Registrar FAX (336) 713-6772 Protocol Registrar E-MAIL (registra@wakehealth.edu) *Protocol Registration is open from 8:30 AM - 4:00 PM, Monday-Friday.  
4. Fax/e-mail ALL eligibility source documents with registration. Patients **will not** be registered without all required supporting documents.
Note: If labs were performed at an outside institution, provide a printout of the results. Ensure that the most recent lab values are sent.  
To complete the registration process, the Registrar will:  
- assign a patient study number
- randomize the patient - register the patient on the study
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5.1 study outcomes and study

5.2.1 Immune effects of single agent pembrolizumab and pembrolizumab combined with carboplatin and paclitaxel.  
5.2.2 Objective response rate, duration of best response, disease control rate, and duration of disease control, as defined by section 8.1.
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5.3 secondary outcomes

5.3.1 Toxicity and tolerability, as assessed by CTCAE version 4.0.  
Immune response in patients with recurrent or metastatic non-small cell lung cancer and performance status of 2 treated with a combination of pembrolizumab and low dose weekly carboplatin/paclitaxel Comprehensive Cancer Center of Wake Forest University (CCCWFU)
CCCWFU \# 62415 5.3.2 QOL, as assessed by EORTC QLQ-30 and EORTC QLQ-LC13 questionnaires.  
5.3.3 Associations between change in immune markers and treatment response (irCR, irPR, irSD, irPD)
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6.1 treatment plan

The proposed study is a randomized, two arm parallel assignment, open label, phase II, basic science study. The study consists of screening (≤ 14 days), subsequent treatment (until disease progression or treatment intolerance), and long-term follow-up. The enrollment period of the study is expected to be approximately 18 months. Enrollment in the study will end when 40 subjects have been randomized and have received at least one dose of therapy. The duration of participation will vary among individual subjects due to factors such as disease progression and time of enrollment. However, patients will receive active therapy up to two years if clinically indicated. Whenever possible, enrolled subjects should complete the study per protocol. However, individual subjects may withdraw from the study prematurely at any time, (e.g., subject decides to discontinue participation due to an adverse event). Subjects who are noncompliant with the study's requirements may also be removed from the study at any time by the investigator.
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6.2 study-related activities

After providing written informed consent, subjects will be screened for eligibility within 14 days of randomization (28 days for CT or PET/CT and 42 days for MRI) (Appendices A, B, and F). Qualified subjects will be staged by a CT chest/abdomen or CT portion of a PET/CT, and a brain MRI at baseline (Appendix E). Qualified subjects will be randomized 1:1 ratio to receive single agent pembrolizumab every three weeks or the combination of pembrolizumab every three weeks and low dose carboplatin and paclitaxel given on a weekly schedule. Randomization of all subjects will be stratified by receipt of prior systemic chemotherapy for recurrent metastatic disease (yes or no) and histology
(squamous vs. non squamous).  
Target and non-target lesions will be followed by CT or MRI for PFS according to immune-related Response Evaluation Criteria In Solid Tumors (irRECIST) at Week 8 (± 3 days), and every 12 weeks (± 7 days) thereafter (Appendix E). If there is suspicion of tumor progression at eight weeks, a second CT/MRI study four weeks after will need to be done as a confirmatory test (Appendix E). Treatment will be discontinued for subjects with confirmed radiographic disease progression. Upon discontinuation of treatment, subjects will complete the End of Treatment visit (Appendix G) and will be followed for survival (Appendix H).  
Immune response in patients with recurrent or metastatic non-small cell lung cancer and performance status of 2 treated with a combination of pembrolizumab and low dose weekly carboplatin/paclitaxel Comprehensive Cancer Center of Wake Forest University (CCCWFU)
CCCWFU \# 62415  
| PreStudy a                                                                                                                                                                                                                                                                                                                                                                                    | Prior to Each  Pembrolizumab  Treatmentb   | Week 8(± 3  days), then   |    |    |    |    |    |
|------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|--------------------------------------------|---------------------------|----|----|----|----|----|
| every 12 weeks (± 7 days)                                                                                                                                                                                                                                                                                                                                                          | Every 12                                   | Week 20 (± 3              |    |    |    |    |    |
| weeks                                                                                                                                                                                                                                                                                                                                                                              | days), then                                |                           |    |    |    |    |    |
| every 8 weeks (± 7 days)                                                                                                                                                                                                                                                                                                                                                           | End of                                     |                           |    |    |    |    |    |
| Treatment  visitc                                                                                                                                                                                                                                                                                                                                                                  | Followup                                            |                           |    |    |    |    |    |
| Informed consent                                                                                                                                                                                                                                                                                                                                                                   | X                                          |                           |    |    |    |    |    |
| Demographics                                                                                                                                                                                                                                                                                                                                                                       | X                                          |                           |    |    |    |    |    |
| Medical historyd                                                                                                                                                                                                                                                                                                                                                                   | X                                          |                           |    |    |    |    |    |
| Concurrent meds                                                                                                                                                                                                                                                                                                                                                                    | X                                          | X                         | X  |    |    |    |    |
| Physical exam                                                                                                                                                                                                                                                                                                                                                                      | X                                          | X                         | X  |    |    |    |    |
| Vital signse                                                                                                                                                                                                                                                                                                                                                                       | X                                          | X                         | X  |    |    |    |    |
| Height (Pre-Study and EOT  only), Weight, M2                                                                                                                                                                                                                                                                                                                                       | X                                          | X                         | X  |    |    |    |    |
| ECOG Performance Status                                                                                                                                                                                                                                                                                                                                                            | X                                          | X                         | X  |    |    |    |    |
| Tumor measurementsf                                                                                                                                                                                                                                                                                                                                                                | X                                          | X                         | Xg |    |    |    |    |
| CBC w/diff, platelets                                                                                                                                                                                                                                                                                                                                                              | X                                          | X                         | X  |    |    |    |    |
| Serum chemistryh                                                                                                                                                                                                                                                                                                                                                                   | X                                          | X                         | X  |    |    |    |    |
| B-HCGi                                                                                                                                                                                                                                                                                                                                                                             | X                                          |                           |    |    |    |    |    |
| TSH, T3, T4                                                                                                                                                                                                                                                                                                                                                                        | X                                          | Xj                        |    |    |    |    |    |
| Urinalysis                                                                                                                                                                                                                                                                                                                                                                         | X                                          | X                         | X  |    |    |    |    |
| Tumor biopsyk                                                                                                                                                                                                                                                                                                                                                                      | X                                          |                           |    |    |    |    |    |
| Tumor correlative studiesl                                                                                                                                                                                                                                                                                                                                                         | X                                          |                           |    |    |    |    |    |
| Blood correlative studiesm                                                                                                                                                                                                                                                                                                                                                         | Xn                                         | X                         |    |    |    |    |    |
| Quality of Life                                                                                                                                                                                                                                                                                                                                                                    | X                                          | X                         |    |    |    |    |    |
| questionnaireso Adverse event evaluation                                                                                                                                                                                                                                                                                                                                           | X                                          | X                         | X  | X  | X  | X  | X  |
| a Pre-study requirements listed in table must be completed within 14 days prior to randomization (28 days for CT or PET/CT and 42 days for MRI ). Tumor correlative studies report (Appendix M) can be obtained within 28 days ofrandomization. b Appendix G. c if not completed within the previous 14 days, and prior to initiation of other anti-cancer therapy. See AppendixG. |                                            |                           |    |    |    |    |    |  
Immune response in patients with recurrent or metastatic non-small cell lung cancer and performance status of 2 treated with a combination of pembrolizumab and low dose weekly carboplatin/paclitaxel Comprehensive Cancer Center of Wake Forest University (CCCWFU)
CCCWFU \# 62415  
| d Including history of prior anticancer interventions and histological or cytological confirmation of NSLC. e temperature, T; blood pressure, BP; respiration rate, RR; heart rate, HR. f Appendix E. Qualified subjects will be staged by a CT chest/abdomen or CT portion of a PET/CT (within 28 days of randomization,  and a brain MRI (within 42 days prior to randomization). g for subjects who have not had an imaging study within the previous 4 weeks. h total bilirubin, BUN, creatinine, creatinine clearance, potassium, SGOT[AST], SGPT[ALT]. i Serum pregnancy test (women of childbearing potential). j Prior to each infusion of pembrolizumab only. k A fresh tumor tissue sample should be collected prior to enrollment for patients. See Inclusion Criteria 3.1.2 for additional information. l Appendix M. m Section 11.2 and Appendix N. n prior to receiving the first dose of pembrolizumab treatment (C1D1), and on C2D1 and C3D1 prior to pembrolizumab treatment  administration. Twenty (20) ml of blood is to be collected in two EDTA-containing vacutainers and sent to Dr. Triozzi's laboratory,  Room 5029, Hanes Building. o Appendices I - L.   |
|--------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|
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6.3 treatment administration

Treatment can be administered on an inpatient or outpatient basis. Reported adverse events and potential risks are described in Section 9.0. Appropriate dose modifications for are described in Section 7.0. No investigational or commercial agents or therapies other than those described below may be administered with the intent to treat the patient's malignancy. Patients will receive active therapy up to two years if clinically indicated.  
| REGIMEN DESCRIPTION                                                            | Cycle    |                                                                                             |                                          |         |
|--------------------------------------------------------------------------------|----------|---------------------------------------------------------------------------------------------|------------------------------------------|---------|
| Agent                                                                          | Dose     | Route                                                                                       | Schedule                                 | Length  |
| Cohort 1 Pembrolizumab                                                         | 200 mg   | 30 minute intravenous                                                                       | Day 1                                    | 3 weeks |
| infusion                                                                       |          |                                                                                             |                                          |         |
| Cohort 2 Pembrolizumab                                                         | 200 mg   | 30 minute intravenous                                                                       |                                          |         |
| infusion at least 1 hour prior to administration of paclitaxel and carboplatin | Day 1    | 3 weeks                                                                                     |                                          |         |
| Paclitaxel                                                                     | 25 mg/m2 | 1 hour intravenous infusion beginning at least 1 hour after the completion of pembroluzumab | Days 1, 8 and 15                         |         |
| Carboplatin                                                                    | AUC = 1  | 1 hour intravenous infusion following completion of paclitaxel                              | Days 1, 8 and 15 for 4 cycles (12 weeks) |         |
| mg/mL/min                                                                      |          |                                                                                             |                                          |         |
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6.3.1 pembrolizumab treatment

Pembrolizumab will be given every three weeks with a dose of 200 mg on Cycle 1 Day 1 (C1D1) and every three weeks thereafter. Patients will Immune response in patients with recurrent or metastatic non-small cell lung cancer and performance status of 2 treated with a combination of pembrolizumab and low dose weekly carboplatin/paclitaxel Comprehensive Cancer Center of Wake Forest University (CCCWFU)
CCCWFU \# 62415 receive active therapy up to two years if clinically indicated. The drug will be administered as a 30 minutes intravenous (IV) infusion.
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6.3.2 paclitaxel treatment

Subjects assigned to the combination therapy will receive Paclitaxel 25 mg/m2 as a 1 hour infusion on C1D1 and then weekly.Paclitaxel administration should begin ≥ 1 hour following completion of Pembrolizumab administration. Patients will receive active therapy up to two years if clinically indicated
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6.3.3 carboplatin treatment

Subjects assigned to the combination therapy will receive Carboplatin at an AUC of 1 mg/mL/min as a 1 hour infusion on C1D1 and then weekly.  
Carboplatin administration should begin following completion of Paclitaxel administration. The carboplatin dose will be based upon the subject's screening glomerular filtration rate (GFR) in mL/min. The Calvert formula will be used for carboplatin dosing: Total Dose (mg) = (target AUC) x (GFR + 25). The carboplatin dose will be capped at 150 mg. Patients will receive active therapy up to 12 weeks if clinically indicated
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6.4 general concomitant medication and

Patients should receive *full supportive care*, including transfusions of blood and blood products, erythropoietin, antibiotics, antiemetics, etc., as clinically indicated. Anti-inflammatory or narcotic analgesics may be offered as needed. Medications considered necessary for the patient's well-being may be given at the discretion of the investigator, i.e., chronic treatments for concomitant medical conditions, as well as agents required for life-threatening medical problems, etc. The reason(s) for treatment, dosage, and dates of treatment should be recorded on the flow sheets.
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6.5 duration of therapy

In the absence of treatment delays due to adverse events, treatment may continue until one of the following criteria applies:  
- Disease progression, - Intercurrent illness that prevents further administration of treatment, - Unacceptable toxicity related to the administration of the study required medications,
- Patient lost to follow-up after repeated attempts to contact, - Onset of an adverse event that would make ongoing treatment in the current clinical trial inadvisable, as deemed by the investigator, medical monitor, or
Immune response in patients with recurrent or metastatic non-small cell lung cancer and performance status of 2 treated with a combination of pembrolizumab and low dose weekly carboplatin/paclitaxel Comprehensive Cancer Center of Wake Forest University (CCCWFU)
CCCWFU \# 62415 study sponsor ( there will be no limit in the number of treatment cycles a patient can receive),
- Patient decides to withdraw from the study, - Patient non-compliance with the study's requirements and/or procedures, as determined by the investigator, medical monitor, or study sponsor, or
- General or specific changes in the patient's condition render the patient unacceptable for further treatment in the judgment of the investigator.  
- Patient completed two years of therapy.  
In the event a subject is withdrawn from treatment prematurely, the End of Treatment evaluations should be completed, and the subject should be followed for survival, if possible.
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6.6 duration of follow up

Patients will be followed for a minimum of 30 days after the last study drug is administered for adverse events monitoring.  
Patients will be followed for a minimum of 30 days after removal from study or until death, whichever occurs first. Patients removed from study for unacceptable adverse events will be followed until resolution or stabilization of the adverse event. Patients will be followed every 8 weeks until death for monitoring survival study endpoints, including vital status, disease state, and initiation of any new anticancer interventions (Appendix H).
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7.1 dosing delays/dose modifications

In order to maintain dose-intensity and cumulative dose-delivery, reasonable efforts should be made to minimize dose reductions and treatment delays. Any subject whose treatment is delayed should be evaluated on a weekly basis until adequate hematologic and non-hematologic parameters have been met. Toxicities may require the dose reduction of one or more of the study required medications. The investigator will carefully assess all treatment-associated toxicities and, whenever possible, determine if the toxicities can reasonably be attributed to a single agent or a causal relationship with one of the agents can reasonably be ruled out. If appropriate, dose reductions should not affect the dose of other products.  
- Toxicity grades are defined using the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI-CTCAE) version 4.0
- Any subject who requires a dose reduction due to drug-related toxicity will continue to receive the reduced dose for the remainder of study treatment
- Dose escalations are not allowed
Immune response in patients with recurrent or metastatic non-small cell lung cancer and performance status of 2 treated with a combination of pembrolizumab and low dose weekly carboplatin/paclitaxel Comprehensive Cancer Center of Wake Forest University (CCCWFU)
CCWFU \# 62415
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7.2 pembrolizumab dose modifications for

| Immune-related   |
|------------------|
| AE               |
| Pneumonitis/ ILD |  
For the general management of immune-related adverse events due to  
| Severity   |
|------------|
| Any Grade  |
| Grade 1    |
| Grade 2    |  
pembrolizumab consider:
1) Patient evaluation to identify any alternative etiology.  
2) In the absence of a clear alternative etiology, all events of an inflammatory nature should be considered to be immune-related.  
3) Symptomatic and topical therapy should be considered for low-grade events.  
4)   Systemic corticosteroids should be considered for a persistent low-grade ent or for a severe event.  
5)  More potent immunosuppressives should be considered for events not responding to systemic steroids.  
See table below for organ specific dose adjustments and management of pembrolizumab immune-related adverse effects.  
| Dose Modifications                                                         | Toxicity Management                                                           |
|----------------------------------------------------------------------------|-------------------------------------------------------------------------------|
| Monitor subjects for signs and symptoms of pneumonitis or ILD (new onset   |                                                                               |
| or worsening shortness of breath or cough).  Subjects should be evaluated  |                                                                               |
| with imaging and pulmonary function tests including other diagnostic       |                                                                               |
| procedures as described below                                              |                                                                               |
| Initial work-up may include clinical evaluation, monitoring of oxygenation |                                                                               |
| via pulse oximetry (resting and exertion), laboratory work-up and high-    |                                                                               |
| resolution CT scan.                                                        |                                                                               |
| For Grade 1 (Radiographic Changes Only)                                    |                                                                               |
| No dose modification required. However,                                    |                                                                               |
| consider holding study drug/study regimen                                  | Monitor and closely follow up in 2-4 days for clinical symptoms, pulse        |
| dosing as clinically appropriate and during                                | oximetry (resting and exertion) and laboratory work-up and then as clinically |
| diagnostic work-up for other etiologies                                    | indicated                                                                     |
| Consider pulmonary and infectious disease consult                          |                                                                               |
| Hold study drug/study regimen dose until Grade                             | For Grade 2 (Mild to Moderate New Symptoms)                                   |
| 2 resolution to Grade <1                                                   | Monitor symptoms daily and consider hospitalization                           |
| - If toxicity worsens then treat as Grade 3 or                             | Discuss with study physician and consider systemic steroids (eg, prednisone   |
| Grade 4                                                                    | 1-2mg/kg/day or IV equivalent                                                 |
| - If toxicity improves to baseline then treat at                           | Reimaging as clinically indicated                                             |
| next scheduled treatment date                                              | If no improvement within 3 to 5 days, additional workup and treatment with    |
| IV methylprednisolone 2-4mg/kg/day should be considered                    |                                                                               |
| If no improvement within 3 to 5 days, further immunosuppressive therapy    |                                                                               |
| (eg, infliximab) should be considered.                                     |                                                                               |
| Once improving, gradually taper steroids over ≥ 4 weeks and consider,      |                                                                               |
| prophylactic antibiotics                                                   |                                                                               |
| Consider pulmonary and infectious disease consults                         |                                                                               |  
Immune response in patients with recurrent or metastatic non-small cell lung cancer and performance status of 2 treated with a combination of pembrolizumab and low dose weekly carboplatin/paclitaxel Comprehensive Cancer Center of Wake Forest University (CCCWFU)
CCWFU \# 62415  
| Toxicity Management                                                            |                                                                 |                                                                    |                                                                       |
|--------------------------------------------------------------------------------|-----------------------------------------------------------------|--------------------------------------------------------------------|-----------------------------------------------------------------------|
| Immune-related                                                                 | Severity                                                        | Dose Modifications                                                 |                                                                       |
| AE                                                                             | Grade 3 or 4                                                    | Permanently discontinue study drug/study                           | For Grade 3 or 4 (severe or new symptoms, new/worsening hypoxia, life |
| regimen                                                                        | threatening                                                     |                                                                    |                                                                       |
| Discuss with study physician                                                   |                                                                 |                                                                    |                                                                       |
| pulmonary and infectious disease  consult                                      |                                                                 |                                                                    |                                                                       |
| Hospitalize the patient                                                        |                                                                 |                                                                    |                                                                       |
| Supportive Care (oxygen, etc.)                                                 |                                                                 |                                                                    |                                                                       |
| Initiate empiric IV corticosteroids (eg. methylprednisolone or equivalent) at  |                                                                 |                                                                    |                                                                       |
| 1 to 4 mg/kg/day                                                               |                                                                 |                                                                    |                                                                       |
| If no improvement within 3 to 5 days, additional workup and treatment with     |                                                                 |                                                                    |                                                                       |
| additional immunosuppressive therapy (eg. infliximab) should be considered     |                                                                 |                                                                    |                                                                       |
| Once improving, gradually taper steroids over >4 weeks and consider            |                                                                 |                                                                    |                                                                       |
| prophylactic antibiotics                                                       |                                                                 |                                                                    |                                                                       |
| Diarrhea/ Enterocolitis                                                        | Any Grade                                                       | Monitor for symptoms that may be related to diarrhea/enterocolitis |                                                                       |
| (abdominal pain, cramping, or changes in bowel habits)                         |                                                                 |                                                                    |                                                                       |
| Subjects should be thoroughly evaluated to rule out any alternative etiology   |                                                                 |                                                                    |                                                                       |
| (eg, disease progression, infections, etc.)                                    |                                                                 |                                                                    |                                                                       |
| Steroids should be considered if an alternative etiology is not determined,    |                                                                 |                                                                    |                                                                       |
| even for low grade events, in order to prevent potential progression to higher |                                                                 |                                                                    |                                                                       |
| grade event                                                                    |                                                                 |                                                                    |                                                                       |
| Use analgesics carefully; they can mask symptoms of perforation and            |                                                                 |                                                                    |                                                                       |
| peritomitis                                                                    |                                                                 |                                                                    |                                                                       |
| Grade 1                                                                        | No dose modification                                            | For Grade 1:                                                       |                                                                       |
| Close monitoring for worsening symptoms                                        |                                                                 |                                                                    |                                                                       |
| .                                                                              | Consider symptomatic treatment including hydration, electrolyte |                                                                    |                                                                       |
| '                                                                              |                                                                 |                                                                    |                                                                       |
| replacement, dietary changes (eg. American Dietetic Association colitis)       |                                                                 |                                                                    |                                                                       |
| diet), and loperamides                                                         |                                                                 |                                                                    |                                                                       |  
Immune response in patients with recurrent or metastatic non-small cell lung cancer and performance status of 2 treated with a combination of pembrolizumab and low dose weekly carboplatin/paclitaxel Comprehensive Cancer Center of Wake Forest University (CCCWFU)
CCWFU \# 62415  
| Immune-related                                                                | Severity                                                                       | Dose Modifications                                                           | Toxicity Management   |
|-------------------------------------------------------------------------------|--------------------------------------------------------------------------------|------------------------------------------------------------------------------|-----------------------|
| AE                                                                            | Grade 2                                                                        | Hold study drug/study regimen until resolution                               | For Grade 2:          |
| to Grade ≤ 1                                                                  | Consider symptomatic treatment including hydration, electrolyte                |                                                                              |                       |
| If toxicity worsens then treat as Grades                                      | replacement, dietary changes (eg. American Dietetic Association colitis        |                                                                              |                       |
| 3 or Grade 4                                                                  | diet), and loperamide and/or budesonide                                        |                                                                              |                       |
| If toxicity improves to baseline then                                         | If event is persistent (> 3 to 5 days) or worsens, consider prednisone 0.5 to  |                                                                              |                       |
| .                                                                             | treat at next scheduled treatment date                                         | 1 mg/kg/day or IV equivalent                                                 |                       |
| If not responsive within 3 to 5 days, consider IV corticosteroids (eg.        |                                                                                |                                                                              |                       |
| methylprednisolone IV or equivalent) at 1 to 2 mg/kg/day                      |                                                                                |                                                                              |                       |
| If event is not responsive within 3 to 5 days or worsens, additional workup   |                                                                                |                                                                              |                       |
| and treatment with IV methylprednisolone 2-4mg/kg/day should be               |                                                                                |                                                                              |                       |
| considered                                                                    |                                                                                |                                                                              |                       |
| If no improvement within 3 to 5 days, further immunosuppressives (eg.         |                                                                                |                                                                              |                       |
| infliximab) should be considered                                              |                                                                                |                                                                              |                       |
| Consult study physician if no resolution to Grade :::1 in 3 to 4 days         |                                                                                |                                                                              |                       |
| Once improving, gradually taper steroids over >4 weeks                        |                                                                                |                                                                              |                       |
| Permanently discontinue study drug/study                                      |                                                                                |                                                                              |                       |
| Grade 3 or 4                                                                  | For Grade 3 or 4:                                                              |                                                                              |                       |
| regimen                                                                       | Discuss with study physician                                                   |                                                                              |                       |
| Monitor stool frequency and volume and maintain hydration                     |                                                                                |                                                                              |                       |
| Urgent GI consult and imaging as appropriate                                  |                                                                                |                                                                              |                       |
| Initiate empiric IV corticosteroids (eg. methylprednisolone IV or equivalent) |                                                                                |                                                                              |                       |
| at 1 to 4 mg/kg/day                                                           |                                                                                |                                                                              |                       |
| If no improvement within 3 to 5 days, consider further immunosuppressives     |                                                                                |                                                                              |                       |
| (eg, infliximab).                                                             |                                                                                |                                                                              |                       |
| Caution: Ensure GI consult to rule out bowel perforation and refer to label   |                                                                                |                                                                              |                       |
| before using infliximab. Once improving, gradually taper steroids over >4     |                                                                                |                                                                              |                       |
| weeks and consider prophylactic antibiotics                                   |                                                                                |                                                                              |                       |
| Hepatitis (Elevated                                                           | Any Grade                                                                      | Monitor and evaluate liver function test: AST, ALT, ALP and total bilirubing |                       |
| LFTs)                                                                         | Evaluate for alternative etiologies (eg, viral hepatitis, disease progression, |                                                                              |                       |
| concomitant medications)                                                      |                                                                                |                                                                              |                       |
| Grade 1                                                                       | No dose modification. If  it worsens, treat as                                 | Continue LFT monitoring per protocol                                         |                       |
| Grade 2 event                                                                 |                                                                                |                                                                              |                       |  
Immune response in patients with recurrent or metastatic non-small cell lung cancer and performance status of 2 treated with a combination of pembrolizumab and low dose weekly carboplatin/paclitaxel Comprehensive Cancer Center of Wake Forest University (CCCWFU)
CCWFU \# 62415  
| Immune-related                                                       | Severity                                                                      | Dose Modifications                                                        | Toxicity Management                                                   |
|----------------------------------------------------------------------|-------------------------------------------------------------------------------|---------------------------------------------------------------------------|-----------------------------------------------------------------------|
| AE                                                                   | Grade 2                                                                       | Hold Study drug/study regimen dose until grade                            | Discuss with study physician if no resolution to Grade <1 in 1-2 days |
| 2 resolution to Grade <l                                             | Recheck LFT's in 1 to 2 days.  If event is persistent (> 3 to 5 days) or      |                                                                           |                                                                       |
| If toxicity worsens then treat as Grade                              | worsens, consider prednisone 0.5 to 1 mg/kg/day or IV equivalent.             |                                                                           |                                                                       |
| 3 or Grade 4                                                         | If no improvement within 3 to 5 days, consider additional workup and          |                                                                           |                                                                       |
| If improves to baseline then treat at                                | treatment with IV methylprednisolone 2-4mg/kg/day                             |                                                                           |                                                                       |
| .                                                                    | next scheduled treatment dated                                                | If no improvement within 3 to 5 days, consider further immunosuppressives |                                                                       |
| (eg, mycophenolate mofetil)                                          |                                                                               |                                                                           |                                                                       |
| Once improving, gradually taper steroids over ≥ 4 weeks and consider |                                                                               |                                                                           |                                                                       |
| prophylactic antibiotics.                                            |                                                                               |                                                                           |                                                                       |
| Grade 3                                                              | For elevations in transaminases < 8 x ULN, or                                 | For Grade 3 or 4:                                                         |                                                                       |
| elevations in bilirubin < 5 × ULN                                    | Discuss with the study physician                                              |                                                                           |                                                                       |
| Hold study drug/study regimen dose                                   | Initiate empiric IV corticosteroids (eg. methylprednisolone IV or equivalent) |                                                                           |                                                                       |
| until resolution to Grade :::1 or baseline                           | at 1 to 4 mg/kg/day                                                           |                                                                           |                                                                       |
| Resume study drug/study regiment                                     | If no improvement within 3 to 5 days, consider further immunosuppressive      |                                                                           |                                                                       |
| administration at the next scheduled dose if                         | therapy (eg. mycophenolate mofetil)                                           |                                                                           |                                                                       |
| elevations downgrade Grade :::1 or baseline                          | If still no further improvement within 3 to 5 days consider other             |                                                                           |                                                                       |
| within 14 days                                                       | immunosuppressive therapy per local guidelines                                |                                                                           |                                                                       |
| Permanently discontinue study drug/study                             | Hepatology consult, abdominal workup, and imaging as appropriate.             |                                                                           |                                                                       |
| regimen if the elevations do not downgrade to                        | Once improving, gradually taper steroids over >4 weeks and consider           |                                                                           |                                                                       |
| Grade < 1 or baseline within 14 days                                 |                                                                               |                                                                           |                                                                       |
| For elevations in transaminases > 8 × ULN or                         | prophylactic antibiotics.                                                     |                                                                           |                                                                       |
| elevations in bilirubin > 5 × ULN, discontinue                       |                                                                               |                                                                           |                                                                       |
| Study drug/study regimen                                             |                                                                               |                                                                           |                                                                       |
| Permanently discontinue study drug/study                             |                                                                               |                                                                           |                                                                       |
| regimen for any case meeting Hy's law criteria                       |                                                                               |                                                                           |                                                                       |
| Grade 4                                                              | Permanently discontinue study drug/study                                      |                                                                           |                                                                       |
| regimen                                                              |                                                                               |                                                                           |                                                                       |
| Rash (excluding Bullous                                              | Any Grade                                                                     | Monitor for signs and symptoms of dermatitis (rash and pruritus)          |                                                                       |
| skin formations)                                                     | *IF THERE IS ANY BULLOUS FORMATION, THE STUDY                                 |                                                                           |                                                                       |
| PHYSICIAN SHOULD BE CONTACTED**                                      |                                                                               |                                                                           |                                                                       |
| Grade 1                                                              | For Grade 1:                                                                  |                                                                           |                                                                       |
| Consider symptomatic treatment including oral antipruritics (eg.     |                                                                               |                                                                           |                                                                       |
| diphenhydramine or hydroxyzine) and topical therapy (eg, urea cream) |                                                                               |                                                                           |                                                                       |  
Immune response in patients with recurrent or metastatic non-small cell lung cancer and performance status of 2 treated with a combination of pembrolizumab and low dose weekly carboplatin/paclitaxel Comprehensive Cancer Center of Wake Forest University (CCCWFU)
CCWFU \# 62415  
| Immune-related                                                                | Severity                                                                     | Dose Modifications                                                         | Toxicity Management                                               |
|-------------------------------------------------------------------------------|------------------------------------------------------------------------------|----------------------------------------------------------------------------|-------------------------------------------------------------------|
| AE                                                                            | Grade 2                                                                      | For persistent (> 1- 2 weeks) Grade 2 events,                              | For Grade 2 :                                                     |
| hold scheduled study drug/study regimen until                                 | Consider symptomatic treatment including oral antipruritics (eg.,            |                                                                            |                                                                   |
| resolution to Grade :::1 or baseline                                          | diphenhydramine or hydroxyzine) and topical therapy (eg. urea cream)         |                                                                            |                                                                   |
| If toxicity worsens then treat as Grade                                       | Consider moderate-strength topical steroid                                   |                                                                            |                                                                   |
| 3                                                                             | If no improvement of rash/skin lesions occurs within 3 to 5 days or          |                                                                            |                                                                   |
| .                                                                             | If toxicity improves then resume                                             | is worsening, discuss with study physician and consider systemic steroids. |                                                                   |
| administration at next scheduled dose                                         | prednisone 0.5 to 1 mg/kg/day or IV equivalent                               |                                                                            |                                                                   |
| Consider dermatology consult                                                  |                                                                              |                                                                            |                                                                   |
| Consider skin biopsy if persistent for > 1-2 weeks or recurs                  |                                                                              |                                                                            |                                                                   |
| Grade 3                                                                       | Hold study drug/study regimen until resolution                               | For Grade 3 or 4:                                                          |                                                                   |
| to Grade sl or baseline                                                       | Discuss with study physician                                                 |                                                                            |                                                                   |
| If temporarily holding the study drug/study                                   | Consider hospitalization.                                                    |                                                                            |                                                                   |
| regimen does not provide improvement of the                                   | Monitor extent of rash [Rule of Nines]                                       |                                                                            |                                                                   |
| Grade 3 skin rash to Grade :::l or baseline within                            |                                                                              |                                                                            |                                                                   |
| 30 days, then permanently discontinue Study                                   | Consult dermatology                                                          |                                                                            |                                                                   |
| drug/study regimen                                                            | Consider skin biopsy (preferably more than 1) as clinically                  |                                                                            |                                                                   |
| Grade 4                                                                       | Permanently discontinue study drug/study                                     | feasible.                                                                  | Initiate empiric IV corticosteroids (eg. methylprednisolone IV or |
| regimen                                                                       | equivalent) at 1 to 4 mg/kg/day                                              |                                                                            |                                                                   |
| Once improving, gradually taper steroids over >4 weeks and                    |                                                                              |                                                                            |                                                                   |
| consider prophylactic antibiotics                                             |                                                                              |                                                                            |                                                                   |
| Endocrinopathy (eg.                                                           | Any Grade                                                                    | Monitor subjects for signs and symptoms of endocrinopathies. Non-specific  |                                                                   |
| hyperthyroidism                                                               | symptoms include headache, fatigue, behavior changes, changed mental         |                                                                            |                                                                   |
| status, vertigo, abdominal pain, unusual bowel habits, hypotension and        |                                                                              |                                                                            |                                                                   |
| hypothyroidism,                                                               |                                                                              |                                                                            |                                                                   |
| hypopituitarism, adrenal                                                      | weakness.                                                                    |                                                                            |                                                                   |
| insufficiency, etc.)                                                          | Subjects should be thoroughly evaluated to rule out any alternative etiology |                                                                            |                                                                   |
| (eg. disease progression including brain metastases, infections, etc.)        |                                                                              |                                                                            |                                                                   |
| Monitor and evaluate thyroid function tests: TSH, free T3 and free T4 and     |                                                                              |                                                                            |                                                                   |
| other relevant endocrine labs depending on suspected endocrinopathy.          |                                                                              |                                                                            |                                                                   |
| If a subject experiences an AE that is thought to be possibly of autoimmune   |                                                                              |                                                                            |                                                                   |
| nature (eg, thyroiditis, pancreatitis, hypophysitis, diabetes insipidus), the |                                                                              |                                                                            |                                                                   |
| investigator should send a blood sample for appropriate autoimmune            |                                                                              |                                                                            |                                                                   |
| antibody testing                                                              |                                                                              |                                                                            |                                                                   |  
Immune response in patients with recurrent or metastatic non-small cell lung cancer and performance status of 2 treated with a combination of pembrolizumab and low dose weekly carboplatin/paclitaxel Comprehensive Cancer Center of Wake Forest University (CCCWFU)
CCWFU \# 62415  
| Immune-related                                                               | Severity                                                                      | Dose Modifications                                                         | Toxicity Management                                            |
|------------------------------------------------------------------------------|-------------------------------------------------------------------------------|----------------------------------------------------------------------------|----------------------------------------------------------------|
| AE                                                                           | Grade 1                                                                       | No dose modification                                                       | For Grade 1: (including those with asymptomatic TSH elevation) |
| Monitor patient with appropriate endocrine function tests                    |                                                                               |                                                                            |                                                                |
| If TSH <0.5X LLN, or TSH >2X ULN or consistently out of range in 2           |                                                                               |                                                                            |                                                                |
| subsequent measurements, include FT4 at subsequent cycles as clinically      |                                                                               |                                                                            |                                                                |
| indicated and consider endocrinology consult.                                |                                                                               |                                                                            |                                                                |
| Grade 2                                                                      | Hold study drug/study regimen dose until                                      | For Grade 2: (including those with symptomatic endocrinopathy)             |                                                                |
| resolution to Grade sl                                                       | Discuss with study physician                                                  |                                                                            |                                                                |
| If worsens then treat as Grade 3 or                                          | Initiate hormone replacement as needed for management                         |                                                                            |                                                                |
| Grade 4 t                                                                    | Evaluate endocrine function, and as clinically indicated, consider pituitary  |                                                                            |                                                                |
| If toxicity improves to baseline then                                        | scan                                                                          |                                                                            |                                                                |
| treat at next scheduled treatment date.                                      | For subjects with abnormal endocrine work up, consider short-term, high-      |                                                                            |                                                                |
| dose corticosteroids (eg, methylprednisolone or IV equivalent) with relevant |                                                                               |                                                                            |                                                                |
| hormone replacement (eg. levothyroxine, hydrocortisone, or sex hormones)     |                                                                               |                                                                            |                                                                |
| For subjects with normal endocrine work up (lab or MRI scans), repeat        |                                                                               |                                                                            |                                                                |
| labs/MRI as clinically indicated.                                            |                                                                               |                                                                            |                                                                |
| Grade 3                                                                      | Hold study drug/study regimen dose until                                      | For Grade 3 or 4;                                                          |                                                                |
| endocrinopathy symptom(s) are controlled                                     | Discuss with study physician                                                  |                                                                            |                                                                |
| Resume study drug/study regimen                                              | Initiate empiric IV corticosteroids (eg. methylprednisolone IV or equivalent) |                                                                            |                                                                |
| administration if controlled at the next scheduled                           | at 1 to 2 mg/kg/day                                                           |                                                                            |                                                                |
| dose                                                                         | Administer hormone replacement therapy as necessary                           |                                                                            |                                                                |
| Grade 4                                                                      | Permanently discontinue study drug/study                                      | For adrenal crisis, severe dehydration, hypotension, or shock: immediately |                                                                |
| regimen                                                                      | initiate intravenous corticosteroids with mineralocorticoid activity          |                                                                            |                                                                |
| Consult endocrinologist                                                      |                                                                               |                                                                            |                                                                |
| Once improving, gradually taper immunosuppressive steroids over ≥ 4 weeks    |                                                                               |                                                                            |                                                                |
| Subjects should be evaluated to rule out any alternative etiology            |                                                                               |                                                                            |                                                                |
| Immune mediated                                                              | Any Grade                                                                     |                                                                            |                                                                |
| Neurotoxicity (except                                                        | (eg, disease progression, infections, metabolic syndromes and medications,    |                                                                            |                                                                |
| etc.)                                                                        |                                                                               |                                                                            |                                                                |
| Myasthenia Gravis and                                                        |                                                                               |                                                                            |                                                                |
| Guillain-Barre)                                                              | Momtor subject for general symptoms (headache, nausea, vertigo,               |                                                                            |                                                                |
| behavior change, or weakness)                                                |                                                                               |                                                                            |                                                                |
| Consider appropriate diagnostic testing (eg electromyogram and               |                                                                               |                                                                            |                                                                |
| nerve conduction investigations)                                             |                                                                               |                                                                            |                                                                |
| Symptomatic treatment with neurological consult as appropriate               |                                                                               |                                                                            |                                                                |
| Immune-related                                                               | Dose Modifications                                                            | Toxicity Management                                                        |                                                                |
| Severity                                                                     |                                                                               |                                                                            |                                                                |
| AE                                                                           | Grade 1                                                                       | No modifications                                                           |                                                                |
| Grade 2                                                                      | For acute motor neuropathies or neurotoxicity,                                | Discuss with the study physician                                           |                                                                |
| hold study drug/study regimen dose until                                     | Consider Neurology Consult                                                    |                                                                            |                                                                |
| resolution to Grade <l                                                       | Sensory neuropathy/neuropathic pain may be managed by appropriate             |                                                                            |                                                                |
| For sensory neuropathy/neuropathic pain,                                     | medications (eg, gabapentin, duloxetine, etc.)                                |                                                                            |                                                                |
| consider holding study drug/study regimen dose                               | Consider systemic steroids prednisone 1-2mg/kg/day or IV equivalent at 0.5    |                                                                            |                                                                |
| until resolution to Grade <l.                                                | to 1 mg/kg/day                                                                |                                                                            |                                                                |
| If toxicity worsens then treat as Grade 3 or                                 | If no improvement within 3 to 5 days, consider additional workup and          |                                                                            |                                                                |
| Grade 4                                                                      | treatment with addstional immunosuppressive therapy (eg IVIgG)                |                                                                            |                                                                |
| If toxicity improves to baseline then treat at next                          |                                                                               |                                                                            |                                                                |
| scheduled treatment date.                                                    |                                                                               |                                                                            |                                                                |
| Grade 3                                                                      | Hold Study drug/study regimen dose                                            | Discuss with study physician                                               |                                                                |
| until resolution to Grade <l                                                 | Consult Neurology Consult                                                     |                                                                            |                                                                |
| Permanently discontinue Study                                                | Consider hospitalization                                                      |                                                                            |                                                                |
| drug/study regimen if Grade 3 irAE does not                                  | Consider empiric IV corticosteroids (eg, methylprednisolone or IV             |                                                                            |                                                                |
| resolve to Grade ≤ 1 within 30 days.                                         | equivalent) at 1 to 2 mg/kg/day                                               |                                                                            |                                                                |
| Grade 4                                                                      | Permanently discontinue study drug/study                                      | If no improvement within 3 to 5 days, consider additional workup and       |                                                                |
| regimen                                                                      | treatment with additional immunosuppressants (eg IVIgG)                       |                                                                            |                                                                |
| Once stable, gradually taper steroids over ≥ 4 weeks.                        |                                                                               |                                                                            |                                                                |  
Immune response in patients with recurrent or metastatic non-small cell lung cancer and performance status of 2 treated with a combination of pembrolizumab and low dose weekly carboplatin/paclitaxel Comprehensive Cancer Center of Wake Forest University (CCCWFU)
CCWFU \# 62415  
| Immune-related                                                                 | Severity                                                                    | Dose Modifications                                    | Toxicity Management   |
|--------------------------------------------------------------------------------|-----------------------------------------------------------------------------|-------------------------------------------------------|-----------------------|
| AE                                                                             | The prompt diagnosis of immune-mediated peripheral neuromotor               |                                                       |                       |
| Immune-mediated                                                                | Any Grade                                                                   |                                                       |                       |
| peripheral neuromotos                                                          | syndromes is important, since certain subjects may unpredictably experience |                                                       |                       |
| syndromes, such as                                                             | acute decompensations which can result in substantial morbidity or in the   |                                                       |                       |
| Guillain-Barre and                                                             | worst case, death. Special care should be taken for certain sentinel        |                                                       |                       |
| Myasthenia Gravis                                                              | symptoms which may predict a more severe outcome, such as prominent         |                                                       |                       |
| dysphagia, rapidly progressive weakness, and signs of respiratory.             |                                                                             |                                                       |                       |
| insufficiency or autonomic instability                                         |                                                                             |                                                       |                       |
| Subjects should be evaluated to rule out any alternative etiology (eg. disease |                                                                             |                                                       |                       |
| progression, infections, metabolic syndromes and medications, etc.). It        |                                                                             |                                                       |                       |
| should be noted that the diagnosis of immune-mediated peripheral               |                                                                             |                                                       |                       |
| neuromotor syndromes can be particularly challenging in subjects with          |                                                                             |                                                       |                       |
| uderlying cancer, due to the multiple potential confounding effects of         |                                                                             |                                                       |                       |
| cancer (and its treatments) throughout the neuraxis.  Given the importance of  |                                                                             |                                                       |                       |
| prompt and accurate diagnosis, it is essential to have a low threshold to      |                                                                             |                                                       |                       |
| obtain a neurological consult                                                  |                                                                             |                                                       |                       |
| Neurophysiologic diagnostic testing (eg, electromyogram and nerve              |                                                                             |                                                       |                       |
| conduction investigations, and "repetitive stimulation" if myasthenia is       |                                                                             |                                                       |                       |
| suspected) are routinely indicated upon suspicion of such conditions and       |                                                                             |                                                       |                       |
| may be best facilitated by means of a neurology consultation                   |                                                                             |                                                       |                       |
| Important to consider that the use of steroids as the primary treatment of     |                                                                             |                                                       |                       |
| Guillain-Barre is not typically considered effective.  Subjects requiring      |                                                                             |                                                       |                       |
| treatment should be considered for plasmapheresis (or IVIgG, as an             |                                                                             |                                                       |                       |
| aternative)                                                                    |                                                                             |                                                       |                       |
| Grade 1                                                                        | No dose modification                                                        | Discuss with the study physician                      |                       |
| Care should be taken to monitor subjects for sentinel symptoms of a            |                                                                             |                                                       |                       |
| potential decompensation as described above.                                   |                                                                             |                                                       |                       |
| Consider a neurology consult unless the symptoms are very minor and stable     |                                                                             |                                                       |                       |
| Toxicity Management                                                            |                                                                             |                                                       |                       |
| Immune-related                                                                 | Severity                                                                    | Dose Modifications                                    |                       |
| AE                                                                             | Grade 2                                                                     | Hold study drug/study regimen dose until              | Grade 2 : Moderates   |
| resolution to Grade <l                                                         | Discuss with the study physician                                            |                                                       |                       |
| Permanently discontinue study drug/study                                       | Care should be taken to monitor subjects for sentinel symptoms of a         |                                                       |                       |
| regimen if it does not resolve to Grade < 1 within                             | potential decompensation as described above                                 |                                                       |                       |
| 30 days or if there are signs of respiratory                                   | Obtain a Neurology Consult                                                  |                                                       |                       |
| insufficiency or autonomic instability                                         | Sensory neuropathy/neuropathic pain may be managed by appropriate           |                                                       |                       |
| medications (eg, gabapentin, duloxetine, etc.)                                 |                                                                             |                                                       |                       |
| MYASTHENIA GRAVIS                                                              |                                                                             |                                                       |                       |
| Steroids may be successfully used to treat Myasthenia Gravis. Important to     |                                                                             |                                                       |                       |
| consider that steroid therapy (especially with high doses) may result in       |                                                                             |                                                       |                       |
| transient worsening of myasthenia and should typically be administered in a    |                                                                             |                                                       |                       |
| monitored setting under supervision of a consulting neurologist.               |                                                                             |                                                       |                       |
| Subjects unable to tolerate steroids may be candidates for treatment with      |                                                                             |                                                       |                       |
| plasmapheresis or IVIgG. Such decisions are best made in consultation with     |                                                                             |                                                       |                       |
| a neurologist, taking into account the unique needs of each patient            |                                                                             |                                                       |                       |
| If Myasthenia Gravis-like neurotoxicity present, consider starting             |                                                                             |                                                       |                       |
| acetylcholine esterase (AChE) inhibitor therapy in addition to steroids. Such  |                                                                             |                                                       |                       |
| therapy, if successful, can also serve to reinforce the diagnosis.             |                                                                             |                                                       |                       |
| GUILLAIN-BARRE:                                                                |                                                                             |                                                       |                       |
| Important to consider here that the use of steroids as the primary treatment   |                                                                             |                                                       |                       |
| of Guillain-Barre is not typically considered effective.  Subjects requiring   |                                                                             |                                                       |                       |
| treatment should be considered for plasmapharesis (or IVIgG, as an             |                                                                             |                                                       |                       |
| altemative).                                                                   |                                                                             |                                                       |                       |
| Grade 3                                                                        | Hold study drug/study regimen dose until                                    | For severe or life threatening (Grade 3 or 4) events: |                       |
| resolution to Grade < 1                                                        | Discuss with study physician                                                |                                                       |                       |
| Permanently discontinue Study drug/study                                       | Recommend hospitalization                                                   |                                                       |                       |
| regimen if Grade 3 irAE does not resolve to                                    |                                                                             |                                                       |                       |
| Grade < 1 within 30 days or if there are signs of                              | Monitor symptoms and obtain neurological consult                            |                                                       |                       |
| MYASTHENIA GRAVIS                                                              |                                                                             |                                                       |                       |
| respiratory insufficiency or autonomic instability.                            |                                                                             |                                                       |                       |  
Immune response in patients with recurrent or metastatic non-small cell lung cancer and performance status of 2 treated with a combination of pembrolizumab and low dose weekly carboplatin/paclitaxel Comprehensive Cancer Center of Wake Forest University (CCCWFU)
CCCWFU \# 62415
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7.3 pembrolizumab dose modifications for

Dose modifications are not required for adverse events that are not deemed to be related to study treatment (ie events due to underlying disease) or for laboratory abnormalities not deemed to be clinically significant. Grade 1: No dose modification.  
Grade 2: Hold Pembrolizumab dose until resolution to Grade ≤1 or baseline.  
Grade 3: Hold Study Regimen until resolution to Grade ≤ 1 or baseline.  
For adverse events that downgrade to Grade ≤ 2 within 7 days or resolve to Grade ≤1 or baseline within 14 days, resume Pembrolizumab administration at next scheduled dose. Otherwise, discontinue Pembrolizumab.  
Grade 4: Discontinue Pembrolizumab Immune response in patients with recurrent or metastatic non-small cell lung cancer and performance status of 2 treated with a combination of pembrolizumab and low dose weekly carboplatin/paclitaxel Comprehensive Cancer Center of Wake Forest University (CCCWFU)
CCCWFU \# 62415  
| NCI CTCAE Grade                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                              | Treatment                                                                                                                                                                                                                                                     | Premedication atsubsequent  dosing   |
|------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|---------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|--------------------------------------|
| Grade 1 Mild reaction; infusioninterruption  not indicated; intervention not  indicated                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                      | Increase monitoring of vital signs asmedically  indicated until the subject is deemedmedically  stable in the opinion of theinvestigator.                                                                                                                     | None                                 |
| Grade 2 Requires infusion interruption but  responds promptly to symptomatic  treatment (e.g., antihistamines,  NSAIDS, narcotics, IV fluids);  prophylactic medications indicatedfor < =24 hrs                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                              | Subject may be premedicated 1.5h  (± 30 minutes) prior to infusion of  pembrolizumab (MK-3475) with:                                                                                                                                                          |                                      |
| Stop Infusion and monitor symptoms.  Additional appropriate medical therapymay  include but is not limited to: IV fluids  Antihistamines  NSAIDS Acetaminophen  Narcotics Increase monitoring of vital signs asmedically  indicated until the subject is deemedmedically  stable in the opinion of theinvestigator. If symptoms resolve within one hour ofstopping  drug infusion, the infusion may be restarted at  50% of the original infusion rate (e.g., from100  mL/hr to 50 mL/hr). Otherwise dosing willbe  held until symptoms resolve and the subject  should be premedicated for the nextscheduled  dose. Subjects who develop Grade 2 toxicity despite  adequate premedication should be  permanently discontinued from further trial  treatment administration. | Diphenhydramine 50 mg po (or  equivalent dose of antihistamine). Acetaminophen 500-1000 mg po  (or equivalent dose of antipyretic).                                                                                                                           |                                      |
| Grades 3 or 4                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                | Stop Infusion. Additional appropriate medical therapymay  include but is not limited to: IV fluids  Antihistamines  NSAIDS Acetaminophen  Narcotics  Oxygen  Pressors  Corticosteroids  Epinephrine                                                           | No subsequent dosing                 |
| Grade 3: Prolonged (i.e., not rapidlyresponsive  to symptomatic medication and/or  brief interruption of infusion);  recurrence of symptoms following  initial improvement; hospitalization  indicated for other clinicalsequelae  (e.g., renal impairment, pulmonary  infiltrates) Grade 4: Life-threatening; pressor or ventilatory  support indicated                                                                                                                                                                                                                                                                                                                                                                                                                     | Increase monitoring of vital signs asmedically  indicated until the subject is deemedmedically  stable in the opinion of theinvestigator. Hospitalization may be indicated. Subject is permanently discontinued from  further trial treatment administration. |                                      |
| Appropriate resuscitation equipment should be available in the room and a physician readily available during the period of drug  administration.                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                             |                                                                                                                                                                                                                                                               |                                      |
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7.4 management of infusion reactions

Signs and symptoms usually develop during or shortly after drug infusion and generally resolve completely within 24 hours of completion of infusion. See table below for infusion reaction treatment guidelines.  
Immune response in patients with recurrent or metastatic non-small cell lung cancer and performance status of 2 treated with a combination of pembrolizumab and low dose weekly carboplatin/paclitaxel Comprehensive Cancer Center of Wake Forest University (CCCWFU)
CCCWFU \# 62415
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7.5 paclitaxel and carboplatin dose

Nausea and vomiting may be acute (onset 1–4 hours after infusion) or delayed (begins or persists ≥ 24 hours after infusion). To combat chemotherapy-induced nausea and vomiting, the following algorithm should be used:
a) Nonsteroidal anti-emetics, such as a 5-HT3 antagonist (e.g.,
ondansetron), should be utilized for first-line management of symptoms b) If dexamethasone on Day 1 followed by nonsteroidal antiemetics on subsequent days does not sufficiently manage symptoms, dexamethasone 8 mg orally may be administered on Day 2 and/or Day 3.
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8.1 measurement of effect 8.2

Qualified subjects will be staged by a CT chest/abdomen or CT portion of a PET/CT, and a brain MRI at baseline (Appendix E). Target and non-target lesions will be followed by CT or MRI for PFS according to immune-related Response Evaluation Criteria In Solid Tumors (irRECIST) at Week 8 (± 3 days),
and every 12 weeks (± 7 days) thereafter (Appendix E). If there is suspicion of tumor progression at eight weeks, a second CT/MRI study four weeks after will need to be done as a confirmatory test.  
Immune response in patients with recurrent or metastatic non-small cell lung cancer and performance status of 2 treated with a combination of pembrolizumab and low dose weekly carboplatin/paclitaxel Comprehensive Cancer Center of Wake Forest University (CCCWFU)
CCCWFU \# 62415
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8.2.1 definitions

- Evaluable for toxicity: All patients will be evaluable for toxicity from the time of their first treatment with pemetrexed
- Inevaluable for objective response: When no imaging/measurement is done at all at a particular time point, the patient is not evaluable (NE) at that time point.  
o If only a subset of lesion measurements are made at an assessment, usually the case is also considered NE at that time point, unless a convincing argument can be made that the contribution of the individual missing lesion(s) would not change the assigned time point response. This would most likely happen in the case of PD.
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8.2.2 methods for evaluation of

Unscheduled evaluations may be done at the discretion of the investigator as needed to assess the subject's clinical status. The imaging technique used for each subject (CT or MRI) is at the discretion of the investigator, but the same technique must be used for each individual subject throughout the study. Imaging should not be delayed in case of missed doses or dose delays.
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8.2.3 response criteria - irrecist

The total measured tumor burden (TMTB) is established at baseline as the sum of the longest diameters (SOD)—the shortest axes should be used for lymph nodes—of all target lesions (≤ 2 lesions per organ, ≤ 5 lesions total). At each subsequent tumor assessment (TA), the SOD of new, measurable lesions (≥ 10 mm [lymph nodes ≥ 15 mm in shortest diameter]; ≤ 2 new lesions per organ, ≤ 5 new lesions total) is added to the SOD of the target lesions to provide the updated TMTB:
TMTB = SOD target lesions + SOD new, measurable lesions Percentage changes in TMTB at each TA describe the size and growth kinetics of both old and new, measurable lesions as they appear. At each TA, the response in TMTB is defined as follows:
o Complete Response (irCR): Complete disappearance of all target and new, measurable lesions, with the exceptions of lymph nodes which must decrease to < 10 mm in short axis o Partial Response (irPR): Decrease in TMTB ≥ 30% relative to baseline Immune response in patients with recurrent or metastatic non-small cell lung cancer and performance status of 2 treated with a combination of pembrolizumab and low dose weekly carboplatin/paclitaxel Comprehensive Cancer Center of Wake Forest University (CCCWFU)
CCCWFU \# 62415  
o Stable Disease (irSD): Not meeting criteria for irCR or irPR, in absence of irPD
o Progressive Disease (irPD): Increase in TMTB ≥ 20% relative to nadir
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response in non-target lesions

The presence of non-target lesions is established at baseline; at each TA,
the presence of any new, non-measurable lesions is assessed. The presence of new, non-measurable lesions will rule out an overall response of irCR. An increase in the size or number of new, nonmeasurable lesions does not necessarily imply an overall response of irPD; if these lesions become measurable (≥ 10 mm [lymph nodes ≥ 15 mm in shortest diameter]; up to 2 new lesions per organ, total 5 new lesions) at a subsequent TA, their measurement will, at that point, start to contribute to the TMTB. The response in non-target lesions is defined as follows:
o Complete Response (irCR): Complete disappearance of all nontarget lesions o non-irCR/non-irPD: Non-target lesions do not meet the criteria for irCR or irPD
o Progressive Disease (irPD): Unequivocal increase in the number or size of non-target lesions. To achieve unequivocal progression of non-target lesions, there must be a substantial worsening of non-target disease of a magnitude that, according to the treating physician, warrants a change in anticancer therapy NOTE: Equivocal findings of progression of non-target lesions (e.g., small and uncertain new lesions; cystic changes or necrosis in existing lesions) should be considered irSD and treatment may continue until the next scheduled assessment.
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overall response

The overall response according to irRECIST is derived from the responses in TMTB as well as the presence of any non-target lesions as follows:
o Complete Response (irCR): Complete disappearance of all lesions (whether measurable or not); lymph nodes must decrease to < 10 mm in shortest dimension o Partial Response (irPR): Decrease in TMTB ≥ 30% relative to baseline o Stable Disease (irSD): Not meeting criteria for irCR or irPR, in absence of irPD
o Progressive Disease (irPD): Increase in TMTB ≥ 20% relative to nadir Immune response in patients with recurrent or metastatic non-small cell lung cancer and performance status of 2 treated with a combination of pembrolizumab and low dose weekly carboplatin/paclitaxel Comprehensive Cancer Center of Wake Forest University (CCCWFU)
CCCWFU \# 62415
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8.2.4 assessment for efficacy

The following efficacy parameters will be assessed by independent radiology review according to irRECIST, and are defined as follows:
Objective response rate: the proportion of subjects who achieve complete or partial response Duration of best response: the duration of time from the date measurement criteria are first met for irCR, or irPR (if irCR is never met), until the first date that irPD is confirmed by independent radiology review or death, whichever comes first Disease control rate: the percentage of subjects who achieved irCR, irPR,
or irSD Duration of disease control: the duration of time from the date measurement criteria are first met for irCR, irPR, or irSD, until thefirst date that irPD is confirmed by independent radiology review or death, whichever comes first
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8.2.5 survival outcomes

Progression-free survival: the duration of time from randomization to the time of irPD or death, whichever comes first. Overall survival is defined as the duration of time from randomization to the time of death due to any cause, or the date the subject was last confirmed to be alive.
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9.1 adverse events list and

9.2 **Adverse Event Lists**
Pembrolizumab: Most common adverse reactions (reported in ≥20% of patients) included fatigue, cough, nausea, pruritus, rash, decreased appetite, constipation, arthralgia, and diarrhea. The most frequent serious adverse drug reactions reported in 2% or more of patients were renal failure, dyspnea, pneumonia, and cellulitis.  
Paclitaxel: The most common adverse reactions (incidence ≥25%) include neutropenia, leukopenia, anemia, infections, hypersensitivity reactions, abnormal ECG, peripheral neuropathy, myalgia/arthralgia, nausea/vomiting, diarrhea, mucositis, and alopecia.  
Carboplatin: Bone marrow suppression is the dose-limiting toxicity of Carboplatin.  
The most common adverse reactions (incidence ≥20%) during therapy with carboplatin as a single agent were thrombocytopenia, neutropenia, leukopenia, Immune response in patients with recurrent or metastatic non-small cell lung cancer and performance status of 2 treated with a combination of pembrolizumab and low dose weekly carboplatin/paclitaxel Comprehensive Cancer Center of Wake Forest University (CCCWFU)
CCCWFU \# 62415 anemia, nausea/vomiting, blood urea elevation, alkaline phosphatase elevation, electrolyte depletion, and pain.
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9.3 adverse event characteristics

- CTCAE term (AE description) and **grade:** The descriptions and grading scales found in the revised NCI Common Terminology Criteria for Adverse Events (CTCAE) version 4.03 will be utilized for AE reporting. All appropriate treatment areas should have access to a copy of the CTCAE version 4.03. A copy of the CTCAE version 4.03 can be downloaded from the CTEP web site (http://ctep.cancer.gov).  
- **'Expectedness'**: AEs can be 'Unexpected' or 'Expected' (see Section 7.1 above) for expedited reporting purposes only.
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- attribution of the ae

- Definite - The AE **is clearly related** to the study treatment.  
- Probable - The AE **is likely related** to the study treatment. - Possible - The AE **may be related** to the study treatment.  
- Unlikely - The AE **is doubtfully related** to the study treatment.  
- Unrelated - The AE **is clearly NOT related** to the study treatment.
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9.4 dsmc sae reporting requirements

The Date and Safety Monitoring Committee is responsible for reviewing SAEs for WFBCCC Institutional studies are outlined in Appendix D. All Adverse Events that occur during protocol intervention and are coded as either 1) unexpected grade 4, 2) unplanned inpatient hospitalization ≥ 24 hours (regardless of grade), or grade 5 (death)
must be reported to the DSMC using the SAE console in WISER.  
All WFBCCC Clinical Protocol and Data Management (CPDM) staff members assisting a Principal Investigator in investigating, documenting and reporting an SAE qualifying for DSMC reporting are responsible for informing a clinical member of the DSMC as well as the entire committee via the email notification procedure of the occurrence of an SAE.
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9.5 wfuhs irb ae reporting

Any unanticipated problems involving risks to subjects or others and adverse events shall be promptly reported to the IRB, according to institutional policy. Reporting to the IRB is required regardless of the funding source, study sponsor, or whether the event involves an investigational or marketed drug, biologic or device. Reportable events are not limited to physical injury, but include psychological, economic and social harm.  
Reportable events may arise as a result of drugs, biological agents, devices, procedures or other interventions, or as a result of questionnaires, surveys, observations or other interactions with research subjects.  
Immune response in patients with recurrent or metastatic non-small cell lung cancer and performance status of 2 treated with a combination of pembrolizumab and low dose weekly carboplatin/paclitaxel Comprehensive Cancer Center of Wake Forest University (CCCWFU)
CCCWFU \# 62415 All members of the research team are responsible for the appropriate reporting to the IRB and other applicable parties of unanticipated problems involving risk to subjects or others. The Principal Investigator, however, is ultimately responsible for ensuring the prompt reporting of unanticipated problems involving risk to subjects or others to the IRB. The Principal Investigator is also responsible for ensuring that all reported unanticipated risks to subjects and others which they receive are reviewed to determine whether the report represents a change in the risks and/or benefits to studyparticipants, and whether any changes in the informed consent, protocol or other study-related documents are required. Any unanticipated problems involving risks to subjects or others occurring at a site where the study has been approved by the WFUHS IRB (internal events) must be reported to the WFUHS IRB within 7 calendar days of the investigator or other members of the study team becoming aware of the event. Any unanticipated problems involving risks to subjects or others occurring at another site conducting the same study that has been approved by the WFUHS IRB (external events) must be reported to the WFUHS IRB within 7 calendar days of the investigator or other members of the study team becoming aware of the event. Any event, incident, experience, or outcome that alters the risk versus potential benefit of the research and as a result warrants a substantive change in the research protocol or informed consent process/document in order to insure the safety, rights or welfare of research subjects.
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9.6 sponsor reporting requirements 9.5.1

A serious adverse event is any adverse event occurring at any dose or during any use of Merck's product that:
- Results in death; - Is life threatening;
- Results in persistent or significant disability/incapacity; - Results in or prolongs an existing inpatient hospitalization;
- Is a congenital anomaly/birth defect; - Is a new cancer (that is not a condition of the study); - Is associated with an overdose; - Is another important medical event
Any serious adverse event, or follow up to a serious adverse event, including death due to any cause other than progression of the cancer under study that occurs to any subject from the time the consent is signed through 90 days following cessation of treatment, or the initiation of new anti-cancer therapy, whichever is earlier, whether or not related to Merck product, must be reported within 24 hours to the Sponsor and within 2 working days to Merck GlobalSafety.  
Non-serious Events of Clinical Interest will be forwarded to Merck Global Safety and will be handled in the same manner as SAEs.  
Immune response in patients with recurrent or metastatic non-small cell lung cancer and performance status of 2 treated with a combination of pembrolizumab and low dose weekly carboplatin/paclitaxel Comprehensive Cancer Center of Wake Forest University (CCCWFU)
CCCWFU \# 62415 Additionally, any serious adverse event, considered by an investigator who is a qualified physician to be related to Merck product that is brought to the attention of the investigator at any time outside of the time period specified in the previous paragraph also must be reported immediately to the Sponsor and to Merck. SAE reports and any other relevant safety information are to be forwarded to the Merck Global Safety facsimile number: +1-215-993-1220 A copy of all 15 Day Reports and Annual Progress Reports is submitted as required by FDA. Investigators will cross reference this submission according to local regulations to the Merck Investigational Compound Number (IND, CSA, etc.) at the time of submission. Additionally investigators will submit a copy of these reports to Merck & Co., Inc. (Attn: Worldwide Product Safety; FAX 215 993-1220) at the time of submission to FDA. All subjects with serious adverse events must be followed up for outcome.
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9.5.2 events of clinical interest

Selected non-serious and serious adverse events are also known as Events of Clinical Interest (ECI) and must be recorded as such on the Adverse **Event**
case report forms/worksheets and reported within 24 hours to the Sponsor and within 2 working days to Merck Global Safety. (Attn: Worldwide Product Safety; FAX 215 993-1220) Events of clinical interest for this trial include:  
1. an overdose of Merck product that is not associated with clinical symptoms or abnormal laboratory results.  
2. an elevated AST or ALT lab value that is greater than or equal to 3X the upper limit of normal and an elevated total bilirubin lab value that is greater than or equal to 2X the upper limit of normal and, at the same time, an alkaline phosphatase lab value that is less than 2X the upper limit of normal, as determined by way of protocol-specified laboratory testing or unscheduled laboratory testing.  
1. Additional adverse events:
A separate guidance document has been provided entitled "Event of Clinical Interest Guidance Document" (previously entitled, "Event of Clinical Interest and Immune-Related Adverse Event Guidance Document"). This document can be found in Appendix O and provides guidance regarding identification, evaluation and management of ECIs and irAEs.  
ECIs (both non-serious and serious adverse events) identified in this guidance document from the date of first dose through 90 days following cessation of treatment, or 30 days after the initiation of a new anticancer therapy, whichever is earlier, need to be reported within 24 hours to the Sponsor and within 2 working Immune response in patients with recurrent or metastatic non-small cell lung cancer and performance status of 2 treated with a combination of pembrolizumab and low dose weekly carboplatin/paclitaxel Comprehensive Cancer Center of Wake Forest University (CCCWFU)
CCCWFU \# 62415 days to Merck Global Safety. (Attn: Worldwide Product Safety; FAX 215 9931220), regardless of attribution to study treatment, consistent with standardSAE
reporting guidelines. Subjects should be assessed for possible ECIs prior to each dose. Lab results should be evaluated and subjects should be asked for signs and symptoms suggestive of an immune-related event. Subjects who develop an ECI thought to be immune-related should have additional testing to rule out other etiologic causes. If lab results or symptoms indicate a possible immune-related ECI, then additional testing should be performed to rule out other etiologic causes. If no other cause is found, then it is assumed to be immune-related.
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9.5.3 sponsor responsibility for reporting

All Adverse Events will be reported to regulatory authorities, IRB/IECs and investigators in accordance with all applicable global laws and regulations.
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10.1 pharmaceutical information

A list of the adverse events and potential risks associated with the investigational or commercial agents administered in this study can be found in Section 9.0.
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10.3 keytruda (pembrolizumab)

Product description: Include the available dosage forms, ingredients, and packaging, as appropriate. Also state the agent's supplier.  
Marketed Packs: When Study Drug is provided in the marketed package, Merck will not supply any Chemistry, Manufacturing, Control (CMC) information. Institution's regulatory submission should reference the Merck Marketing Authorization. If any additional labelling of containers is required, e.g. to add Study Protocol number, and it has not been agreed for Merck to perform the additional labelling, it is Institution's responsibility to arrange for this action to be done in accordance with U.S. regulations.
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solution preparation

Reconstitution of KEYTRUDA for Injection (Lyophilized Powder)
- Add 2.3 mL of Sterile Water for Injection, USP by injecting the water along the walls of the vial and not directly on the lyophilized powder (resulting concentration 25 mg/mL).  
Immune response in patients with recurrent or metastatic non-small cell lung cancer and performance status of 2 treated with a combination of pembrolizumab and low dose weekly carboplatin/paclitaxel Comprehensive Cancer Center of Wake Forest University (CCCWFU)
CCCWFU \# 62415
- Slowly swirl the vial. Allow up to 5 minutes for the bubbles to clear. Do not shake the vial.  
Preparation for Intravenous Infusion
- Visually inspect the solution for particulate matter and discoloration prior to administration. The solution is clear to slightly opalescent, colorless to slightly yellow. Discard the vial if visible particles are observed.  
- Dilute KEYTRUDA injection (solution) or reconstituted lyophilized powder prior to intravenous administration.  
- Withdraw the required volume from the vial(s) of KEYTRUDA and transfer into an intravenous (IV) bag containing 0.9% Sodium Chloride Injection, USP or 5% Dextrose Injection, USP. Mix diluted solution by gentle inversion. The final concentration of the diluted solution should be between 1 mg/mL to 10 mg/mL.  
- Discard any unused portion left in the vial.
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storage requirements

Do not freeze. The product does not contain a preservative. Store the reconstituted and diluted solution from the KEYTRUDA 50 mg vial either:
- At room temperature for no more than 6 hours from the time of reconstitution. This includes room temperature storage of reconstituted vials, storage of the infusion solution in the IV bag, and the duration of infusion.  
- Under refrigeration at 2°C to 8°C (36°F to 46°F) for no more than 24 hours from the time of reconstitution. If refrigerated, allow the diluted solution to come to room temperature prior to administration.  
Store the diluted solution from the KEYTRUDA 100 mg/4 mL vial either:
- At room temperature for no more than 6 hours from the time of dilution.This includes room temperature storage of the infusion solution in the IV bag, and the duration of infusion.  
- Under refrigeration at 2°C to 8°C (36°F to 46°F) for no more than 24 hours from the time of dilution. If refrigerated, allow the diluted solution to come to room temperature prior to administration.  
Stability: Include the stability of the original dosage form, reconstituted solution, and final diluted product, as applicable.  
Route of administration: Administer infusion solution intravenously over 30 minutes through an intravenous line containing a sterile, non-pyrogenic, lowprotein binding 0.2 micron to 5 micron in-line or add-on filter. Do not coadminister other drugs through the same infusion line.  
Disposal: To minimize the risk of dermal exposure, always wear impervious gloves when handling vials containing paclitaxel. If paclitaxel contacts the skin, immediately wash the skin thoroughly with soap and water. If paclitaxel contacts mucous membranes, the membranes should be flushed immediately and thoroughly with water.  
Immune response in patients with recurrent or metastatic non-small cell lung cancer and performance status of 2 treated with a combination of pembrolizumab and low dose weekly carboplatin/paclitaxel Comprehensive Cancer Center of Wake Forest University (CCCWFU)
CCCWFU \# 62415
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10.4 taxol (paclitaxel)

Product description: Paclitaxel is a natural product with antitumor activity. Taxol
(paclitaxel) is obtained via a semi-synthetic process from *Taxus baccata*. The chemical name for paclitaxel is 5β,20-Epoxy-1,2α,4,7β,10β,13α-hexahydroxytax11-en-9-one 4,10-diacetate 2-benzoate 13-ester with (2R,3S)-N-benzoyl-3phenylisoserine. Taxol (paclitaxel) Injection is a clear, colorless to slightly yellow viscous solution.  
Solution preparation: It is supplied as a nonaqueous solution intended for dilution with a suitable parenteral fluid prior to intravenous infusion. Taxol is available in 30 mg (5 mL), 100 mg (16.7 mL), and 300 mg (50 mL) multidose vials. Each mL of sterile nonpyrogenic solution contains 6 mg paclitaxel, 527 mg of purified Cremophor® EL* (polyoxyethylated castor oil) and 49.7% (v/v) dehydrated alcohol, USP. Taxol should be diluted in 0.9% Sodium Chloride Injection, USP; 5% Dextrose Injection, USP; 5% Dextrose and 0.9% Sodium Chloride Injection, USP; or 5% Dextrose in Ringer's Injection to a final concentration of 0.3 to 1.2 mg/mL.  
Storage requirements and Stability: Unopened vials of Taxol (paclitaxel)
Injection are stable until the date indicated on the package when stored between 20°–25° C (68°–77° F), in the original package. Neither freezing nor refrigeration adversely affects the stability of the product. Upon refrigeration, components in the Taxol vial may precipitate, but will redissolve upon reaching room temperature with little or no agitation. There is no impact on product quality under these circumstances. If the solution remains cloudy or if an insoluble precipitate is noted, the vial should be discarded. Solutions for infusion prepared as recommended are stable at ambient temperature (approximately 25° C) and lighting conditions for up to 27 hours. Store the vials in original cartons between 20°–25° C (68°–77° F). Retain in the original package to protect from light.  
Route of administration: Intravenous. Taxol should be administered through an in-line filter with a microporous membrane not greater than 0.22 microns.  
Drug interactions: The metabolism of Taxol is catalyzed by cytochromeP450 isoenzymes CYP2C8 and CYP3A4. Caution should be exercised when Taxol is concomitantly administered with known substrates (eg, midazolam, buspirone, felodipine, lovastatin, eletriptan, sildenafil, simvastatin, and triazolam), inhibitors (eg, atazanavir, clarithromycin, indinavir, itraconazole, ketoconazole, nefazodone, nelfinavir, ritonavir, saquinavir, and telithromycin), and inducers (eg, rifampin and carbamazepine) of CYP3A4. Caution should also be exercised when Taxol is concomitantly administered with known substrates (eg, repaglinide and rosiglitazone), inhibitors (eg, gemfibrozil), and inducers (eg, rifampin) of CYP2C8.  
Disposal: To minimize the risk of dermal exposure, always wear impervious gloves when handling vials containing paclitaxel. If paclitaxel contacts the skin, Immune response in patients with recurrent or metastatic non-small cell lung cancer and performance status of 2 treated with a combination of pembrolizumab and low dose weekly carboplatin/paclitaxel Comprehensive Cancer Center of Wake Forest University (CCCWFU)
CCCWFU \# 62415 immediately wash the skin thoroughly with soap and water. If paclitaxel contacts mucous membranes, the membranes should be flushed immediately and thoroughly with water.
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10.5 carboplatin

Product description: The chemical name for Carboplatin is platinum, diammine
[1,1-cyclobutanedicarboxylato(2-)-*O,O'*]-,(SP-4-2). It is supplied as a sterile, pyrogen-free, 10 mg/mL aqueous solution.  
Solution preparation: Carboplatin injection is a premixed aqueous solution of 10 mg/mL Carboplatin. Carboplatin aqueous solution can be further diluted to concentrations as low as 0.5 mg/mL with 5% Dextrose in Water (D5W) or 0.9% Sodium Chloride Injection, USP. Needles or intravenous administration sets containing aluminum parts that may come in contact with Carboplatin injection should not be used for the preparation or administration of the drug. Aluminum can react with Carboplatin causing precipitate formation and loss of potency.  
Storage requirements and Stability: When prepared as directed, Carboplatin aqueous solutions are stable for 8 hours at room temperature (25° C). Since no antibacterial preservative is contained in the formulation, it is recommended that Carboplatin aqueous solutions be discarded 8 hours after dilution. Unopened vials of Carboplatin injection are stable to the date indicated on the package when stored at 20° - 25° C (68° to 77° F) [see USP Controlled Room Temperature]. Protect from light. Carboplatin injection multidose vials maintain microbial, chemical, and physical stability for up to 14 days at 25° C following multiple needle entries. Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration.
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route of administration intravenous

Drug interactions: The renal effects of nephrotoxic compounds may be potentiated by Carboplatin.  
Disposal: To minimize the risk of dermal exposure, always wear impervious gloves when handling vials containing Carboplatin injection. If Carboplatin injection contacts the skin, immediately wash the skin thoroughly with soap and water. If Carboplatin injection contacts mucous membranes, the membranes should be flushed immediately and thoroughly with water.