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11.2 calendar

A visit window of +/- 3 days is allowed for labs (hematology and chemistries including TSH, T3, T4 and HCG, vital signs, weight and performance status)
A visit window of +/- 1 day is allowed for treatment. A visit window of +/- 7 days is allowed for 3 month follow-up visits.  
A visit window of +/- 3 days is allowed for the 30 Day follow-up visit.  
| After  completion  of 3 cycles  of  treatment                | 30 Day                                                  | Long Term   |                     |                      |    |    |
|--------------------------------------------------------------|---------------------------------------------------------|-------------|---------------------|----------------------|----|----|
| Follow-Up                                                    | Follow-Up (see section  11.1.4 for  details)            |             |                     |                      |    |    |
| REQUIRED  ASSESSMENTS Informed Consent                       | X                                                       |             |                     |                      |    |    |
| Demographics                                                 | X                                                       |             |                     |                      |    |    |
| Medical History                                              | X                                                       |             |                     |                      |    |    |
| Height                                                       | X                                                       |             |                     |                      |    |    |
| Weight and Body Surface  Analysis                            | X                                                       | X           | X                   | X                    | X  | X  |
| Vitals including blood  pressure                             | X                                                       | X           | X                   | X                    | X  | X  |
| Physical Examination                                         | X                                                       | X           | X                   | X                    |    |    |
| Concomitant medication+  allergy assessment                  | X                                                       | X           | X                   | X                    | X  | X  |
| ECOG PS                                                      | X                                                       | X           | X                   | X                    | X  | X  |
| Baseline Symptoms                                            | X                                                       | X           |                     |                      |    |    |
| Adverse Event Assessment                                     | X                                                       | X           | X                   | X                    | X  | X  |
| CBC / diff / platelets                                       | X                                                       | X           | X                   | X                    | X  | X  |
| Serum Chemistry                                              | X                                                       | X           | X                   | X                    | X  | X  |
| Urinalysis                                                   | X                                                       |             |                     |                      |    |    |
| TSH, T4 Thyroxine, T35                                       | X                                                       | X           |                     |                      |    |    |
| ß-HCG, women of  childbearing potential                      | X                                                       | X           |                     |                      |    |    |
| (Cycle 1 only)                                               | Cycles                                                  |             |                     |                      |    |    |
| Study Days                                                   | Screening                                               | 1-n 1 Day 1 | Cycles  1-n 1 Day 8 | Cycles  1-n 1 Day 15 |    |    |
| DISEASE ASSESSMENT MRI Brain (see section  11.1 for details) | X                                                       | X           | X                   | X                    |    |    |
| CT Chest, Abdomen and  Pelvis 3                              | X                                                       | X           |                     |                      |    |    |
| Bone Scan                                                    | X                                                       | X           |                     |                      |    |    |
| TREATMENT Nab-paclitaxel4                                    | X                                                       | X           | X                   |                      |    |    |
| Carboplatin4                                                 | X                                                       |             |                     |                      |    |    |
| Pembrolizumab4                                               | X                                                       |             |                     |                      |    |    |
| CORRELATIVE                                                  | X (Optional  after  completion  of 1st 3  cycles only)2 |             |                     |                      |    |    |
| 1 Patients may receive treatment for up to 24 months         |                                                         |             |                     |                      |    |    |
| Biopsy                                                       | X                                                       |             |                     |                      |    |    |  
X (Optional after completion of 1st 3 cycles only)2 1 Patients may receive treatment for up to 24 months 2Biopsy must be completed before the initiation of cycle 4 3Cycle 3 assessment scans must be done at the conclusion of cycle 3 but before the initiation of cycle 4.  
4 Patients who discontinue carboplatin and/or nab-paclitaxel due to experiencing known toxicities to carboplatin and/or nab-paclitaxel will continue to follow the study calendar for all tests and procedures done on Day 1 of each consecutive cycle if they continue to receive carboplatin or on Day1, 8 and 15 of each consecutive cycles if they continue to receive nab-paclitaxel. Patients receiving pembrolizumab only will follow the study calendar for all tests and procedures done on Day 15 of each consecutive cycle.  
5 Patients receiving pembrolizumab only will have thyroid testing done on Day 15 of each consecutive cycle.
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12.0 measurement of effect

Clinical response will be scored according to RECIST Criteria v1.1. As an exploratory objective, we will score clinical response using irRECIST criteria [40].
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13.0 data reporting / regulatory

Adverse event lists, guidelines, and instructions for AE reporting can be found in Section 8.0 (Adverse Events: List and Reporting Requirements).
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13.1 data reporting

The OnCore® and Forte EDC Databases will be utilized, as required by the Case Comprehensive Cancer Center, to provide data collection for both accrual entry and trial data management. OnCore® is a Clinical Trials Management System housed on secure servers maintained at Case Western Reserve University. Forte EDC is an electronic data capture system which supports 21 CFR Part 11 compliance. Access to data through Forte EDC is restricted by user accounts and assigned roles. Once logged into the OnCore ®
and Forte EDC systems with a user ID and password, defined roles for each user limit access to appropriate data. User information and password can be obtained by contacting the OnCore ®Administrator at OnCore-registration@case.edu.  
OnCore® and Forte EDC are designed with the capability for study setup, activation, tracking, reporting, data monitoring and review, and eligibility verification. This study will utilize electronic Case Report Form completion in the Forte EDC database. A
calendar of events and required forms are available in OnCore® and Forte EDC
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13.2 regulatory considerations

The study will be conducted in compliance with ICH guidelines and with all applicable federal (including 21 CFR parts 56 & 50), state or local laws.
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13.2.1 written informed consent

Provision of written informed consent must be obtained prior to any study-related procedures. The Principal Investigator will ensure that the subject is given full and adequate oral and written information about the nature, purpose, possible risks and benefits of the study as well as the subject's financial responsibility. Subjects must also be notified that they are free to discontinue from the study at any time. The subject should be given the opportunity to ask questions and be allowed time to consider the information provided. The original, signed written Informed Consent Form must be kept with the Research Chart in conformance with the institution's standard operating procedures. A copy of the signed written Informed Consent Form must be given to the subject. Additionally, documentation of the consenting process should be located in the research chart.
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13.2.2 subject data protection

In accordance with the Health Information Portability and Accountability Act (HIPAA), a subject must sign an authorization to release medical information to the sponsor and/or allow the sponsor, a regulatory authority, or Institutional Review Board access to subject's medical information that includes all hospital records relevant to the study, including subjects' medical history.
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13.2.3 retention of records

The Principal Investigator of The Case Comprehensive Cancer Center supervises the retention of all documentation of adverse events, records of study drug receipt and dispensation, and all IRB correspondence for as long as needed to comply with local, national and international regulations. No records will be destroyed until the Principal Investigator confirms destruction is permitted.
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13.2.4 audits and inspections

Authorized representatives of the sponsor, a regulatory authority, an Independent Ethics Committee (IEC) or an Institutional Review Board (IRB) may visit the site to perform audits or inspections, including source data verification. The purpose of an audit or inspection is to systematically and independently examine all study-related activities and documents to determine whether these activities were conducted, and data were recorded, analysed, and accurately reported according to the protocol, Good Clinical Practice (GCP), guidelines of the International Conference on Harmonization (ICH), and any applicable regulatory requirements. For multi-center studies, participating sites must inform the sponsor-investigator of pending audits.
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14.0 statistical considerations aim 1.

Clinical response will be scored using Response Evaluation Criteria in Solid Tumors (RECIST 1.1) criteria. In order to determine the sample size of this study, a confidence interval approach was used. Under the proposed treatment, the expected clinical response is about 35%. With the precision of the 2-sided 95% confidence interval for the response rate set to 0.17 (the distance to the expected response rate of 35%), then the sample size required for the study is 30 patients. The true response rate of the therapy for this patient population will be estimated based on the number of responses using a binomial distribution and its confidence intervals will be estimated using Wilson's method [41].  
The same method will be used to estimate disease control rate. Safety/tolerability data will be summarized using descriptive statistics.
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aim 2. determine pfs in

The Kaplan-Meier method [42] will be used to estimate PFS. Factors including pathologic and genomic correlates that predict survival outcomes will be identified by Cox model [43] or extensions of Cox model [44].
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aim 3.identify pathologic and genomic

The IHC, morphometric and genomic correlates will be assessed by comparing responders and non-responders with each specific marker as a continuous variable (TIL, Immune scores) or dichotomous variable (TNBC subtypes, Pathway analysis, IHC for PDL1). T-test and chi-square test will be used for the comparison of continuous variables and dichotomous variable, respectively. Furthermore, the pathologic and genomic predictors on overall response (CR+PR) and disease control (CR+PR+SD) will be identified using logistic regressions. With the limited the sample size, the analysis will be exploratory in nature.
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15.0 references

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appendix i
15.0 references

| ECOG Performance Status Scale   |                                                                                                                                                                                           |
|---------------------------------|-------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|
| Grade                           | Description                                                                                                                                                                               |
| 0                               | Normal activity. Full active, able  to carry on all pre-disease  performance without restriction.  Symptoms, but ambulatory.                                                              |
| 1                               | Restricted in physically strenuous  activity, but ambulatory and able  to carry out work of a light or  sedentary nature (e.g., light  housework, office work). In bed < 50% of the time. |
| 2                               | Ambulatory and capable of all  self-care, but unable to carry out  any work activities. Up and about  more than 50% if waking hours. In bed > 50% of the time.                            |
| 3                               | Capable of only limited self-care,  confined to bed or chair more than  50% of waking hours. 100% bedridden. Completely                                                                   |
| 4                               | disabled. Cannot carry on any  self-care. Totally confined to bed  or chair.                                                                                                              |
| 5                               | Dead.                                                                                                                                                                                     |
performance status criteria appendix ii
15.0 references

| KEYTRUDA                                             |            |         |         |         |         |
|------------------------------------------------------|------------|---------|---------|---------|---------|
| 2 mg/kg every 3 weeks or 10 mg/kg every 2 or 3 weeks |            |         |         |         |         |
| n=1562                                               |            |         |         |         |         |
| Adverse Reaction                                     | All Grades | Grade 2 | Grade 3 | Grade 4 | Grade 5 |
| (%)                                                  | (%)        | (%)     | (%)     | (%)     |         |
| Hypothyroidism                                       | 72         | 0       | 0.1     |         |         |
| Pneumonitis                                          | 2.9*       | 0.8     | 0.1     | 0.1     |         |
| 1.0                                                  |            |         |         |         |         |
| Hyperthyroidism                                      | 0.5        | 0.2     |         |         |         |
| Colitis                                              | 0.4        | 0.8     | 0       |         |         |
| 0                                                    |            |         |         |         |         |
| Hypophysitis                                         | 0.7        | 0.3     | 0.3     | 0.1     | 0       |
| Hepatitis                                            | 0.5        | 0.1     | 0.3     | 0.1     | 0       |
| Nephritis                                            | 0.3        | 0.1     | 0.1     | 0.1     | 0       |
| Diabetes Mellitus                                    | 0.1        | 0.1     | 0       | 0       | 0       |
| Incidence was 3.5% in subjects with NSCLC            |            |         |         |         |         |
| These events were reported in subjects with NSCLC    |            |         |         |         |         |  
Endocrinopathies: The median time to onset of hypophysitis was 1.7 months (range 1 day to 6.5 months). The median duration was 3.3 months (range 0.8 months to 12.7 months).  
Hypophysitis led to discontinuation of KEYTRUDA  in 4 (0.3%) subjects. Hypophysitis resolved in 5 subjects. The median time to onset of hyperthyroidism was 1.4 months (range 1 day to 21.9 months). The median duration was 2.8 months (range 1.4 weeks to 12.8 months).  
Hyperthyroidism led to discontinuation of KEYTRUDA  in 2 (0.1%) subjects. Hyperthyroidism resolved in 25 subjects. The median time to onset of hypothyroidism was 3.5 months (range 5 days to 18.9 months). The median duration was 6.4 months (range 0.9 weeks to 2.3 months). No subjects discontinued KEYTRUDA due to hypothyroidism. Pneumonitis: The median time to onset of pneumonitis was 3.1 months (range 2 days to 19.3 months). The median duration was 1.7 months (range 0.3 weeks to 15.1 months).  
Pneumonitis led to discontinuation of KEYTRUDA  in 20 (1.3%) subjects. Pneumonitis resolved in 28 subjects.  
Colitis: The median time to onset of colitis was 3.4 months (range 1.3 weeks to 9.7 months).  
The median duration was 1.2 months (range 0.6 weeks to 7.2 months). Colitis led to discontinuation of KEYTRUDA  in 7 (0.4%) subjects. Colitis resolved in 19 subjects.  
Hepatitis: The median time to onset of hepatitis was 3.1 weeks (range 1.1 weeks to 21.4 months).  
The median duration was 1.3 months (range 1.1 weeks to 2.2 months). Hepatitis led to discontinuation of KEYTRUDA  in 2 (0.1%) subjects. Hepatitis resolved in 6 subjects. Nephritis: The median time to onset of nephritis was 6.8 months (range 1.7 weeks to 12.8 months). The median duration was 1.1 months (range 2.1 weeks to 3.3 months). Nephritis led to discontinuation of KEYTRUDA  in 1 (0.1%) subject. Nephritis resolved in 3 subjects.