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complete response

- Target lesion: Disappearance of all target lesions. Any pathological lymph nodes (whether target or non-target) must have reduction in short axis to <10 mm.  
- Non-target lesion: Disappearance of all non-target lesions. All lymph nodes must be non-pathological in size (<10 mm short axis).
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partial response

- Target lesion: At least a 30% decrease in the sum of diameters of target, taking as reference the baseline sum diameters.  
- Non-target lesion: Not applicable
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stable disease

- Target lesion: Neither sufficient shrinkage to qualify for a partial response, nor sufficient increase to qualify for progressive disease, taking as reference the smallest sum diameters while on study.  
- Non-target lesion: Not applicable.
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progressive disease

- Target lesion: At least a 20% increase in the sum of diameters of target lesions, taking as reference the smallest sum on study (this includes the baseline sum if that is the smallest on study). In addition to the relative increase of 20%, the sum must also demonstrate an absolute increase of at least 5 mm. (Note: the appearance of one or more new lesions is also considered progression).  
- Non-target lesion: Unequivocal progression (as described in RECIST version 1.1) of existing non-target lesions. (Note: the appearance of one or more new lesions is also considered progression).
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non-complete response / non-progressive disease

- Target lesion: Not applicable
- Non-target lesion: Persistence of one or more non-target lesion(s)
Table 8: Summary of RECIST 1.1 (Subjects with measurable disease)  
|                                                                                                                      |                    |                        |         |                                                   |
|----------------------------------------------------------------------------------------------------------------------|--------------------|------------------------|---------|---------------------------------------------------|
| Target                                                                                                               | Non-target Lesions | New Lesions            | Overall | Best Response for this                            |
| Lesions                                                                                                              | Response           | Category also requires |         |                                                   |
| CR                                                                                                                   | CR                 | No                     | CR      | Documented at least once   4 weeks from baseline |
| CR                                                                                                                   | Not-evaluated      | No                     | PR      | NA                                                |
| CR                                                                                                                   | Non-CR/Non-PD      | No                     | PR      | Documented at least once                          |
| PR                                                                                                                   | Non-PD or NE       | No                     | PR      |  4 weeks from baseline                           |
| SD                                                                                                                   | Non-PD or NE       | No                     | SD      | Documented at least once   4 weeks from baseline |
| Not all  evaluated                                                                                                   | Non-PD             | No                     | NE      | NA                                                |
| PD                                                                                                                   | Any                | Yes or No              | PD      |                                                   |
| Any                                                                                                                  | PD*                | Yes or No              | PD      | No prior SD, PR or CR                             |
| Any                                                                                                                  | Any                | Yes                    | PD      |                                                   |
| * In exceptional circumstances, unequivocal progression in nontarget lesions may be accepted as disease progression. |                    |                        |         |                                                   |  
| Non-target Lesions   | New Lesions   | Overall Response   |
|----------------------|---------------|--------------------|
| CR                   | No            | CR                 |
| Non-CR/Non-PD        | No            | Non-CR/ Non-PD     |
| Not all evaluated    | No            | NE                 |
| Unequivocal PD       | Yes or No     | PD                 |
| Any                  | Yes           | PD                 |  
RECIST 1.1 will be adapted as follows to account for the unique tumor response seen in this class of therapeutics, **irRECIST**.  
If imaging shows PD, tumor assessment should be repeated ≥4 weeks later in order to confirm PD with the option of continuing treatment for clinically stable subjects as discussed below in Table 10. Clinically stable is defined by the following criteria:
- Absence of signs and symptoms indicating disease progression
- No decline in ECOG performance status
- Absence of rapid progression of disease
- Absence of progressive tumor at critical anatomical sites (e.g., cord compression) requiring urgent alternative medical intervention  
Table 10: irRECIST: Imaging and Treatment after 1st Radiologic Evidence of PD  
| Clinically Stable    | Clinically Unstable            |                                                                                                             |                                     |                       |
|----------------------|--------------------------------|-------------------------------------------------------------------------------------------------------------|-------------------------------------|-----------------------|
| Imaging              | Treatment                      | Imaging                                                                                                     | Treatment                           |                       |
| 1 st radiologic      | Repeat imaging at > 4          |                                                                                                             |                                     |                       |
| evidence of PD       | weeks at site to  confirm PD   | May continue study  treatment at the  Investigator's  discretion while  awaiting confirmatory  scan by site | N/A                                 | Discontinue treatment |
| Repeat scan confirms | No additional imaging          | Discontinue treatment                                                                                       |                                     |                       |
| PD                   | required                       | (exception is possible  upon consultation  with Sponsor).                                                   | N/A No additional imaging  required | N/A                   |
| Repeat scan shows    | Continue regularly             |                                                                                                             |                                     |                       |
| SD, PR or CR         | scheduled imaging  assessments | Continue study  treatment at the  Investigator's  discretion                                                | N/A                                 | N/A                   |  
In determining whether or not the tumor burden has increased, decreased or stayed stable, site investigators should consider all target lesions as well as non-target lesions. Any subject deemed clinically unstable should be discontinued from study treatment at first evidence of progressive disease by tumor imaging and is not required to have repeat tumor imaging for confirmation. For a clinically stable subject with first radiologic evidence of progressive disease (i.e., unconfirmed progression of disease), it is at the discretion of the site investigator to continue treating the subject with the assigned study treatment per protocol until progression of disease is confirmed at least 28 days from the date of the tumor imaging first suggesting PD. If progression is not confirmed on the subsequent tumor imaging, the subject should continue to receive study therapy and have tumor imaging performed as outlined in Section 4.5.6 to monitor disease status. If radiologic progression is confirmed by subsequent tumor imaging, then the subject will be discontinued from study treatment. NOTE: If a subject with confirmed progression by tumor imaging (i.e. two scans at least 28 days apart demonstrating progressive disease) is clinically stable or clinically improved, and there is no further increase in the tumor burden at the confirmatory scan, an exception may be considered to continue study treatment upon consultation with the Sponsor. Subjects exhibiting intolerable toxicity from trial therapy may NOT continue to receive trial therapy. NOTE: In subjects who discontinue study therapy without documented disease progression, every effort should be made to continue monitoring their disease status by tumor imaging as outlined in Section 4.5.6 until (1) the start of new anti-cancer treatment, (2) disease progression (3) death, or (4) the end of the study, whichever occurs first. The same imaging modality (i.e., CT or MRI), acquisition and technical parameters should be used throughout the study for a given subject.
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12. statistical consideration 12.1. sample

This is an open-label randomized pilot study designed primarily to evaluate the safety and feasibility of the two regimens described earlier (Cohort A [phased regimen] and Cohort B [concurrent regimen]), in subjects with metastatic HER2-negative breast cancer who have received no more than three prior lines of chemotherapy for metastatic disease. Based on the Bayesian stopping rules described in Section 12.4.4, 20 subjects per arm will enable an assessment for each regimen regarding whether or not evidence suggests the overall grade 3 or 4 study treatment-related adverse event rate convincingly exceeds 0.35 (the reported rate for weekly paclitaxel). Randomization to this study will continue until at least 20 subjects per arm have been randomized and begin study therapy.
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12.2. endpoint definitions 12.2.1. grade

Grade 3 or 4 study treatment-related adverse events will be determined for each subject as a binary variable indicating whether or not the subject experienced any grade 3 or 4 study treatment-related adverse events according to the NCI Common Terminology for Adverse Events, version 4.0. An adverse event will be considered study treatment related if it is determined that the event is at least possibly related to either paclitaxel, pembrolizumab, or both.
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12.2.2. overall survival

Overall survival (OS) is defined as the duration of time from randomization to death from any cause. Subjects who are alive or lost to follow-up at the time of the analysis will be censored at the last known date they were alive.
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12.2.3. progression-free survival

Progression-Free Survival (PFS) is defined as the duration of time from randomization to first occurrence of either progressive disease or death. Disease progression must be objectively determined as per Section 11, where the date of progression is the date of the radiologic assessment that identified progressive disease. If the subject died without documented disease progression, the date of progression will be the date of death. For surviving subjects who do not have documented disease progression, PFS will be censored at the date of last radiologic assessment. For subjects who receive subsequent anti-cancer therapy prior to documented disease progression, PFS will be censored at the date of last radiologic assessment prior to the commencement of subsequent therapy. Subjects who have an initial PFS event immediately following 2 or more consecutive missed assessments will be censored at the date of the last assessment prior to those missed assessments. For participants with only one missed assessment, the documented progressive disease status and assessment date will be used. PFS will be determined for each subject using the RECIST 1.1 criteria. For subjects treated with pembrolizumab, PFS will also be calculated using the irRECIST criteria as an exploratory endpoint.
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12.2.4. objective response

Objective response will be determined for each subject as a binary variable indicating whether or not the subject achieved a best overall response of CR or PR as determined by criteria described in Section 11. Objective response will be determined for each subject using the RECIST 1.1 criteria. For subjects treated with pembrolizumab, objective response will also be calculated using the irRECIST criteria as an exploratory endpoint.
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12.2.5. duration of response

Duration of Response (DoR) is defined as the duration of time from the first assessment that determined a CR or PR to the date of the first occurrence of progressive disease or death. Progression events and the censoring mechanism for DoR will be the same as described for PFS in Section 12.2.3. DoR will be determined for each subject using the RECIST 1.1 criteria. For subjects treated with pembrolizumab, DoR will also be calculated using the irRECIST criteria as an exploratory endpoint.
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12.2.6. disease control

Disease control will be determined for each subject as a binary variable indicating whether or not the subject achieved a best overall response of CR, PR, or SD (for at least 24 weeks), as determined by the criteria described in Section 11. Disease control will be determined for each subject using the RECIST 1.1 criteria. For subjects treated with pembrolizumab, disease control will also be calculated using the irRECIST criteria as an exploratory endpoint.
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12.2.7. safety endpoints

Safety endpoints will include study treatment administration (total number of doses taken, and total doses taken as a percent of total number of intended doses), AEs, SAEs, deaths while on study therapy, and selected laboratory determinations.
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12.3. analysis populations

The intent-to-treat (ITT) population will consist of all randomized subjects. The ITT population will be used for the purposes of the subject disposition summary. The evaluable population will consist of all randomized subjects who begin study therapy. OS, PFS, and all safety analyses will be conducted on the evaluable population. Analyses of objective response, DoR, and disease control will be conducted on those subjects in the evaluable population who have measureable disease at baseline.
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12.4. analysis methods 12.4.1. timing

Analyses on this study will be conducted on a continuous basis in order to assess the Bayesian stopping rules for toxicity described in Section 12.4.4. An analysis of all endpoints will occur after the best overall response for each subject has been determined. A final analysis of the study will be conducted after the PFS censoring rate reduces to 20% or when all subjects have been on study for at least two years (whichever occurs first).
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12.4.2. subject disposition

An accounting of all consenting subjects will be provided at the end of the study. This will include a breakdown of subjects who consented, were randomized, treated, discontinued study treatment, died, and were lost to follow-up or withdrew consent.
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12.4.3. baseline patient and disease

A summary of subject demographics and disease-related characteristics will be completed and subject medical history will be assessed.
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12.4.4. primary analysis

This study is planned to enroll approximately 20 subjects in each study treatment arm. The primary objective is to evaluate the overall grade 3 or 4 study treatment related adverse event rate for each study arm. It is not anticipated that the addition of pembrolizumab to standard chemotherapy will increase the grade 3 or 4 toxicity rate. It has been reported that the rate of any grade 3 or 4 toxicity with weekly paclitaxel is 0.35 [Budd, ASCO abstract 2013, CRA1008]. If it becomes evident that the grade 3 or 4 toxicity rate on either arm convincingly exceeds 0.35, the study arm will be halted. The stopping rule will hold enrollment if the posterior probability of grade 3 or 4 toxicity risk exceeding 0.35 is 0.50 or higher. The prior distribution for this monitoring rule is beta (7,13). This means that our prior assumption regarding the proportion of grade 3 or 4 toxicity is 0.35, and there is 90% probability that this proportion is between 0.188 and 0.530. The operating characteristics of the stopping rule are given in the following table and are based on 5000 simulations.  
| Number of grade 3 or   | Max. Denominator Cutoff for Early   | Posterior Probability   |
|------------------------|-------------------------------------|-------------------------|
| 4Toxicities            | Stopping                            | Pr(Risk>0.35|Data)      |
| 1                      | 2                                   | 0.5352                  |
| 2                      | 5                                   | 0.5302                  |
| 3                      | 8                                   | 0.5216                  |
| 4                      | 11                                  | 0.5148                  |
| 5                      | 14                                  | 0.5040                  |
| 6                      | 16                                  | 0.5438                  |
| 7                      | 19                                  | 0.5334                  |
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12.4.5. secondary analyses

Overall survival and PFS will be analyzed by study arm using Kaplan Meier techniques. Medians, 25th, and 75th percentiles will be estimated. Selected landmarks for OS and PFS rates will be obtained from the Kaplan Meier estimates. Differences between the arms will be assessed qualitatively using a stratified Cox proportional hazards model, including hormone receptor status as the stratification variable. An estimate of the hazard ratio and 95% confidence interval will be provided. Duration of response will be analyzed in a similar fashion as described for OS and PFS. Objective response rate and disease control rate will be estimated for each arm along with corresponding 95% Clopper-Pearson confidence intervals. Differences between the arms will be assessed qualitatively using a stratified logistic regression, including hormone receptor status as the stratification variable. Estimates of the odds ratios and 95% confidence intervals will be provided.
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12.4.6. safety analyses

Incident rates for treatment-emergent adverse events, SAEs, and deaths while on study therapy will be summarized. Treatment-emergent adverse events are defined as follows:
- An adverse event that occurs after study treatment start that was not present at the time of study treatment start; or
- An adverse event that increases in severity after study treatment start if the event was present at the time of study treatment start.
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12.4.7. exploratory analyses

Cox proportional hazards models and logistic regression will be used to assess the correlation between additional baseline biomarkers with clinical outcomes. The biomarkers identified in Section 1.4 will be assessed qualitatively as deemed appropriate.
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12.5. interim analyses

No formal interim analysis for efficacy is planned for this study. However, results will be continuously monitored for safety using the Bayesian stopping rules described in Section 12.4.4.
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13. study completion 13.1. completion

The study will be considered complete when one or more of the following conditions is met:
- All subjects have completed all study visits. - All subjects have discontinued from the study. - The IRB, FDA, LCI DSMC, Sponsor-Investigator discontinues the study because of safety considerations.  
- The Sponsor-Investigator defines an administrative or clinical cut-off date.
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13.2. termination

The study will be terminated when one or more of the following conditions occur:
If risk-benefit ratio becomes unacceptable owing to, for example:
- Safety findings from this study (e.g. SAEs)
- Results of any interim analysis
- Results of parallel clinical studies
- Results of parallel animal studies (e.g. toxicity, teratogenicity, carcinogenicity or reproduction toxicity).  
- If the study conduct (e.g. recruitment rate; drop-out rate; data quality; protocol compliance) does not suggest a proper completion of the trial within a reasonable time frame.  
The Sponsor-Investigator has the right to close the trial at any site and at any time.  
For any of the above closures, the following applies:
- Closures should occur only after consultation between involved parties.  
- All affected institutions must be informed as applicable according to local law.  
- In case of a partial study closure, ongoing subjects, including those in follow-up, must be taken care of in an ethical manner.
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14. retention of records

Essential documentation (e.g. adverse events, records of study drug receipt and dispensation), including all IRB correspondence, will be retained for at least 2 years after the investigation is completed. Documentation will be readily available upon request.
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15. ethical and legal issues

The procedures set out in this protocol, pertaining to the conduct, evaluation, and documentation of this study, are designed to ensure that the Investigator abide by Good Clinical Practice (GCP) guidelines and under the guiding principles detailed in the Declaration of Helsinki. The study will also be carried out in keeping with applicable local law(s) and regulation(s). Documented approval from appropriate agencies (e.g. DSMC, IRB, FDA) will be obtained for all participating centers before start of the study, according to GCP, local laws, regulations and organizations. When necessary, an extension, amendment or renewal of IRB approval must be obtained and forwarded to Merck (if applicable).  
Strict adherence to all specifications laid down in this protocol is required for all aspects of study conduct; the Investigators may not modify or alter the procedures described in this protocol.  
Modifications to the study protocol will not be implemented by the Sponsor-Investigator without discussion and agreement by Merck (if applicable). However, the Investigators may implement a deviation from, or a change of, the protocol to eliminate an immediate hazard(s) to the trial subjects without prior approval from applicable agencies. As soon as possible, the implemented deviation or change, the reasons for it and if appropriate the proposed protocol amendment should be submitted to the appropriate agencies. Any deviations from the protocol must be explained and documented by the Investigator.  
The Sponsor-Investigator is responsible for the conduct of the clinical trial at the sites in accordance with Title 21 of the Code of Federal Regulations and/or the Declaration of Helsinki. The Sponsor-Investigator is responsible for personally overseeing the treatment of all study subjects. The Sponsor-Investigator must assure that all study site personnel, including sub-investigators and other study staff members, adhere to the study protocol and all applicable regulations and guidelines regarding clinical trials both during and after study completion. The Sponsor-Investigator will be responsible for assuring that all the required data will be collected and properly documented.
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15.2. confidentiality

All records identifying the subject will be kept confidential and, to the extent permitted by the applicable laws and/or regulations, will not be made publicly available.
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16. publication policy

The Investigator must send a draft manuscript of the publication or abstract to Merck Sharp & Dohme Corp, prior to submission of the final version for publication or congress presentation. All relevant aspects regarding data reporting and publication will be part of the contract between Merck Sharp & Dohme Corp and the Investigator. The Investigator will ensure that the information regarding the study be publicly available on the internet at www.clinicaltrials.gov.
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references

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2. Piccart-Gebhart MJ, Burzykowski T, Buyse M, et al: Taxanes alone or in combination with anthracyclines as first-line therapy of patients with metastatic breast cancer. J Clin Oncol 26:1980-6, 2008 3. Seidman AD, Tiersten A, Hudis C, et al: Phase II trial of paclitaxel by 3-hour infusion as initial and salvage chemotherapy for metastatic breast cancer. J Clin Oncol 13:257581, 1995 4. Nabholtz JM, Gelmon K, Bontenbal M, et al: Multicenter, randomized comparative study of two doses of paclitaxel in patients with metastatic breast cancer. J Clin Oncol 14:1858-67, 1996 5. Seidman AD, Berry D, Cirrincione C, et al: Randomized phase III trial of weekly compared with every-3-weeks paclitaxel for metastatic breast cancer, with trastuzumab for all HER-2 overexpressors and random assignment to trastuzumab or not in HER-2 nonoverexpressors: final results of Cancer and Leukemia Group B protocol 9840. J Clin Oncol 26:1642-9, 2008 6. Mauri D, Kamposioras K, Tsali L, et al: Overall survival benefit for weekly vs.  
three-weekly taxanes regimens in advanced breast cancer: A meta-analysis. Cancer Treat Rev 36:69-74, 2010 7. Hodi FS, O'Day SJ, McDermott DF, et al: Improved survival with ipilimumab in patients with metastatic melanoma. N Engl J Med 363:711-23, 2010 8. Kantoff PW, Higano CS, Shore ND, et al: Sipuleucel-T immunotherapy for castration-resistant prostate cancer. N Engl J Med 363:411-22, 2010 9. Chen DS, Irving BA, Hodi FS: Molecular pathways: next-generation immunotherapy--inhibiting programmed death-ligand 1 and programmed death-1. Clin Cancer Res 18:6580-7, 2012 10. Pedoeem A, Azoulay-Alfaguter I, Strazza M, et al: Programmed death-1 pathway in cancer and autoimmunity. Clin Immunol 153:145-52, 2014 11. Sheppard KA, Fitz LJ, Lee JM, et al: PD-1 inhibits T-cell receptor induced phosphorylation of the ZAP70/CD3zeta signalosome and downstream signaling to PKCtheta. FEBS Lett 574:37-41, 2004 12. Yao S, Chen L: PD-1 as an immune modulatory receptor. Cancer J 20:262-4, 2014 13. Keir ME, Butte MJ, Freeman GJ, et al: PD-1 and its ligands in tolerance and immunity. Annu Rev Immunol 26:677-704, 2008 14. Sanmamed MF, Chen L: Inducible expression of B7-H1 (PD-L1) and its selective role in tumor site immune modulation. Cancer J 20:256-61, 2014 15. Topalian SL, Drake CG, Pardoll DM: Immune checkpoint blockade: a common denominator approach to cancer therapy. Cancer Cell 27:450-61, 2015 16. Pembrolizumab Investigator's Brochure. Edition 9. 17. Robert C, Ribas A, Wolchok JD, et al: Anti-programmed-death-receptor-1 treatment with pembrolizumab in ipilimumab-refractory advanced melanoma: a randomised dose-comparison cohort of a phase 1 trial. Lancet 384:1109-17, 2014 18. Ribas A, Puzanov I, Dummer R, et al: Pembrolizumab versus investigator-choice chemotherapy for ipilimumab-refractory melanoma (KEYNOTE-002): a randomised, controlled, phase 2 trial. Lancet Oncol 16:908-18, 2015 19. Robert C, Schachter J, Long GV, et al: Pembrolizumab versus Ipilimumab in Advanced Melanoma. N Engl J Med 372:2521-32, 2015 20. Nanda R, Chow Q, Dees C, et al. Pembrolizumab in patients with advanced triplenegative breast cancer: Phase Ib KEYNOTE-012 study. J Clin Oncol. 2016:Published online on May 2, 2016.  
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Cancer Immunol Immunother 62:203-16, 2013 22. National Comprehensive Cancer Network Clincal Practice Guidelines in Oncology. Breast. Version 1.2016.  
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Cancer Invest 20:666-72, 2002 36. Mittendorf EA, Philips AV, Meric-Bernstam F, et al: PD-L1 expression in triplenegative breast cancer. Cancer Immunol Res 2:361-70, 2014 37. Basu GD, Ghazalpour A, Vader R, et al. Expression of novel immunotherapeutic targets in luminal breast cancer patients. Presented at San Antonio Breast Cancer Symposium. December 9-13, 2014. San Antonio, TX. Abstract P5-04-08.  
38. Loi S, Sirtaine N, Piette F, et al: Prognostic and predictive value of tumorinfiltrating lymphocytes in a phase III randomized adjuvant breast cancer trial in node-positive breast cancer comparing the addition of docetaxel to doxorubicin with doxorubicin-based chemotherapy: BIG 02-98. J Clin Oncol 31:860-7, 2013 39. Adams S, Gray RJ, Demaria S, et al: Prognostic value of tumor-infiltrating lymphocytes in triple-negative breast cancers from two phase III randomized adjuvant breast cancer trials: ECOG 2197 and ECOG 1199. J Clin Oncol 32:2959-66, 2014 40. Salgado R, Denkert C, Demaria S, et al: The evaluation of tumor-infiltrating lymphocytes (TILs) in breast cancer: recommendations by an International TILs Working Group 2014. Ann Oncol 26:259-71, 2015 41. Schalper KA: PD-L1 expression and tumor-infiltrating lymphocytes: Revisiting the antitumor immune response potential in breast cancer. Oncoimmunology 3:e29288, 2014 42. Le DT, Uram JN, Wang H, et al: PD-1 Blockade in Tumors with MismatchRepair Deficiency. N Engl J Med 372:2509-20, 2015 43. Lipson EJ, Velculescu VE, Pritchard TS, et al: Circulating tumor DNA analysis as a real-time method for monitoring tumor burden in melanoma patients undergoing treatment with immune checkpoint blockade. J Immunother Cancer 2:42, 2014  
| APPENDIX 1: ECOG PERFORMANCE SCALE   |                                                                                                                                                                                     |
|--------------------------------------|-------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|
| Grade                                | Description                                                                                                                                                                         |
| 0                                    | Normal activity, fully active, able to carry on all pre-disease  performance without restriction.                                                                                   |
| 1                                    | Symptoms, but fully ambulatory, restricted in physically  strenuous but ambulatory and able to carry out work of a light or  sedentary nature (e.g., light housework, office work). |
| 2                                    | Ambulatory and capable of all self-care but unable to carry out  any work activities. Up and about more than 50% of waking  hours.                                                  |
| 3                                    | Capable of only limited self-care, confined to bed or chair more  than 50% of waking hours.                                                                                         |
| 4                                    | Completely disabled. Cannot carry on any self-care. Totally  confined to bed or chair.                                                                                              |
| 5                                    | Dead                                                                                                                                                                                |