nct # 02395627 reversing therapy
stable disease (sd)

Neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD, taking as reference the smallest sum LD since the treatment started. Evaluation of Non-Target Lesions Complete Response (CR) Disappearance of all non-target lesions and normalization of tumor marker level. All lymph nodes must be non-pathological in size (< 10 mm short axis). Incomplete Response/Stable Disease (SD)
Persistence of one or more non-target lesion(s) and/or maintenance of tumor marker level above the normal limits.
nct # 02395627 reversing therapy
progressive disease (pd)

Appearance of one or more new lesions and/or unequivocal progression of existing non-target lesions. Evaluation of Best Overall Response The best overall response is the best response recorded from the start of the treatment until disease progression/recurrence (taking as reference for progressive disease the smallest measurements recorded since the treatment started). The patient's best response assignment will depend on the achievement of both measurement and confirmation criteria.
nct # 02395627 reversing therapy
table 7 response criteria

| Target                                                                               | Non-Target     | Overall     | Best Response for this Category   |                        |    |       |      |     |
|--------------------------------------------------------------------------------------|----------------|-------------|-----------------------------------|------------------------|----|-------|------|-----|
| Lesions                                                                              | Lesions        | New Lesions | Response                          | Also Requires          |    |       |      |     |
| CR                                                                                   | CR             | No          | CR                                | > 4 weeks confirmation |    |       |      |     |
| CR                                                                                   | Non-CR/ Non-PD | No          | PR                                | > 4 weeks confirmation |    |       |      |     |
| PR                                                                                   | Non-PD         | No          | PR                                |                        |    |       |      |     |
| SD                                                                                   | Non-PD         | No          | SD                                | documented             | at | least | once | > 4 |
| weeks from baseline                                                                  |                |             |                                   |                        |    |       |      |     |
| 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 non-target lesions may be |                |             |                                   |                        |    |       |      |     |
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duration of response duration of

The duration of overall response is measured from the time measurement criteria are met for CR or PR (whichever is first recorded) until the first date that recurrent or progressive disease is objectively documented (taking as reference for progressive disease the smallest measurements recorded since the treatment started). The duration of overall CR is measured from the time measurement criteria are first met for CR until the first date that recurrent disease is objectively documented.
nct # 02395627 reversing therapy
duration of stable disease

Stable disease is measured from the start of the treatment until the criteria for progression are met, taking as reference the smallest measurements recorded since the treatment started.
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progression-free survival

Progression-free survival (PFS) is defined as the duration of time from start of treatment to time of progression.
nct # 02395627 reversing therapy
7.4 evaluation of safety

Analyses will be performed for all patients having received at least one dose of study drug. The study will use the CTCAE v4.0 for reporting of non-hematologic adverse events and modified criteria for hematologic adverse events, see Section 7.5.  
For multicenter studies, the Principal Investigator at the UCSF Coordinating Center will hold the role of Study Chair. The Study Chair is responsible for the overall conduct of the study and for monitoring its safety and progress at all participating sites.
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7.5 adverse events 7.5.1 adverse

The investigator or qualified designee will assess each subject to evaluate for potential new or worsening AEs as specified in the Trial Flow Chart and more frequently if clinically indicated. Adverse experiences will be graded and recorded throughout the study and during the follow-up period according to NCI CTCAE Version 4.0 (see Section 7.5). Toxicities will be characterized in terms regarding seriousness, causality, toxicity grading, and action taken with regard to trial treatment. All AEs of unknown etiology associated with pembrolizumab exposure should be evaluated to determine if it is possibly an event of clinical interest (ECI) of a potentially immunologic etiology (irAE). Please refer to section 7.5 for detailed information regarding the assessment and recording of AEs.
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7.5.2 definition of adverse event

An adverse event (also known as an adverse experience) is defined as any untoward medical occurrence associated with the use of a drug in humans, whether or not considered drug related. More specifically, an adverse event (can be any unfavorable and unintended sign (e.g., an abnormal laboratory finding), symptom, or disease temporally associated with the use of a drug, without any judgment about causality. An adverse event can arise from any use of the drug (e.g., off-label use, use in combination with another drug) and from any route of administration, formulation, or dose, including an overdose.
nct # 02395627 reversing therapy
7.5.3 adverse reaction

An adverse reaction is defined as any adverse event caused by the use of a drug. Adverse reactions are a subset of all suspected adverse reactions for which there is reason to conclude that the drug caused the event.
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7.5.3.1 suspected

A suspected adverse reaction is defined as any adverse event for which there is a reasonable possibility that the drug caused the adverse event. For the purposes of IND safety reporting, "reasonable possibility" indicates that there is evidence to suggest a causal relationship between the drug and the adverse event. A suspected adverse reaction implies a lesser degree of certainty about causality than an adverse reaction.
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7.5.3.2 unexpected

An adverse event or suspected adverse reaction is considered unexpected if it is not listed in the investigator brochure or package insert(s), or is not listed at the specificity or severity that has been observed, or, if an investigator brochure is not required or available, is not consistent with the risk information described in the general investigational plan or elsewhere in the current application. "Unexpected," as used in this definition, also refers to adverse events or suspected adverse reactions that are mentioned in the investigator brochure as occurring with a class of drugs or as anticipated from the pharmacological properties of the drug, but are not specifically mentioned as occurring with the particular drug under investigation. Adverse events that would be anticipated to occur as part of the disease process are considered unexpected for the purposes of reporting because they would not be listed in the investigator brochure. For example, a certain number of non-acute deaths in a cancer trial would be anticipated as an outcome of the underlying disease, but such deaths would generally not be listed as a suspected adverse reaction in the investigator brochure. Some adverse events are listed in the Investigator Brochure as occurring with the same class of drugs, or as anticipated from the pharmacological properties of the drug, even though they have not been observed with the drug under investigation. Such events would be considered unexpected until they have been observed with the drug under investigation. For example, although angioedema is anticipated to occur in some patients exposed to drugs in the ACE inhibitor class and angioedema would be described in the investigator brochure as a class effect, the first case of angioedema observed with the drug under investigation should be considered unexpected for reporting purposes.
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7.5.3.3 serious

An adverse event or suspected adverse reaction is considered serious if, in the view of either the study PI or Merck, it results in any of the following outcomes:
- Death - Life-threatening adverse event - Inpatient hospitalization or prolongation of existing hospitalization - A persistent or significant incapacity or substantial disruption of the ability to conduct normal life function
- Congenital anomaly/birth defect
Important medical events that may not result in death, are life-threatening, or require hospitalization may be considered serious when, based upon appropriate medical judgment, they may jeopardize the patient or subject and may require medical or surgical intervention to prevent one of the outcomes listed in this definition. Examples of such medical events include allergic bronchospasm requiring intensive treatment in an emergency room or at home, blood dyscrasias or convulsions that do not result in inpatient hospitalization, or the development of drug dependency or drug abuse.
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7.5.3.4 life-threatening

An adverse event or suspected adverse reaction is considered life-threatening if, in the view of either the study PI or Merck, its occurrence places the patient or subject at immediate risk of death. It does not include an adverse event or suspected adverse reaction that, had it occurred in a more severe form, might have caused death.
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7.6 evaluation of an adverse

All grade 3 and above adverse events will be entered into OnCore®, whether or not the event is believed to be associated with use of the study drug. Data about these events and their severity will be recorded using the NCI CTCAE v4.0.  
The Investigator will assign attribution of the possible association of the event with use of the investigational drug, and this information will be entered into OnCore® using the classification system listed below:  
| Relationship      | Attribution   | Description  intervention   |
|-------------------|---------------|-----------------------------|
| Unrelated         | to            | investigational             |
| drug/intervention |               |                             |  
Unrelated The AE is clearly NOT related to the  
intervention Unrelated to investigational  
drug/intervention Unlikely The AE is doubtfully related to the intervention  
Possible The AE may be related to the intervention  
Probable The AE is likely related to the intervention Related to investigational  
drug/intervention  
Definite The AE is clearly related to the intervention  
Signs or symptoms reported as adverse events will be graded and recorded by the Investigator according to the CTCAE. When specific adverse events are not listed in the CTCAE they will be graded by the Investigator as none, mild, moderate or severe according to the following grades and definitions:  
Grade 0 No AE (or within normal limits) Grade 1 Mild; asymptomatic or mild symptoms; clinical or diagnostic observations only; intervention not indicated Grade 2 Moderate; minimal, local, or noninvasive intervention (e.g., packing, cautery)
indicated; limiting age-appropriate instrumental activities of daily living (ADL)
Grade 3: Severe or medically significant but not immediately life-threatening; hospitalization or prolongation of hospitalization indicated; disabling; limiting self-care ADL
Grade 4: Life-threatening consequences; urgent intervention indicated Grade 5: Death related to AE
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7.6.1 nci common terminology for

An investigator who is a qualified physician will evaluate all adverse events according to the NCI Common Terminology for Adverse Events (CTCAE), version 4.0. Any adverse event which changes CTCAE grade over the course of a given episode will have each change of grade recorded on the adverse event case report forms/worksheets. All adverse events regardless of CTCAE grade must also be evaluated for seriousness
nct # 02395627 reversing therapy
table 7.6 evaluating adverse events

| V4.0 CTCAE   | Grade 1                                                   | Mild;   | asymptomatic   | or   | mid   | symptoms;   | clinical   | or   |
|--------------|-----------------------------------------------------------|---------|----------------|------|-------|-------------|------------|------|
| Grading      | diagnostic observations only; intervention not indicated. |         |                |      |       |             |            |      |
| Grade 2      | Moderate; minimal, local or noninvasive intervention      |         |                |      |       |             |            |      |  
| indicated; limiting age-appropriate instrumental ADL.   |                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                   |             |               |        |              |
|---------------------------------------------------------|-----------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|-------------|---------------|--------|--------------|
| Grade 3                                                 | Severe or medically significant but not immediately lifethreatening; hospitalization or prolongation or  hospitalization indicated; disabling; limiting self-care ADL.                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                   |             |               |        |              |
| Grade 4                                                 | Life                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                              | threatening | consequences; | urgent | intervention |
| indicated.                                              |                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                   |             |               |        |              |
| Grade 5                                                 | Death related to AE                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                               |             |               |        |              |
| Seriousness                                             | A serious adverse event is any adverse event occurring at any dose or  during any use of Merck product that: †Results in death; or †Is life threatening; or places the subject, in the view of the  investigator, at immediate risk of death from the event as it occurred  (Note: This does not include an adverse event that, had it occurred in a  more severe form, might have caused death.); or †Results in a persistent or significant disability/incapacity (substantial disruption of one's ability to conduct normal life functions); or †Results in or prolongs an existing inpatient hospitalization (hospitalization is defined as an inpatient admission, regardless of length  of stay, even if the hospitalization is a precautionary measure for  continued observation. (Note: Hospitalization [including hospitalization  for an elective procedure] for a preexisting condition which has not  worsened does not constitute a serious adverse event.); or †Is a congenital anomaly/birth defect (in offspring of subject taking  the product regardless of time to diagnosis);or Is a new cancer; (that is not a condition of the study) or Is an overdose (whether accidental or intentional). Any adverse event  associated with an overdose is considered a serious adverse event. An  overdose that is not associated with an adverse event is considered a  non-serious event of clinical interest and must be reported within 24  hours to site UCSF CHR and Merck Other important medical events that may not result in death, not be  life threatening, or not require hospitalization may be considered a  serious adverse event when, based upon appropriate medical judgment,  the event may jeopardize the subject and may require medical or  surgical intervention to prevent one of the outcomes listed previously  (designated above by a †). |             |               |        |              |
| Duration                                                | Record the start and stop dates of the adverse event. If less than 1 day,  indicate the appropriate length of time and units                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                      |             |               |        |              |
| Action taken                                            | Did the adverse event cause the Merck product to be discontinued?                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                 |             |               |        |              |
| Relationship                                            | Did the Merck product cause the adverse event? The determination of                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                               |             |               |        |              |
| to test drug                                            | the likelihood that the Merck product caused the adverse event will be  provided by an investigator who is a qualified physician. The  investigator's signed/dated initials on the source document or worksheet  that supports the causality noted on the AE form, ensures that a  medically qualified assessment of causality was done. This initialed  document must be retained for the required regulatory time frame. The  criteria below are intended as reference guidelines to assist the  investigator in assessing the likelihood of a relationship between the test  drug and the adverse event based upon the available information.  The following components are to be used to assess the                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                           |             |               |        |              |  
| relationship between the Merck product and the AE; the greater the  correlation with the components and their respective elements (in  number and/or intensity), the more likely the Merck product caused the  adverse event (AE): Exposure Is there evidence that the subject was actually exposed to  the Merck product such as: reliable history, acceptable  compliance assessment (pill count, diary, etc.), expected  pharmacologic effect, or measurement of drug/metabolite  in bodily specimen? Time  Did the AE follow in a reasonable temporal sequence  Course from administration of the Merck product?  Is the time of onset of the AE compatible with a druginduced effect (applies to trials with investigational  medicinal product)? Likely  Is the AE not reasonably explained by another etiology  Cause such as underlying disease, other drug(s)/vaccine(s), or  other host or environmental factors   |
|---|
nct # 02395627 reversing therapy
7.7 follow-up of adverse events

All adverse events will be followed with appropriate medical management until resolved. Patients removed from study for unacceptable adverse events will be followed until resolution or stabilization of the adverse event. For selected adverse events for which administration of the investigational drug was stopped, a re-challenge of the subject with the investigational drug may be conducted if considered both safe and ethical by the Investigator.
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7.8 adverse events reporting

All adverse events, whether or not unexpected, and whether or not considered to be associated with the use of the study drug, will be entered into OnCore®, as noted above.  
The Investigator will assess all adverse events and determine reportability requirements to the UCSF Data and Safety Monitoring Committee (DSMC) and UCSF's Institutional Review Board, the Committee on Human Research (CHR); and, when the study is conducted under an Investigational New Drug Application (IND), to the Food and Drug Administration (FDA) if it meets the FDA reporting criteria.  
All adverse events entered into OnCore® will be reviewed by the Helen Diller Family Comprehensive Cancer Center Site Committee on a weekly basis. The Site Committee will review and discuss at each weekly meeting the selected toxicity, the toxicity grade, and the attribution of relationship of the adverse event to the administration of the study drug(s). All grade(s) 3-5 adverse events entered into OnCore® will be reviewed on a monthly basis at the Site Committee meetings. The Site Committee will review and discuss the selected toxicity, the toxicity grade, and the attribution of relationship of the adverse event to the administration of the study drug(s). In addition, all suspected adverse reactions considered "serious" entered into OnCore®, will be reviewed and monitored by the Data and Safety Monitoring Committee on an ongoing basis and discussed at DSMC meetings, which take place every six weeks. For a detailed description of the Data and Safety Monitoring Plan for a Multicenter Phase 2 or 3 Institutional Study at the Helen Diller Comprehensive Cancer Center please refer Appendix 4 Multicenter Institutional Studies.\
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7.8.1 definition of an overdose

For purposes of this trial, an overdose will be defined as any dose exceeding the prescribed dose for pembrolizumab by 20% over the prescribed dose. No specific information is available on the treatment of overdose of pembrolizumab. In the event of overdose, the subject should be observed closely for signs of toxicity. Appropriate supportive treatment should be provided if clinically indicated. If an adverse event(s) is associated with ("results from") the overdose of a Merck product, the adverse event(s) is reported as a serious adverse event, even if no other seriousness criteria are met. If a dose of Merck's product meeting the protocol definition of overdose is taken without any associated clinical symptoms or abnormal laboratory results, the overdose is reported as a nonserious Event of Clinical Interest (ECI), using the terminology "accidental or intentional overdose without adverse effect."
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all reports of overdose with

A serious adverse event is any adverse event occurring at any dose or during any use of Merck's product that: Refer to Table X for additional details regarding each of the above criteria. Progression of the cancer under study is not considered an adverse event unless it results in hospitalization or death. 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 30 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 Global Safety.  
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
Non-serious Events of Clinical Interest will be forwarded to Merck Global Safety and will be handled in the same manner as SAEs. 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.
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sae reports and any other

A copy of all 15 Day Reports and Annual Progress Reports is submitted as required by FDA, European Union (EU), Pharmaceutical and Medical Devices agency (PMDA) or other local regulators. 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.  
at the time of submission to FDA.  
All subjects with serious adverse events must be followed up for outcome.
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7.8.3 reporting of pregnancy and

Although pregnancy and lactation are not considered adverse events, it is the responsibility of investigators or their designees to report any pregnancy or lactation in a subject (spontaneously reported to them), including the pregnancy of a male subject's female partner that occurs during the trial or within 120 days of completing the trial completing the trial, or 30 days following cessation of treatment if the subject initiates new anticancer therapy, whichever is earlier. All subjects and female partners of male subjects who become pregnant must be followed to the completion/termination of the pregnancy. Pregnancy outcomes of spontaneous abortion, missed abortion, benign hydatidiform mole, blighted ovum, fetal death, intrauterine death, miscarriage and stillbirth must be reported as serious events (Important Medical Events). If the pregnancy continues to term, the outcome (health of infant) must also be reported. Such events must be reported within 2 working days to Merck Global Safety.
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7.9 expedited reporting

Reporting to the Data and Safety Monitoring Committee If a death occurs during the treatment phase of the study or within 30 days after the last administration of the study drug(s) and it is determined to be related either to the study drug(s) or to a study procedure, the Investigator or his/her designee must notify the DSMC Chair (or qualified alternate) within 1 business day of knowledge of the event. The contact may be by phone or e-mail. Reporting to UCSF Committee on Human Research (Institutional Review Board) The Principal Investigator must report events meeting the UCSF CHR definition of "Unanticipated Problem" (UP) within 10 business days of his/her awareness of the event. Reporting to Sponsor - Merck & Co Any serious adverse event, that are unexpected and related, 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 30 days following cessation of treatment if the subject initiates new anticancer therapy, whichever is earlier, whether or not related to the Sponsor's product, must be reported within 24 hours to the Sponsor either by electronic media or paper. Sponsor Contact information can be found in the Investigator Trial File Binder (or equivalent). Additionally, any serious adverse event, considered by an investigator who is a qualified physician to be related to the Sponsor's 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. Expedited Reporting to the Food and Drug Administration If the study is being conducted under an IND, the Sponsor-Investigator is responsible for determining whether or not the suspected adverse reaction meets the criteria for expedited reporting in accordance with Federal Regulations (21 CFR §312.32). The Investigator must report in an IND safety report any suspected adverse reaction that is both serious and unexpected. The Sponsor-Investigator needs to ensure that the event meets all three definitions:
- Suspected adverse reaction - Unexpected - Serious If the adverse event does not meet all three of the definitions, it should not be submitted as an expedited IND safety report. The timeline for submitting an IND safety report to FDA is no later than 15 calendar days after the Investigator determines that the suspected adverse reaction qualifies for reporting (21 CFR 312.32(c)(1)). Any unexpected fatal or life-threatening suspected adverse reaction will be reported to FDA no later than 7 calendar days after the Investigator's initial receipt of the information (21 CFR 312.32(c)(2)). Any relevant additional information that pertains to a previously submitted IND safety report will be submitted to FDA as a Follow-up IND Safety Report without delay, as soon as the information is available (21 CFR 312.32(d)(2)).
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8.0 statistical considerations and evaluation

This trial will determine whether epigenetic priming may enhance the effects of PD-1 inhibitors in patients with ER+ metastatic breast cancer who have progressed on prior hormone therapy and chemotherapy. The trial will contain three arms. Within each arm we will determine whether epigenetic priming will required prolonged pre-exposure to epigenetic modulators or concomitant administration. Three arms will be tested, with each independent assessment. Patients will be stratified by prior number of hormonal therapy and chemotherapy, then randomized across arms by Dr. Scott Thomas, UCSF. 8.1 Response rates to chemotherapy in breast cancer are less than 20%. Historical response rates to pembrolizumab and MPDL3280A have been 18% and 19%, respectively, in patients whose tumors are PD-L1 positive. Hence, we expect the response rate for unselected patients and patients with no PD-L1 expression would be 10% or less. In contrast, we anticipate that vorinostat will increase the response rate to 30%Sample Size and Power Estimate Response rates to hormonal therapy and MTOR or HDAC inhibitors have been reported as 520% (19% for VOR-Tam, 6% for entinostat-exemestane, 12% for exemestane-everolimus). Given the recent additions to hormonal therapy this trial will treat a patient population that has received more lines of therapy than these trials, however we are interested in an ORR of >30%. 8.2 For each arm: Using an Optimal Simon's two-stage design (Simon, 1989), the null hypothesis (H_0) that the true response rate is 10% will be tested against a one-sided alternative. In the first stage, 10 patients will be accrued and a decision will be made to continue or stop accrual based on the observed objective response rate (ORR). If there are 0 or 1 objective responses at 24 weeks in these 10 patients, accrual to this arm of the study will be stopped. Otherwise, 19 additional patients will be accrued for a total of n=29. We estimate that each regimen under evaluation will achieve ORR ≥ 30%. This study is designed to have an alpha of 0.0471, and a power of 80.5% to test the null hypothesis H_0: ORR = 10% against an alternative hypothesis, H_A: ORR = 30%, where ORR is defined as CR, PR, or SD > 24 weeks where arms are enrolled independently. Interim Analyses In addition to the interim analysis for efficacy that is built into the Simon 2-stage design (see above), in each arm we will evaluate the need for dose modification after 6 patients have been enrolled. If 2 or more patients have a grade 3 non-hematologic toxicity that is clearly related to pembrolizumab, this agent will be reduced to 75%. Dose modification of vorinostat should be undertaken as per dose modification guidelines, a prior study with vorinostat and tamoxifen suggest that there is a high interpatient variability and tolerance and vorinostat will be adjusted per dose modification guidelines individually.
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8.3 analyses plans 8.3.1 analysis

We will conduct an intention-to-treat analysis of efficacy. All patients who were randomized will be evaluated. For evaluation of safety, we will restrict the arm-specific samples to all patients who have received at least one dose of investigational therapy.
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8.3.2 evaluation of efficacy

For each arm objective response rate (ORR) will be defined as the proportion of participants randomized to that arm whose status is SD or better (CR, PR) at 24 weeks' follow-up. In addition to calculating the ORR, we will calculate the corresponding Agresti-Coull interval 95% confidence interval (CI) (Ref: Agresti, Alan; Coull, Brent A. (1998). "Approximate is better than 'exact' for interval estimation of binomial proportions". The American Statistician 52*: 119–126.* doi:10.2307/2685469). If the lower bound of the 95% CI exceeds 10%, we will reject the null hypothesis that the regimen is ineffective and conclude that it is sufficiently effective to warrant further study.
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8.3.3 evaluation of safety

Analyses will be performed for all patients having received at least one dose of study drug. The study will use the NCI CTCAE v4.0.
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8.3.4 analyses of exploratory endpoints

Note: Tissue will be used for multiple different exploratory assays. In the event that there is insufficient tissue to perform all assays for an individual subject, the tissue should be prioritized for assays as follows, in which the first assay described is the highest priority.
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tumor pd-l1 assessment

PD-L1 protein expression on tumor tissue from pre-treatment and post-Cycle-3 biopsies, and any other tumor biospecimens obtained, will be evaluated immunohistochemically and scored on a scale of 0, 1, 2, or 3. This scoring will be used for the determination of relationships between tumor PD-L1 expression and clinical responses described above. Specifically, in addition to hypothesizing that delayed pembrolizumab treatment (i.e., Arm A) will increase tumor response, we hypothesize that (i) PD-L1 expression will stimulate tumor response, (ii) but will not be associated with treatment (because PD-L1 is stimulated by vorinostat not pembrolizumab). For analysis, PD-L1 expression level, scored as {0,1,2,3}, will be classified as binary (0 =negative; 1-3 =positive); across two time-points, this defines four types of PD-L1 participants: {0,0; 0,1; 1,0; 1,1}. We will use logistic regression to estimate Cycle-6 tumor response rate (95% CI) as a function of study arm and PD-L1 level at baseline and Cycle 3. Either time-point will be eliminated from the model if its effect is weak (p>0.2), leaving two types of PD-L1 participants: either {0,0; 1;1} or {0,0; 0,1}.
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tissue immune subset quantification and

For all subjects, immune cell subsets and localization will be summarized by changes from baseline to after treatment using descriptive statistics.
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immune cell mrna signatures of

To identify individual genes whose expression levels at pre-treatment are associated with pCR, we will apply two-sample t tests to compare responders and non-responders. Adjusted P values controlling for false discovery rate (Benjamini and Hochberg method) will be derived. In addition, to assess association of pre-specified immune gene signature with response, the median expression level of the component genes will be used to represent the signature and twosample t tests will be used. For genes or signatures that emerge as significantly associated with response, logistic regression models will be used to assess their independent association with response after adjusting for known clinical prognostic factors. To identify pharmacodynamic markers, paired t-test will be carried out to examine immune gene expression differences between pre-treatment and post treatment samples. Additionally, association of gene expression levels after epigenetic priming with long term efficacy outcomes, such as PFS and DFS, will be explored using the Cox proportional hazards regression model. Hierarchical clustering superimposed with response status, relevant baseline or prognostic characteristics or experimental factors will be performed using Spearman correlation and complete linkage to visualize the discriminating power of the immune gene expression and the correlative structure among the genes and the samples.
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t cell receptor (tcr) deep

The change in tumor-infiltrating TCR between pre-treatment and post-epigenetic priming will be assessed by calculating the number of unique clonotypes comprising the top 25th percentile of cumulative reads after sorting by clone abundance. Repertoire change between sequencing experiments will be measured using Morisita's distance. This analysis will also be performed in subjects receiving adjuvant chemotherapy using the same statistical techniques to evaluate the impact of adjuvant MPDL3280A on circulating T cell repertoire remodeling.
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genomic signatures of response

It is hypothesized that tumors with highly mutated or copy-aberrant genomes will either overexpress native proteins or express novel mutant proteins, both of which may be recognized by the immune system and serve as tumor-specific antigens. Therefore the effect of genomic mutations on the immune landscape will be investigated in each of the cohorts in this study as follows. Tumor DNA will be isolated from pre-treatment tissue and from post-epigenetic priming specimens, and will be analyzed for copy number using the Human Genome CGH 244K Microarray (Agilent, Santa Clara, CA) and/or by next-generation sequencing. Results will be analyzed with DNA Analytics software (Agilent) and with the assistance of the UCSF Genome Core and the UCSF Biostatistics core. For copy number paired Wilcoxon signed-rank test will be applied to test difference of tumor gene copy number between pre and post treatment. Twosample Wilcoxon signed-rank test will be used to test the gene copy number between tumor responders and non-responders for pre-treatment, post-treatment and changes before and after the treatment, separately. Multiple testing adjustment will be done by controlling false positive rate. Next-generation sequencing will take place using appropriate methods and biostatistical analyses. Annotation will be based on NCBI and UCSC databases. Chi-square test will be applied to obtain the significant variants associated with the clinical response.
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8.3.4.2 immune endpoints immune cell

For each arm individually, flow cytometry of circulating immune cell subsets will also be performed on pre-treatment blood and again after 9 weeks on vorinostat (post epigenetic priming). Established flow cytometry panels will examine T cell activation. Immune cell quantification will be summarized by changes from baseline to after treatment using descriptive statistics. Furthermore, paired Wilcox on signed-rank test will be applied to test the pre-post treatment changes. When available, immune cells digested from resected tumor tissues will also be assessed by flow cytometry.
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circulating antibody detection and characterization

Spotted antigen arrays will be used to detect circulating antibodies will be performed on sera derived from the pretreatment and after 9 weeks on vorinostat. . After standard preprocessing of the protein array data, Cluster and Treeview software will be used for unsupervised clustering of the data with Pearson correlation and complete linkage. For each array, an antigen is identified as being detected if its value is above the median. To determine the number of up- and downmodulated antibodies, the difference in log2 intensity values of pretreatment and posttreatment samples will be taken for each patient to identify antigens that are detected differentially due to treatment. Number of antibodies with at least 2- or 4-fold difference between pretreatment and post-treatment samples will be compared between clinical responders and nonresponders by performing two-sided Wilcoxon rank sum test.  
All correlative studies and assays will be performed in the Munster lab, in conjunction with Merck, with the help of Dr. Lawrence Fong and other experts in the field.
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9.0 study management 9.1 pre-study

This study will be conducted in accordance with the ethical principles that have their origin in the Declaration of Helsinki as stated in 21 CFR §312.120(c)(4); consistent with GCP and all applicable regulatory requirements. Before initiating this trial, the Investigator will have written and dated approval from the Institutional Review Board for the protocol, written informed consent form, subject recruitment materials, and any other written information to be provided to subjects before any protocol related procedures are performed on any subjects. The clinical investigation will not begin until either FDA has determined that the study under the Investigational Drug Application (IND) is allowed to proceed or the Investigator has received a letter from FDA stating that the study is exempt from IND requirements.
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9.2 institutional review board approval

The protocol, the proposed informed consent form, and all forms of participant information related to the study (e.g., advertisements used to recruit participants) will be reviewed and approved by the UCSF CHR (UCSF Institutional Review Board). Prior to obtaining CHR approval, the protocol must be approved by the Helen Diller Family Comprehensive Cancer Center Site Committee and by the Protocol Review Committee (PRC). The initial protocol and all protocol amendments must be approved by the IRB prior to implementation.
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9.3 informed consent

All participants must be provided a consent form describing the study with sufficient information for each participant to make an informed decision regarding their participation. Participants must sign the CHR-approved informed consent form prior to participation in any study specific procedure. The participant must receive a copy of the signed and dated consent document. The original signed copy of the consent document must be retained in the medical record or research file.
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9.4 changes in the protocol

Once the protocol has been approved by the UCSF CHR, any changes to the protocol must be documented in the form of an amendment. The amendment must be signed by the Investigator and approved by PRC and the CHR prior to implementation. If it becomes necessary to alter the protocol to eliminate an immediate hazard to patients, an amendment may be implemented prior to CHR approval. In this circumstance, however, the Investigator must then notify the CHR in writing within five (5) working days after implementation. The Study Chair and the UCSF study team will be responsible for updating any participating sites.
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9.5 handling and documentation of

The UCSF Principal Investigator and each participating site will maintain complete records showing the receipt, dispensation, return, or other disposition of all investigational drugs. The date, quantity and batch or code number of the drug, and the identification of patients to whom study drug has been dispensed by patient number and initials will be included. The sponsorinvestigator will maintain written records of any disposition of the study drug.  
The Principal Investigator shall not make the investigational drug available to any individuals other than to qualified study patients. Furthermore, the Principal Investigator will not allow the investigational drug to be used in any manner other than that specified in this protocol.
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9.6 case report forms (crfs)

The Principal Investigator and/or his/her designee will prepare and maintain adequate and accurate participant case histories with observations and data pertinent to the study. Study specific Case Report Forms (CRFs) will document safety and treatment outcomes for safety monitoring and data analysis. All study data will be entered into OnCore® via standardized CRFs in accordance with the CTMS study calendar, using single data entry with a secure access account. The Clinical Research Coordinator (CRC) will complete the CRFs as soon as possible upon completion of the study visit; the Investigator will review and approve the completed CRFs. The information collected on CRFs shall be identical to that appearing in original source documents. Source documents will be found in the patient's medical records maintained by UCSF personnel. All source documentation should be kept in separate research folders for each patient. In accordance with federal regulations, the Investigator is responsible for the accuracy and authenticity of all clinical and laboratory data entered onto CRFs. The PI will approve all completed CRFs to attest that the information contained on the CRFs is true and accurate. All source documentation and CTMS data will be available for review/monitoring by the UCSF DSMC and regulatory agencies. The Principal Investigator will be responsible for ensuring the accurate capture of study data. At study completion, when the CRFs have been declared to be complete and accurate, the database will be locked. Any changes to the data entered into the CRFs after that time can only be made by joint written agreement among the Study Chair, the Trial Statistician, and the Protocol Project Manager.
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9.7 oversight and monitoring plan

The UCSF Helen Diller Family Comprehensive Cancer Center DSMC will be the monitoring entity for this study. The UCSF DSMC will monitor the study in accordance with the NCIapproved Data and Safety Monitoring Plan (DSMP). The DSMC will routinely review all adverse events and suspected adverse reactions considered "serious". The DSMC will audit studyrelated activities to ensure that the study is conducted in accordance with the protocol, local standard operating procedures, FDA regulations, and Good Clinical Practice (GCP). Significant results of the DSMC audit will be communicated to the IRB and the appropriate regulatory authorities at the time of continuing review, or in an expedited fashion, as applicable. See Appendix 2 Data and Safety Monitoring Plan for a Phase 2 or 3 Institutional Study, for additional information.
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9.8 record keeping and record

The Principal Investigator is required to maintain adequate records of the disposition of the drug, including dates, quantity, and use by subjects, as well as written records of the disposition of the drug when the study ends.  
The Principal Investigator is required to prepare and maintain adequate and accurate case histories that record all observations and other data pertinent to the investigation on each individual administered the investigational drug or employed as a control in the investigation. Case histories include the case report forms and supporting data (e.g., signed and dated consent forms and medical records, such as progress notes of the physician, the individual's hospital chart(s), and the nurses' notes. The case history for each individual shall document that informed consent was obtained prior to participation in the study. Study documentation includes all CRFs, data correction forms or queries, source documents, Sponsor-Investigator correspondence, monitoring logs/letters, and regulatory documents (e.g., protocol and amendments, CHR correspondence and approval, signed patient consent forms). Source documents include all recordings of observations or notations of clinical activities and all reports and records necessary for the evaluation and reconstruction of the clinical research study. In accordance with FDA regulations, the investigator shall retain records for a period of 2 years following the date a marketing application is approved for the drug for the indication for which it is being investigated; or, if no application is to be filed or if the application is not approved for such indication, until 2 years after the investigation is discontinued and FDA is notified.
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9.9 coordinating center documentation of

It is the responsibility of the Study Chair to maintain adequate files documenting the distribution of study documents as well as their receipt (when possible). The HDFCCC recommends that the Study Chair maintain a correspondence file and log for each segment of distribution (e.g., FDA, drug manufacturer, participating sites, etc.). Correspondence file: should contain copies (paper or electronic) of all protocol versions, cover letters, amendment outlines (summary of changes), etc., along with distribution documentation and (when available) documentation of receipt.  
Correspondence log: should be a brief list of all documents distributed including the date sent, recipient(s), and (if available) a tracking number and date received. At a minimum, the Study Chair must keep documentation of when and to whom the protocol, its updates and safety information are distributed.
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10 protection of human subjects

Each clinical site is responsible for protecting all subjects involved in human experimentation. This is accomplished through the CHR mechanism and the process of informed consent. The CHR reviews all proposed studies involving human experimentation and ensures that the subject's rights and welfare are protected and that the potential benefits and/or the importance of the knowledge to be gained outweigh the risks to the individual. The CHR also reviews the informed consent document associated with each study in order to ensure that the consent document accurately and clearly communicates the nature of the research to be done and its associated risks and benefits.
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10.2 protection of privacy

Patients will be informed of the extent to which their confidential health information generated from this study may be used for research purposes. Following this discussion, they will be asked to sign the HIPAA form and informed consent documents. The original signed document will become part of the patient's medical records, and each patient will receive a copy of the signed document. The use and disclosure of protected health information will be limited to the individuals described in the informed consent document.
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references

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Release of methyl CpG binding proteins and histone deacetylase 1 from the estrogen receptor alpha (ER) promoter upon reactivation in ER-negative human breast cancer cells. *Mol Endocrinol*. 2005;19(7):1740-1751. 8. Hirokawa Y, Arnold M, Nakajima H, Zalcberg J, Maruta H. Signal therapy of breast cancers by the HDAC inhibitor FK228 that blocks the activation of PAK1 and abrogates the tamoxifen-resistance. *Cancer* Biol Ther. 2005;4(9):956-960. 9. Early Breast Cancer Trialists' Collaborative Group (EBCTCG). Effects of chemotherapy and hormonal therapy for early breast cancer on recurrence and 15-year survival: An overview of the randomised trials. Lancet. 2005;365(9472):1687-1717. 10. Thurlimann B, Hess D, Koberle D, et al. Anastrozole ('arimidex') versus tamoxifen as first-line therapy in postmenopausal women with advanced breast cancer: Results of the double-blind cross-over SAKK trial 21/95--a sub-study of the TARGET (tamoxifen or 'arimidex' randomized group efficacy and tolerability) trial. *Breast Cancer Res Treat*. 2004;85(3):247-254. 11. Mouridsen H, Gershanovich M, Sun Y, et al. Phase III study of letrozole versus tamoxifen as first-line therapy of advanced breast cancer in postmenopausal women: Analysis of survival and update of efficacy from the international letrozole breast cancer group. *J Clin Oncol*. 2003;21(11):2101-2109. 12. Bonneterre J, Buzdar A, Nabholtz JM, et al. Anastrozole is superior to tamoxifen as first-line therapy in hormone receptor positive advanced breast carcinoma. *Cancer*. 2001;92(9):2247-2258. 13. Nabholtz JM, Buzdar A, Pollak M, et al. 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Leukocyte infiltration and tumor cell plasticity are parameters of aggressiveness in primary cutaneous melanoma. *Cancer Immunol Immunother*. 2008;57(1):97-106. 31. Lee HE, Chae SW, Lee YJ, et al. Prognostic implications of type and density of tumour-infiltrating lymphocytes in gastric cancer. *Br J Cancer*. 2008;99(10):1704-1711. 32. Leffers N, Gooden MJ, de Jong RA, et al. Prognostic significance of tumor-infiltrating T-lymphocytes in primary and metastatic lesions of advanced stage ovarian cancer. *Cancer Immunol Immunother*.  
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34. Liotta F, Gacci M, Frosali F, et al. Frequency of regulatory T cells in peripheral blood and in tumourinfiltrating lymphocytes correlates with poor prognosis in renal cell carcinoma. *BJU Int*. 2011;107(9):15001506. 35. Fisher B, Costantino JP, Wickerham DL, et al. Tamoxifen for the prevention of breast cancer: Current status of the national surgical adjuvant breast and bowel project P-1 study. *J Natl Cancer Inst*. 2005;97(22):1652-1662. 36. Marks PA, Richon VM, Breslow R, Rifkind RA. Histone deacetylase inhibitors as new cancer drugs. Curr Opin Oncol. 2001;13(6):477-483. 37. Marks P, Rifkind RA, Richon VM, Breslow R, Miller T, Kelly WK. Histone deacetylases and cancer: Causes and therapies. *Nat Rev Cancer*. 2001;1(3):194-202. 38. Cress WD, Seto E. Histone deacetylases, transcriptional control, and cancer. *J Cell Physiol*. 2000;184(1):1-16. 39. Grunstein M. Histone acetylation in chromatin structure and transcription. *Nature*. 1997;389(6649):349-352. 40. Yang WM, Tsai SC, Wen YD, Fejer G, Seto E. Functional domains of histone deacetylase-3. J Biol Chem. 2002;277(11):9447-9454. 41. Yang WM, Yao YL, Sun JM, Davie JR, Seto E. Isolation and characterization of cDNAs corresponding to an additional member of the human histone deacetylase gene family. *J Biol Chem*. 1997;272(44):28001-28007. 42. Lin RJ, Nagy L, Inoue S, Shao W, Miller WH,Jr, Evans RM. Role of the histone deacetylase complex in acute promyelocytic leukaemia. *Nature*. 1998;391(6669):811-814. 43. Muraoka M, Konishi M, Kikuchi-Yanoshita R, et al. P300 gene alterations in colorectal and gastric carcinomas. *Oncogene*. 1996;12(7):1565-1569. 44. Marks PA, Rifkind RA, Richon VM, Breslow R. Inhibitors of histone deacetylase are potentially effective anticancer agents. *Clin Cancer Res*. 2001;7(4):759-760. 45. Finnin MS, Donigian JR, Cohen A, et al. Structures of a histone deacetylase homologue bound to the TSA and SAHA inhibitors. *Nature*. 1999;401(6749):188-193. 46. Gore SD, Weng LJ, Figg WD, et al. Impact of prolonged infusions of the putative differentiating agent sodium phenylbutyrate on myelodysplastic syndromes and acute myeloid leukemia. *Clin Cancer Res*. 2002;8(4):963-970. 47. Gilbert J, Baker SD, Bowling MK, et al. A phase I dose escalation and bioavailability study of oral sodium phenylbutyrate in patients with refractory solid tumor malignancies. *Clin Cancer Res*. 2001;7(8):2292-2300. 48. Piekarz RL, Robey R, Sandor V, et al. Inhibitor of histone deacetylation, depsipeptide (FR901228), in the treatment of peripheral and cutaneous T-cell lymphoma: A case report. *Blood*. 2001;98(9):2865-2868. 49. Kelly WK, O'Connor OA, Marks PA. Histone deacetylase inhibitors: From target to clinical trials. Expert Opin Investig Drugs. 2002;11(12):1695-1713. 50. Richon VM, Emiliani S, Verdin E, et al. A class of hybrid polar inducers of transformed cell differentiation inhibits histone deacetylases. *Proc Natl Acad Sci U S A*. 1998;95(6):3003-3007. 51. Amin HM, Saeed S, Alkan S. Histone deacetylase inhibitors induce caspase-dependent apoptosis and downregulation of daxx in acute promyelocytic leukaemia with t(15;17). *Br J Haematol*.  
2001;115(2):287-297.  
52. Nimmanapalli R, Fuino L, Stobaugh C, Richon V, Bhalla K. Cotreatment with the histone deacetylase inhibitor suberoylanilide hydroxamic acid (SAHA) enhances imatinib-induced apoptosis of bcr-abl-positive human acute leukemia cells. *Blood*. 2003;101(8):3236-3239. 53. Yu C, Rahmani M, Almenara J, et al. Histone deacetylase inhibitors promote STI571-mediated apoptosis in STI571-sensitive and -resistant bcr/abl+ human myeloid leukemia cells. *Cancer Res*. 2003;63(9):2118-2126. 54. Mitsiades N, Mitsiades CS, Richardson PG, et al. Molecular sequelae of histone deacetylase inhibition in human malignant B cells. *Blood*. 2003;101(10):4055-4062. 55. Mitsiades CS, Mitsiades N, Richardson PG, Treon SP, Anderson KC. Novel biologically based therapies for waldenstrom's macroglobulinemia. *Semin Oncol*. 2003;30(2):309-312. 56. Peart MJ, Tainton KM, Ruefli AA, et al. Novel mechanisms of apoptosis induced by histone deacetylase inhibitors. *Cancer Res*. 2003;63(15):4460-4471. 57. Butler LM, Agus DB, Scher HI, et al. Suberoylanilide hydroxamic acid, an inhibitor of histone deacetylase, suppresses the growth of prostate cancer cells in vitro and in vivo. *Cancer Res*. 2000;60(18):5165-5170. 58. Huang L, Pardee AB. Suberoylanilide hydroxamic acid as a potential therapeutic agent for human breast cancer treatment. *Mol Med*. 2000;6(10):849-866.  
59. Said TK, Moraes RC, Sinha R, Medina D. Mechanisms of suberoylanilide hydroxamic acid inhibition of mammary cell growth. *Breast Cancer Res*. 2001;3(2):122-133. 60. Munster PN, Troso-Sandoval T, Rosen N, Rifkind R, Marks PA, Richon VM. The histone deacetylase inhibitor suberoylanilide hydroxamic acid induces differentiation of human breast cancer cells. Cancer Res. 2001;61(23):8492-8497. 61. Richon VM, Sandhoff TW, Rifkind RA, Marks PA. Histone deacetylase inhibitor selectively induces p21WAF1 expression and gene-associated histone acetylation. *Proc Natl Acad Sci U S A*. 2000;97(18):10014-10019. 62. He LZ, Tolentino T, Grayson P, et al. Histone deacetylase inhibitors induce remission in transgenic models of therapy-resistant acute promyelocytic leukemia. *J Clin Invest*. 2001;108(9):1321-1330.  
63. Cohen LA, Amin S, Marks PA, Rifkind RA, Desai D, Richon VM. Chemoprevention of carcinogeninduced mammary tumorigenesis by the hybrid polar cytodifferentiation agent, suberanilohydroxamic acid
(SAHA). *Anticancer Res*. 1999;19(6B):4999-5005. 64. Patnaik A, Kang SP, Tolcher AW, et al. Phase I study of MK-3475 (anti-PD-1 monoclonal antibody) in patients with advanced solid tumors. *J Clin Oncol*. 2012;30:2512. 65. Hamid O, Robert C, Daud A, et al. Safety and tumor responses with lambrolizumab (anti-PD-1) in melanoma. *N Engl J Med*. 2013;369(2):134-144. 66. Yardley DA, Ismail-Khan RR, Melichar B, et al. Randomized phase II, double-blind, placebo-controlled study of exemestane with or without entinostat in postmenopausal women with locally recurrent or metastatic estrogen receptor-positive breast cancer progressing on treatment with a nonsteroidal aromatase inhibitor. *J Clin Oncol*. 2013;31(17):2128-2135. 67. Pan F, Fan H, Liu Z, Jiang S. T cell signaling targets for enhancing regulatory or effector function. *Sci* Signal. 2012;5(235):pe32.  
lXs= Helen Diller Family Comprehensive Cancer Center
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appendices

| Appendix 1                                                                                     | Performance Status Criteria                                 |                                       |                                                                                |                                      |
|------------------------------------------------------------------------------------------------|-------------------------------------------------------------|---------------------------------------|--------------------------------------------------------------------------------|--------------------------------------|
| ECOG Performance Status Scale                                                                  | Karnofsky Performance Scale                                 |                                       |                                                                                |                                      |
| Grade                                                                                          | Descriptions                                                | Percent                               | Description                                                                    |                                      |
| 100                                                                                            | Normal, no complaints, no evidence of                       |                                       |                                                                                |                                      |
| 0                                                                                              | Normal activity                                             | disease                               |                                                                                |                                      |
| Fully active, able to carry on all  pre-disease performance without  90                        | Able to carry on normal activity; minor                     |                                       |                                                                                |                                      |
| restriction                                                                                    | signs or symptoms of disease                                |                                       |                                                                                |                                      |
| 1                                                                                              | Symptoms, but ambulatory                                    | 80                                    | Normal activity with effort; some signs                                        |                                      |
| Restricted in physically strenuous                                                             | or symptoms of disease                                      |                                       |                                                                                |                                      |
| activity, but ambulatory and able to  carry out work of a light or  70                         | Cares for self, unable to carry on                          |                                       |                                                                                |                                      |
| sedentary                                                                                      | nature                                                      | (e.g.,                                | light                                                                          | normal activity or to do active work |
| housework, office work)                                                                        |                                                             |                                       |                                                                                |                                      |
| 2                                                                                              | In bed < 50% of the time                                    | 60                                    | Requires occasional assistance, but is  able to care for most of his/her needs |                                      |
| Ambulatory and capable of all selfcare, but unable to carry out any  work activities Up and about more than 50% of  waking hours 50                                                                                                | Requires considerable assistance and  frequent medical care |                                       |                                                                                |                                      |
| 40                                                                                             | Disabled, requires special care and                         |                                       |                                                                                |                                      |
| 3                                                                                              | In bed > 50% of the time                                    | assistance                            |                                                                                |                                      |
| Capable of only limited self-care,  confined to bed or chair more than  50% of waking hours 30 | Severely                                                    | disabled,                             | hospitalization                                                                |                                      |
| indicated Death not imminent                                                                   |                                                             |                                       |                                                                                |                                      |
| 4                                                                                              | 100% bedridden                                              | 20                                    | Very sick, hospitalization indicated                                           |                                      |
| Completely disabled                                                                            | Death not imminent                                          |                                       |                                                                                |                                      |
| Cannot carry on any self-care                                                                  | 10                                                          | Moribund, fatal processes progressing |                                                                                |                                      |
| Totally confined to bed or chair                                                               | rapidly                                                     |                                       |                                                                                |                                      |
| 5                                                                                              | Dead                                                        | 0                                     | Dead                                                                           |                                      |
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appendix 2 data and safety

The UCSF Helen Diller Family Comprehensive Cancer Center (HDFCCC) Data and Safety Monitoring Committee (DSMC) is responsible for monitoring data quality and subject safety for all HDFCCC institutional clinical studies. A summary of DSMC activities for this study include:
- Review of subject data - Review of suspected adverse reactions considered "serious" - Monitoring every six months (depending on study accrual) - Minimum of a yearly regulatory audit
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monitoring and reporting guidelines

Investigators will conduct continuous review of data and subject safety and discuss each subject's treatment at monthly Site Committee meetings. These discussions are documented in the Site Committee meeting minutes. The discussion will include the number of subjects, significant toxicities in accordance with the protocol, and observed responses. All institutional Phase 2 or 3 studies are designated with a moderate risk assessment. The data is monitored twice per year with twenty percent of the subjects monitored (or at least three subjects if the calculated value is less than three).
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adverse event review and monitoring

All grade(s) 3-5 adverse events, whether or not unexpected, and whether or not considered to be associated with the use of the study drug, will be entered into OnCore®, UCSF's Clinical Trial Management System. All grade(s) 3-5 adverse events entered into OnCore® will be reviewed on a monthly basis at the Site Committee meetings. The Site Committee will review and discuss the selected toxicity, the toxicity grade, and the attribution of relationship of the adverse event to the administration of the study drug(s). In addition, all suspected adverse reactions considered "serious" entered into OnCore®, will be reviewed and monitored by the Data and Safety Monitoring Committee on an ongoing basis and discussed at DSMC meetings, which take place every six weeks. If a death occurs during the treatment phase of the study or within 30 days after the last administration of the study drug(s) and is determined to be related either to the investigational drug or any research related procedure, the Investigator or or the assigned designee must be notified within 1 business day from the participating site(s) and the Study Chair must then notify the DSMC Chair or qualified alternate within 1 business day of knowledge of this event. The contact may be by phone or e-mail.
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increase in adverse event rates

If an increase in the frequency of Grade 3 or 4 adverse events (above the rate reported in the Investigator Brochure or package insert) is noted in the study, a report should be submitted to the DSMC at the time the increased rate is identified. The report will indicate if the incidence of adverse events observed in the study is above the range stated in the Investigator Brochure or package insert. If at any time the Study Chair stops enrollment or stops the study due to safety issues, the DSMC Chair and DSMC Manager must be notified within 1 business day via e-mail. The DSMC must receive a formal letter within 10 business days and the CHR must be notified.  
  
* DSMP approved by NCI 09/February2012 UCSF Helen Diller Family Comprehensive  
  
 Cancer Center San Francisco, CA 94143
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appendix 3 ucsf policy/procedure for

This policy defines the required Regulatory Documents for Single Site and Multicenter Investigator Initiated Oncology Clinical Trials at the Helen Diller Family Comprehensive Cancer Center (HDFCCC) where the Principal Investigator (PI) holds the IND.
nct # 02395627 reversing therapy
background

The International Conference on Harmonization (ICH) Good Clinical Practices (GCP) Guidelines define Essential Regulatory Documents as those documents which individually and collectively permit evaluation of the conduct of a trial and the quality of data produced. These documents serve to demonstrate compliance with standards of GCP and with all applicable regulatory requirements. Filing essential documents in a timely manner can greatly assist in the successful management of a clinical trial.  
The Regulatory Documents will consist of electronic files in both iMedRIS and OnCore®, as well as paper files in the Regulatory Binders for both the Coordinating Site and the Participating Site(s) in the HDFCCC Investigator Initiated Oncology Clinical Trials.
nct # 02395627 reversing therapy
procedures

1. HDFCCC Essential Regulatory Documents Documents Filed in iMedRIS:  
· CHR approvals for initial submission of application, all modifications, and continuing annual renewals
· Current and prior approved protocol versions with signed protocol signature page(s) · Committee for Human Research (CHR) approval letters and Informed Consent Form(s)
(ICF)
· Current and prior versions of the Investigator Brochure (IB). · Serious Adverse Event Reporting · Protocol Violations and Single Patient Exception (SPE) Reports to CHR with supporting fax documentation
nct # 02395627 reversing therapy
documents filed in oncore

· Package Insert (if the study drug is commercial) or Investigator Brochure · Protocol Review Committee (PRC) approved protocols, protocol amendments and Summary of Changes (SOC)
· Patient handouts · Screening/enrollment log · Data and Safety Monitoring Committee (DSMC) monitoring reports · OnCore® Case Report Form (CRF) completion manual
nct # 02395627 reversing therapy
documents filed in regulatory binder

· Completed Food and Drug Administration (FDA) 1572 document with Principal Investigator's signature
· For all Principal Investigators and Sub-Investigators listed on the FDA 1572, will need Financial Disclosure Forms, CVs, MD Licenses, Drug Enforcement Agency (DEA) Licenses, and Staff Training Documents (i.e. Collaborative Institute Training Initiative (CITI), etc.)
· Site Initiation Visit (SIV) minutes and correspondence with participating site(s). · As applicable, approvals for Biosafety Committee, Radiation Committee, and Infusion Center
· Serious Adverse Event (SAE) reports to CHR. · MedWatch reporting to FDA · Delegation of Authority Form · Drug Destruction Standard Operating Procedure (SOP) · For all laboratories listed on the FDA 1572, will need CLIA certifications, CAP
certifications, lab licenses, CVs of Lab Directors, and laboratory reference ranges
nct # 02395627 reversing therapy
appendix 4 multicenter institutional studies

4.1 Data and Safety Monitoring Plan for Multicenter Study
(Phase 2 or 3 Institutional Study)
The UCSF Helen Diller Family Comprehensive Cancer Center (HDFCCC) Data and Safety Monitoring Committee (DSMC) is responsible for monitoring data quality and subject safety for all HDFCCC institutional clinical studies. A summary of DSMC activities for this study include:
- Review of subject data - Review of suspected adverse reactions considered "serious" - Monitoring every six months (depending on study accrual) - Minimum of a yearly regulatory audit Monitoring and Reporting Guidelines All institutional Phase 2 or 3 therapeutic studies are designated with a moderate risk assessment. The data is monitored every six months, with twenty percent of the subjects monitored (or at least three subjects if the calculated value is less than three). The UCSF Coordinating Center provides administration, data management, and organizational support for the participating sites in the conduct of a multicenter clinical trial. The UCSF Coordinating Center will also coordinate quarterly conference calls with the participating sites to communicate the review of adverse events, safety data, and other study matters. The Principal Investigator at the UCSF Coordinating Center will hold the role of Study Chair. The Study Chair is responsible for the overall conduct of the study and for monitoring its safety and progress at all participating sites. The Study Chair will conduct continuous review of data and subject safety and discuss each subject's treatment at monthly UCSF Site Committee meetings. The discussions are documented in the UCSF Site Committee meeting minutes. Multicenter communication The UCSF Coordinating Center provides administration, data management, and organizational support for the participating sites in the conduct of a multicenter clinical trial. The UCSF Coordinating Center will also coordinate, at minimum, quarterly conference calls with the participating sites or more frequently as needed to discuss risk assessment. The following issues will be discussed as appropriate:  
- Enrollment information
- Adverse Events (i.e. new adverse events and updates on unresolved adverse events and new safety information)
- Protocol Violations - Other issues affecting the conduct of the study Adverse events reporting to the DSMC will include reports from both the UCSF Coordinating Center, as well as the participating sites. The DSMC will be responsible for monitoring all data entered in OnCore® at the UCSF Coordinating Center and the participating sites. The data (i.e., copies of source documents) from the participating sites will be faxed over to the UCSF Coordinating Center prior to the monitoring visits in order for the DSMC to monitor the participating site's compliance with the protocol, patient safety, and to verify data entry.
nct # 02395627 reversing therapy
adverse event review and monitoring

All grade(s) 3-5 adverse events, whether or not unexpected, and whether or not considered to be associated with the use of the study drug, will be entered into OnCore®, UCSF's Clinical Trial Management System. All Grade 3-5 adverse events entered into OnCore® will be reviewed on a monthly basis at the UCSF Site Committee meetings. All clinically significant adverse events must be reported to the UCSF Coordinating Center by the participating sites within 10 business days of becoming aware of the event or during the next scheduled quarterly conference call, whichever is sooner. The UCSF Site Committee will review and discuss the selected toxicity, the toxicity grade, and the attribution of relationship of the adverse event to the administration of the study drug(s) from the UCSF Coordinating Center and the participating sites. In addition, all suspected adverse reactions considered "serious" must be entered in OnCore® and reported to the UCSF Coordinating Center within 1 business day. The suspected adverse reactions considered "serious" will be reviewed and monitored by the Data and Safety Monitoring Committee on an ongoing basis and discussed at the DSMC meeting, which take place every six (6) weeks. If a death occurs during the treatment phase of the study or within 30 days after the last administration of the study drug(s) and is determined to be related either to the investigational drug or any research related procedure, the Study Chair at the UCSF Coordinating Center or the assigned designee must be notified within 1 business day from the participating site(s) and the Study Chair must then notify the DSMC Chair or qualified alternate within 1 business day of this notification. The contact may be by phone or e-mail.
nct # 02395627 reversing therapy
increase in adverse event rates

If an increase in the frequency of Grade 3 or 4 adverse events (above the rate reported in the Investigator Brochure or package insert) is noted in the study, the Study Chair at the UCSF Coordinating Center is responsible for notifying the DSMC at the time the increased rate is identified. The report will indicate if the incidence of adverse events observed in the study is above the range stated in the Investigator Brochure or package insert. If at any time the Study Chair stops enrollment or stops the study due to safety issues, the DSMC Chair and DSMC Manager must be notified within 1 business day via e-mail. The DSMC must receive a formal letter within 10 business days and the CHR must be notified. Data and Safety Monitoring Committee Contacts  
  
UCSF Helen Diller Family Comprehensive  San Francisco, CA 94143
* DSMP approved by NCI 09/February2012 4.2 UCSF Policy/Procedure for Required Regulatory Documents for a UCSF Multicenter Investigator-Initiated Oncology Clinical Trials with an Investigator held Investigational New Drug (IND)
nct # 02395627 reversing therapy
purpose

This policy defines the required Regulatory Documents for Single Site and Multicenter Investigator Initiated Oncology Clinical Trials at the Helen Diller Family Comprehensive Cancer Center (HDFCCC) where the Principal Investigator (PI) holds the IND.
nct # 02395627 reversing therapy
background

The International Conference on Harmonization (ICH) Good Clinical Practices (GCP) Guidelines define Essential Regulatory Documents as those documents which individually and collectively permit evaluation of the conduct of a trial and the quality of data produced. These documents serve to demonstrate compliance with standards of GCP and with all applicable regulatory requirements. Filing essential documents in a timely manner can greatly assist in the successful management of a clinical trial.  
The Regulatory Documents will consist of electronic files in both iMedRIS and OnCore®, as well as paper files in the Regulatory Binders for both the Coordinating Site and the Participating Site(s) in the HDFCCC Investigator Initiated Oncology Clinical Trials.
nct # 02395627 reversing therapy
procedures

1. HDFCCC Essential Regulatory Documents Documents Filed in iMedRIS:  
· CHR approvals for initial submission of application, all modifications, and continuing annual renewals
· Current and prior approved protocol versions with signed protocol signature page(s) · Committee for Human Research (CHR) approval letters and Informed Consent Form(s)
(ICF)
· Current and prior versions of the Investigator Brochure (IB). · Serious Adverse Event Reporting · Protocol Violations and Single Patient Exception (SPE) Reports to CHR with supporting fax documentation
nct # 02395627 reversing therapy
documents filed in oncore

· Package Insert (if the study drug is commercial) or Investigator Brochure · Protocol Review Committee (PRC) approved protocols, protocol amendments and Summary of Changes (SOC)
· Patient handouts · Screening/enrollment log · Data and Safety Monitoring Committee (DSMC) monitoring reports · OnCore® Case Report Form (CRF) completion manual
nct # 02395627 reversing therapy
documents filed in regulatory binder

· Completed Food and Drug Administration (FDA) 1572 document with Principal Investigator's signature
· For all Principal Investigators and Sub-Investigators listed on the FDA 1572, will need Financial Disclosure Forms, CVs, MD Licenses, Drug Enforcement Agency (DEA) Licenses, and Staff Training Documents (i.e. Collaborative Institute Training Initiative (CITI), etc.)
· Site Initiation Visit (SIV) minutes and correspondence with participating site(s). · As applicable, approvals for Biosafety Committee, Radiation Committee, and Infusion Center
· Serious Adverse Event (SAE) reports to CHR. · MedWatch reporting to FDA · Delegation of Authority Form · Drug Destruction Standard Operating Procedure (SOP) · For all laboratories listed on the FDA 1572, will need CLIA certifications, CAP
certifications, lab licenses, CVs of Lab Directors, and laboratory reference ranges