epigenetic priming for immune therapy
6.5.2 rescue medications & supportive

Subjects should receive appropriate supportive care measures as deemed necessary by the treating investigator, including but not limited to the items outlined below:  
Diarrhea: Subjects should be carefully monitored for signs and symptoms of enterocolitis
(such as diarrhea, abdominal pain, blood or mucus in stool, with or without fever) and bowel perforation (such as peritoneal signs and ileus). In symptomatic subjects, infectious etiologies should be ruled out, and if symptoms are persistent and/or severe, endoscopic evaluation should be considered.  
o In subjects with severe enterocolitis (Grade 3), pembrolizumab will be permanently discontinued, and treatment with systemic corticosteroids should be initiated at a dose of 1 to 2 mg/kg/day of prednisone or equivalent. When symptoms improve to Grade 1 or less, corticosteroid taper should be started and continued over at least 1 month.  
o In subjects with moderate enterocolitis (Grade 2), pembrolizumab should be withheld, and anti-diarrheal treatment should be started. If symptoms are persistent for more than one week, systemic corticosteroids should be initiated (e.g., 0.5 mg/kg/day of prednisone or equivalent). When symptoms improve to Grade 1 or less, corticosteroid taper should be started and continued over at least 1 month. Regarding guidelines for continuing treatment with pembrolizumab, see Section 5.2.1.  
o All subjects who experience diarrhea should be advised to drink liberal quantities of clear fluids. If sufficient oral fluid intake is not feasible, fluid and electrolytes should be substituted via IV infusion.  
Nausea/vomiting: Nausea and vomiting should be treated aggressively, and consideration should be given in subsequent cycles to the administration of prophylactic antiemetic therapy according to standard institutional practice. Subjects should be strongly encouraged to maintain liberal oral fluid intake.  
Anti-infectives: Subjects with a documented infectious complication should receive oral or IV antibiotics or other anti-infective agents as considered appropriate by the treating investigator for a given infectious condition, according to standard institutional practice.  
Immune-related adverse events: Please see Section 5.2 below and the separate guidance document in the administrative binder regarding diagnosis and management of adverse experiences of a potential immunologic etiology.
Management of Infusion Reactions: Acute infusion reactions (which can include cytokine release syndrome, angioedema, or anaphylaxis) are different from allergic/hypersensitive reactions, although some of the manifestations are common to both AEs. Signs and symptoms usually develop during or shortly after drug infusion and generally resolve completely within 24 hours of completion of infusion. Signs/symptoms may include: Allergic reaction/hypersensitivity (including drug fever); Arthralgia (joint pain); Bronchospasm; Cough; Dizziness; Dyspnea (shortness of breath); Fatigue (asthenia, lethargy, malaise); Headache; Hypertension; Hypotension; Myalgia (muscle pain); Nausea; Pruritis/itching; Rash/desquamation; Rigors/chills; Sweating (diaphoresis); Tachycardia; Tumor pain (onset or exacerbation of tumor pain due to treatment); Urticaria (hives, welts, wheals); Vomiting.
epigenetic priming for immune therapy
contraception

Pembrolizumab, tamoxifen, and vorinostat may have adverse effects on a fetus in utero. Furthermore, it is not known if pembrolizumab has transient adverse effects on the composition of sperm. Non-pregnant, non-breast-feeding women may be enrolled if they are willing to use 2 methods of birth control or are considered highly unlikely to conceive. Highly unlikely to conceive is defined as 1) surgically sterilized, or 2) postmenopausal (a woman who is ≥45 years of age and has not had menses for greater than 1 year will be considered postmenopausal), or 3) not heterosexually active for the duration of the study. The two birth control methods can be either two barrier methods or a barrier method plus a hormonal method to prevent pregnancy. Subjects should start using birth control from study visit 1 throughout the study period up to 120 days after the last dose of study therapy. The following are considered adequate barrier methods of contraception: diaphragm, condom (by the partner), intrauterine device, sponge, or spermicide. Appropriate hormonal contraceptives will include any registered and marketed contraceptive agent that contains an estrogen and/or a progestational agent (including oral, subcutaneous, intrauterine, or intramuscular agents). Subjects should be informed that taking the study medication may involve unknown risks to the fetus (unborn baby) if pregnancy were to occur during the study. In order to participate in the study, they must adhere to the contraception requirement (described above) for the duration of the study and during the follow-up period defined in Section 7.3.9 - Reporting of Pregnancy and Lactation to the regulatory agencies and Merck. If there is any question that a subject will not reliably comply with the requirements for contraception, that subject should not be entered into the study.
epigenetic priming for immune therapy
6.6 prohibited medications

Subjects are prohibited from receiving the following therapies during the Screening and Treatment Phase (including retreatment for post-complete response relapse) of this trial:  
Anti-cancer systemic chemotherapy or biological therapy Immunotherapy not specified in this protocol Chemotherapy not specified in this protocol Investigational agents other than Pembrolizumab Radiation therapy o Note: Radiation therapy to a symptomatic solitary lesion or the brain may be allowed after consultation with the study PI and Merck.  
Live vaccines within 30 days prior to the first dose of trial treatment and while participating in the trial. Examples of live vaccines include, but are not limited to, the following: measles, mumps, rubella, chicken pox, yellow fever, rabies, BCG, and typhoid (oral) vaccine. Seasonal influenza vaccines for injection are generally killed virus vaccines and are allowed; however, intranasal influenza vaccines (e.g., Flu-Mist®) are live attenuated vaccines and are not allowed.  
Glucocorticoids for any purpose other than to modulate symptoms from an event of clinical interest of suspected immunologic etiology. The use of physiologic doses of corticosteroids may be approved after consultation with the study PI and Merck.
Subjects who, in the assessment by the investigator, require the use of any of the aforementioned treatments for clinical management should be removed from the trial. Subjects may receive other medications that the investigator deems to be medically necessary. The Exclusion Criteria describes other medications, which are prohibited in this trial. There are no prohibited therapies during the Post-Treatment Follow-up Phase.
epigenetic priming for immune therapy
7 reporting and documentation of

Response and progression in this study will be evaluated using the new international criteria proposed by the revised Response Evaluation Criteria in Solid Tumors (RECIST) guideline
(version 1.1)70. Changes in the largest diameter (unidimensional measurement) of the tumor lesions and the shortest diameter in the case of malignant lymph nodes are used in the RECIST v1.1 criteria.
epigenetic priming for immune therapy
7.1.1 definitions evaluable for toxicity

All participants will be evaluable for toxicity from the time of their first treatment with pembrolizumab, vorinostat, and tamoxifen.
epigenetic priming for immune therapy
evaluable for objective response

Only those participants who have measurable disease present at baseline, have received at least one cycle of therapy, and have had their disease re-evaluated will be considered evaluable for response. These participants will have their response classified according to the definitions stated below. (Note: Participations who exhibit objective disease progression prior to the end of Cycle 1 will also be considered evaluable.)
epigenetic priming for immune therapy
evaluable non-target disease response

Participants who have lesions present at baseline that are evaluable but do not meet the definitions of measurable disease, have received at least one cycle of therapy, and have had their disease re-evaluated will be considered evaluable for non-target disease. The response assessment is based on the presence, absence, or unequivocal progression of the lesions.
epigenetic priming for immune therapy
7.1.2 disease parameters measurable disease

Measurable disease is defined as lesions (or tumors) that can be accurately measured in at least one dimension (longest diameter to be recorded) with a minimum size of 10mm by CT scan (irrespective of scanner type) and MRI (no less than double the slice thickness and a minimum of 10mm), 10mm caliper measurement by clinical exam (when superficial), and/or 20mm by chest X-ray (if clearly defined and surrounded by aerated lung). All tumor measurements will be recorded in millimeters or decimal fractions of centimeters. Previously irradiated lesions are considered non-measurable except in cases of documented progression of the lesion since the completion of radiation therapy.
epigenetic priming for immune therapy
malignant lymph nodes

To be considered pathologically enlarged and measurable, a lymph node must be ≥15 mm (≥1.5 cm) in short axis when assessed by CT scan (CT scan slice thickness recommended to be no greater than 5 mm [0.5 cm]). At baseline and in follow-up, only the short axis will be measured and followed.
epigenetic priming for immune therapy
non-measurable disease (tumor markers)

All other lesions (or sites of disease), including small lesions (longest diameter <10 mm [<1 cm] or pathological lymph nodes with ≥10 to <15 mm [≥1 to <1.5 cm] short axis), are considered non-measurable disease. Bone lesions, leptomeningeal disease, ascites, pleural/pericardial effusions, lymphangitis cutis/pulmonitis, inflammatory breast disease, and abdominal masses (not followed by CT or MRI), are considered as non-measurable. Note: Cystic lesions that meet the criteria for radiographically defined simple cysts should not be considered as malignant lesions (neither measurable nor non-measurable) since they are, by definition, simple cysts. 'Cystic lesions' thought to represent cystic metastases can be considered as measurable lesions if they meet the definition of measurability described above. However, if non-cystic lesions are present in the same patient, these are preferred for selection as target lesions.
epigenetic priming for immune therapy
target lesions

All measurable lesions up to a maximum of 2 lesions per organ and 5 lesions in total, representative of all involved organs, should be identified as target lesions and recorded and measured at baseline. Target lesions should be selected on the basis of their size (lesions with the longest diameter), be representative of all involved organs, but in addition, should be those that lend themselves to reproducible repeated measurements. It may be the case that, on occasion, the largest lesion does not lend itself to reproducible measurement in which circumstance the next largest lesion which can be measured reproducibly should be selected. A sum of the diameters (longest for non-nodal lesions, short axis for nodal lesions) for all target lesions will be calculated and reported as the baseline sum diameters. If lymph nodes are to be included in the sum, then only the short axis is added into the sum. The baseline sum diameters will be used as reference to further characterize any objective tumor regression in the measurable dimension of the disease.
epigenetic priming for immune therapy
non-target lesions

All other lesions (or sites of disease) including any measurable lesions over and above the 5 target lesions should be identified as non-target lesions and should also be recorded at baseline. It is possible to record multiple non-target lesions involving the same organ as a single item on the case record form (e.g. "multiple enlarged pelvic lymph nodes" or "multiple liver metastases"). Bone lesions may be measurable if ≥ 1 cm on MRI. Measurements of these lesions are not required, but the presence or absence of each will be noted throughout followup.
epigenetic priming for immune therapy
non-measurable disease (tumor markers)

Non-measurable disease is all other lesions (or sites of disease), including small lesions (longest diameter <20 mm with conventional techniques or <10 mm using spiral CT scan). Leptomeningeal disease, ascites, pleural or pericardial effusion, inflammatory breast disease, lymphangitic involvement of skin or lung, abdominal masses/abdominal organomegaly identified by physical exam that is not measurable by reproducible imaging techniques are all nonmeasurable (e.g., PSA, CA-125, CA19-9, CEA).
epigenetic priming for immune therapy
7.1.3 methods for evaluation of

All measurements will be taken and recorded in metric notation using a ruler or calipers. All baseline evaluations will be performed as closely as possible to the beginning of treatment and never more than 28 days before the beginning of the treatment. The same method of assessment and the same technique will be used to characterize each identified and reported lesion at baseline and during follow-up. Imaging-based evaluation is preferred to evaluation by clinical examination when both methods have been used to assess the antitumor effect of a treatment.  
Clinical lesions: Clinical lesions will only be considered measurable when they are superficial
(e.g., skin nodules and palpable lymph nodes) and ≥10 mm (≥1 cm) diameter as assessed using calipers (e.g., skin nodules). In the case of skin lesions, documentation by color photography, including a ruler to estimate the size of the lesion, is recommended.  
Chest x-ray: Lesions on chest x-ray are acceptable as measurable lesions when they are clearly defined and surrounded by aerated lung. However, CT is preferable.  
Conventional CT and MRI: This guideline has defined measurability of lesions on CT scan based on the assumption that CT slice thickness is 5 mm (0.5 cm) or less. If CT scans have slice thickness greater than 5 mm (0.5 cm), the minimum size for a measurable lesion should be twice the slice thickness. MRI is also acceptable in certain situations (e.g., for body scans). Use of MRI remains a complex issue. MRI has excellent contrast, spatial, and temporal resolution; however, there are many image acquisition variables involved in MRI, which greatly impact image quality, lesion conspicuity, and measurement. Furthermore, the availability of MRI is variable globally. As with CT, if an MRI is performed, the technical specifications of the scanning sequences used should be optimized for the evaluation of the type and site of disease. Furthermore, as with CT, the modality used at follow-up should be the same as was used at baseline, and the lesions should be measured/assessed on the same pulse sequence. It is beyond the scope of the RECIST guidelines to prescribe specific MRI pulse sequence parameters for all scanners, body parts, and diseases. Ideally, the same type of scanner should be used, and the image acquisition protocol should be followed as closely as possible to prior scans. Body scans should be performed with breath-hold scanning techniques, if possible.
epigenetic priming for immune therapy
7.1.4 response criteria evaluation of

Disappearance of all target lesions, determined by two separate observations conducted not less than 4 weeks apart. Any pathological lymph nodes (whether target or non-target) must have reduction in short axis to <10 mm (the sum may not be "0" if there are target nodes). There can be no appearance of new lesions.
epigenetic priming for immune therapy
partial response (pr)

At least a 30% decrease in the sum of the longest diameter (LD) of target lesions, taking as reference the baseline sum LD. There can be no appearance of new lesions.
epigenetic priming for immune therapy
progressive disease (pd)

At least a 20% increase in the sum of the diameters of target lesions, taking as reference the smallest sum on study (this includes the baseline sum if that is the smallest on study). In addition to the relative increase of 20%, the sum must also demonstrate an absolute increase of at least 5 mm (0.5 cm). (Note: the appearance of one or more new lesions is also considered progressions).
epigenetic priming for immune 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.
epigenetic priming for immune therapy
evaluation of non-target lesions complete

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). Note: If tumor markers are initially above the upper normal limit, they must normalize for a patient to be considered in complete clinical response. 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. Progressive Disease (PD) Appearance of one or more new lesions and/or unequivocal progression of existing non-target lesions.
epigenetic priming for immune therapy
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 participant's best response assignment will depend on the achievement of both measurement and confirmation criteria.  
| Disease)                                                                             |               |             |                                                   |                            |
|--------------------------------------------------------------------------------------|---------------|-------------|---------------------------------------------------|----------------------------|
| Target                                                                               | Non-Target    | New Lesions | Overall                                           | Best Overall Response when |
| Lesions                                                                              | Lesions       | Response    | Confirmation is Required*                         |                            |
| CR                                                                                   | CR            | No          | CR                                                | ≥4 wks. Confirmation**     |
| CR                                                                                   | Non-CR/Non-PD | No          | PR                                                |                            |
| CR                                                                                   | Not evaluated | No          | PR                                                |                            |
| PR                                                                                   | Non-CR/Non               |             |                                                   |                            |
| PD/not evaluated                                                                     | No            | PR          | ≥4 wks. Confirmation**                            |                            |
| SD                                                                                   | Non-CR/Non               |             |                                                   |                            |
| PD/not evaluated                                                                     | No            | SD          | Documented at least once ≥4 wks.  from baseline** |                            |
| PD                                                                                   | Any           | Yes or No   | PD                                                |                            |
| Any                                                                                  | PD***         | Yes or No   | PD                                                | no prior SD, PR or CR      |
| Any                                                                                  | Any           | Yes         | PD                                                |                            |
| * See RECIST 1.1 manuscript for further details on what is evidence of a new lesion. |               |             |                                                   |                            |  
* See RECIST 1.1 manuscript for further details on what is evidence of a new lesion.  
** Only for non-randomized trials with response as primary endpoint. *** In exceptional circumstances, unequivocal progression in non-target lesions may be accepted as disease progression.  
Note: Participants with a global deterioration of health status requiring discontinuation of treatment without objective evidence of disease progression at that time should be reported as
"*symptomatic deterioration."* Every effort should be made to document the objective progression even after discontinuation of treatment.
epigenetic priming for immune therapy
table 7.2 response criteria for

| Non-Target Lesions   | New Lesions                                                                                                                                                                                          | Overall Response   |
|----------------------|------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|--------------------|
| CR                   | No                                                                                                                                                                                                   | CR                 |
| Non-CR/non-PD        | No                                                                                                                                                                                                   | Non-CR/non-PD*     |
| Not all evaluated    | No                                                                                                                                                                                                   | not evaluated      |
| Unequivocal PD       | Yes or No                                                                                                                                                                                            | PD                 |
| Any                  | Yes                                                                                                                                                                                                  | PD                 |
|                     | 'Non-CR/non-PD' is preferred over 'stable disease' for non-target disease since SD is increasingly  used as an endpoint for assessment of efficacy in some trials so to assign this category when no |                    |
epigenetic priming for immune therapy
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. 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. Progression-Free Survival Progression-free survival (PFS) is defined as the duration of time from start of treatment to time of progression or death, whichever occurs first.
epigenetic priming for immune therapy
7.2 evaluation of safety

The safety parameters for this study include all laboratory tests and hematological abnormalities, physical findings, and spontaneous reports of adverse events reported to the investigator by participants. Toxicity will be assessed according to the NCI CTCAE version 5.0. Safety analyses will be performed for all participants who have received at least one dose of study drug.
epigenetic priming for immune therapy
7.3 definitions of adverse events

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 drugrelated. 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.
epigenetic priming for immune therapy
7.3.2 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.
epigenetic priming for immune therapy
7.3.3 suspected adverse reaction

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.
epigenetic priming for immune therapy
7.3.3.1 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 participants exposed to drugs in the angiotensin-converting enzyme 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.
epigenetic priming for immune therapy
7.3.3.2 serious

An adverse event or suspected adverse reaction is considered *serious* if, in the view of either the investigator or sponsor, 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 participant 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.
epigenetic priming for immune therapy
serious adverse events

A serious adverse event is any adverse event occurring at any dose or during any use of Merck's product that:  
Results in death; Is life-threatening; Results in persistent or significant disability/incapacity; Results in or prolongs an existing inpatient hospitalization; Is a congenital anomaly/birth defect; Is a new cancer (that is not a condition of the study);
Is associated with an overdose; Is another important medical event
Note: In addition to the above criteria, adverse events meeting either of the below criteria, although not serious per ICH definition, are reportable to the Merck in the same timeframe as SAEs to meet certain local requirements. Therefore, these events are considered serious by Merck for collection purposes.  
Is a new cancer (that is not a condition of the study); Is associated with an overdose.
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. 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 Merck.
epigenetic priming for immune therapy
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.  
the time of submission to FDA.  
All subjects with serious adverse events must be followed up for outcome.
epigenetic priming for immune therapy
7.3.3.3 life-threatening

An adverse event or suspected adverse reaction is considered life-threatening if, in the view of either the investigator or sponsor, its occurrence places the participant 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.
epigenetic priming for immune therapy
7.3.4 recording of adverse events

Refer to the Data Safety Monitoring Plan, located in Appendix 2.
epigenetic priming for immune therapy
7.3.5 follow-up of adverse events

All participants who experience adverse events will be followed with appropriate medical management until resolved or stabilized, as determined by the investigator, or until the initiation of new anti-cancer therapy, whichever occurs first. For selected adverse events for which administration of the investigational product was stopped, a re-challenge of the subject with the investigational drug may be conducted if considered both safe and ethical by the investigator.
epigenetic priming for immune therapy
7.3.6 adverse events reporting

An adverse event is defined as any untoward medical occurrence in a patient, or clinical investigation participant administered a pharmaceutical product and which does not necessarily have to have a causal relationship with this treatment. An adverse event can, therefore, be any unfavorable and unintended sign (including an abnormal laboratory finding, for example),
symptom, or disease temporally associated with the use of a medicinal product or protocolspecified procedure, whether or not considered related to the medicinal product or protocolspecified procedure. Any worsening (i.e., any clinically significant adverse change in frequency and/or intensity) of a preexisting condition that is temporally associated with the use of the Merck's product is also an adverse event. Changes resulting from normal growth and development that do not vary significantly in frequency or severity from expected levels are not to be considered adverse events. Examples of this may include but are not limited to, teething, typical crying in infants and children and onset of menses or menopause occurring at a physiologically appropriate time. Merck product includes any pharmaceutical product, biological product, device, diagnostic agent or protocol-specified procedure, whether investigational (including placebo or active comparator medication) or marketed, manufactured by, licensed by, provided by or distributed by Merck for human use. Adverse events may occur during the course of the use of Merck product in clinical trials, or as prescribed in clinical practice, from overdose (whether accidental or intentional), from abuse and withdrawal. All AEs, SAEs and other reportable safety events that occur after the consent form is signed but before treatment allocation/randomization must be reported by the investigator if the participant is receiving placebo run-in or other run-in treatment, if the event causes the participant to be excluded from the study, or is the result of a protocol-specified intervention, including but not limited to washout or discontinuation of usual therapy, diet, or a procedure.  
All AEs from the time of treatment allocation/randomization through 30 days following cessation of study treatment must be reported by the investigator.  
All AEs meeting serious criteria, from the time of treatment allocation/randomization through 90 days following cessation of study treatment, or 30 days following cessation of study treatment if the participant initiates new anticancer therapy, whichever is earlier must be reported by the investigator.  
All pregnancies and exposure during breastfeeding, from the time of treatment allocation/randomization through 120 days following cessation of study treatment, or 30 days following cessation of study treatment if the participant initiates new anticancer therapy must be reported by the investigator.  
Additionally, any SAE brought to the attention of an investigator at any time outside of the time period specified above must be reported immediately by the investigator if the event is considered to be drug-related.
Investigators are not obligated to actively seek AE or SAE or other reportable safety events in former study participants. However, if the investigator learns of any SAE, including death, at any time after a participant has been discharged from the study, and he/she considers the event to be reasonably related to the study treatment or study participation, the investigator must promptly notify Merck. 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 (IRB); 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 Phase 2 or 3 Institutional Study at the Helen Diller Comprehensive Cancer Center, please refer to Appendix 2.
epigenetic priming for immune therapy
7.3.7 definition of an overdose

For purposes of this study, an overdose of pembrolizumab will be defined as any dose of 1,000 mg or greater (≥5 times the indicated dose). No specific information is available on the treatment of overdose of pembrolizumab. In the event of overdose, the participant 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."
Page 64 of 82 All reports of overdose with and without an adverse event must be reported within 24 hours to the Sponsor and within 2 working days hours to Merck Global Safety.
epigenetic priming for immune therapy
7.3.7.1 event of clinical interest

Selected non-serious and serious adverse events are also known as Events of Clinical Interest (ECI) and must be reported within 2 working days to Merck Global Safety. For the time period beginning when the consent form is signed until treatment allocation/randomization, any ECI, or follow up to an ECI, that occurs to any participant must be reported within 2 working days to Merck Global Safety if it causes the participant to be excluded from the trial, or is the result of a protocol-specified intervention, including but not limited to washout or discontinuation of usual therapy, diet, placebo treatment or a procedure. For the time period beginning at treatment allocation/randomization through 90 days following cessation of treatment, or 30 days following cessation of treatment if the participant initiates new anticancer therapy, whichever is earlier, any ECI, or follow up to an ECI, whether or not related to Merck product, must be reported within 2 working days to Merck Global Safety. Events of clinical interest for this trial include:  
1. an overdose of Merck product, as defined in Section - Definition of an Overdose for This Protocol and Reporting of Overdose to the Sponsor, that is not associated with clinical symptoms or abnormal laboratory results.  
2. an elevated AST or ALT lab value that is greater than or equal to 3X the upper limit of normal and an elevated total bilirubin lab value that is greater than or equal to 2X the upper limit of normal and, at the same time, an alkaline phosphatase lab value that is less than 2X the upper limit of normal, as determined by way of protocol-specified laboratory testing or unscheduled laboratory testing.*
**Note*: These criteria are based upon available regulatory guidance documents. The purpose of the criteria is to specify a threshold of abnormal hepatic tests that may require an additional evaluation for an underlying etiology.
epigenetic priming for immune therapy
7.3.8 adverse events monitoring

Refer to the Data Safety Monitoring Plan, located in Appendix 2.
epigenetic priming for immune therapy
7.3.9 expedited reporting reporting to

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.
epigenetic priming for immune therapy
reporting to institutional review board

The UCSF PI must report events to the UCSF IRB according to institutional guidelines.  
UCSF IRB website for guidance in reporting adverse events: https://irb.ucsf.edu/adverse-event
epigenetic priming for immune therapy
reporting to sponsor - merck

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.
epigenetic priming for immune therapy
expedited reporting to the fda

If the study is being conducted under an IND, the Sponsor (or 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 Sponsor (or Sponsor-Investigator) must report in an IND safety report any suspected adverse reaction that is both serious and unexpected. The Sponsor 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)).
epigenetic priming for immune therapy
reporting to industry partners

Reporting of Pregnancy and Lactation to the Sponsor and Merck Although pregnancy and infant exposure during breastfeeding are not considered adverse events, it is the responsibility of investigators or their designees to report any pregnancy or lactation in a participant (spontaneously reported to them) that occurs during the study. Pregnancies and infant exposures during breastfeeding that occur after the consent form is signed but before treatment allocation/randomization must be reported by the investigator if they cause the participant to be excluded from the trial, or are the result of a protocol-specified intervention, including but not limited to washout or discontinuation of usual therapy, diet, placebo treatment or a procedure.  
Pregnancies and infant exposures during breastfeeding that occur from the time of treatment allocation/randomization through 120 days following cessation of Sponsor's product, or 30 days following cessation of treatment if the participant initiates new anticancer therapy, whichever is earlier, must be reported by the investigator. All reported pregnancies 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.
epigenetic priming for immune therapy
such events must be reported

This is a randomized two-arm trial with futility early stopping built-in within each treatment arm using a Simon's two-stage design71 (Simon, 1989). The effect of vorinostat on pembrolizumab and the effect of pembrolizumab and tamoxifen in this biomarker-selected population of ER+ breast cancer patients will be first tested against the respectively chosen null rate in the first stage within the treatment arms and then compared between the treatment arms.
epigenetic priming for immune therapy
8.1 sample size considerations 8.1.1

For Arm A (pembro + vorinostat + TAM): The null hypothesis that the true response rate for pembrolizumab and vorinostat in ER+ pretreated patients alone without biomarker enrichment is 0.15 which will be tested against the alternative that response rate of pembrolizumab in a biomarker select population is 0.40. In the first stage, 13 patients will be accrued. If there are 2 or fewer responses in these 13 patients, the study will be stopped. Otherwise, 22 additional patients will be accrued for a total of 35. The null hypothesis will be rejected if 10 or more responses are observed in 35 patients. This design yields a type I error rate of 0.025 and power of 0.9 in this treatment arm when the true response rate is 0.4 in this patient subpopulation.  
For Arm B (pembro + TAM): The null hypothesis that the true response rate for pembrolizumab in ER+ pretreated patients alone is 0.10 which will be tested against the alternative that response rate of pembrolizumab in a biomarker select population is 0.35. In the first stage, 11 patients will be accrued. If there are 1 or fewer responses in these 11 patients, the study will be stopped. Otherwise, 19 additional patients will be accrued for a total of 30. The null hypothesis will be rejected if 7 or more responses are observed in 30 patients. This design yields a type I error rate of 0.025 and power of 0.9 in this treatment arm when the true response rate of pembro and TAM treatment is 0.35 in this patient subpopulation. Based on earlier results in Section 1.3 and hypothesized treatment effects, we will most likely to enroll 46 evaluable patients (~65% chance), whereas the possible enrollment ranges from 24 to 65. For the comparison of the treatment arms, the proposed design will have 72.53% power for the Fisher's exact test at 0.1 significance level when the true response rates are 0.4 and 0.1 for the immune priming and the no immune priming treatment arm.
epigenetic priming for immune therapy
8.1.2 randomization 8.1.3 stratification factors

This is an open-label randomized trial; therefore, the sponsor, investigator, and subject will know the treatment administered. Two arms will be tested, with each independent assessment.  
Patients will be randomized to either arm using a computerized randomization program by Dr. Mi-Ok Kim. Patients will be stratified by prior number of chemo- and hormonal therapies. Ten patients are expected to be eligible yearly based on prior accrual for a similar population. This is a randomized two-arm trial with futility early stopping built-in within each treatment arm using a Simon's two-stage design71.  
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. We will conduct an intention-to-treat analysis of efficacy. All randomized patients 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. 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. Within each treatment arm, the observed ORR will be compared to the respective null (ineffective) rate using the decision rule provided by the Simon's two-stage design. In addition to calculating the ORR, we will calculate the corresponding one-sided 95% confidence interval by appropriately accounting for the Simon's two-stage design: given the observed response number (s), testing of the null hypothesis of H0:p≤p0 will reject the null if the probability of observing as many or less than the observed number of responses (s) is less than the significance level: Prob(S≤s│
p0)<α. Using this hypothesis inversely, we can construct a (1-α)100% one-sided confidence interval is given as a set
{:( ≤ │0 = ) < }
Page 68 of 82 where Prob(S≤s│p0=p)indicates the joint distribution of stage to stop and observed response number (s) as in Chang et al., 198972. Similarly, the observed rates will be compared between the treatment arms using the Z-test and appropriately accounting for the Simon's two-stage design.
epigenetic priming for immune therapy
8.3.3 secondary analysis (or analysis

We will use median (DOR, OS, PFS, computed by the Kaplan-Meier estimator) and percentages (% irRC) to summarize secondary endpoints. The respective confidence intervals will be computed as well.
epigenetic priming for immune therapy
8.3.4 exploratory/correlative analysis/assessments 8.3.4.1 analysis

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.
epigenetic priming for immune therapy
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}.  
Tissue Immune Subset Quantification and Localization For all subjects, immune cell subsets and localization will be summarized by changes from baseline to after treatment using descriptive statistics.
epigenetic priming for immune therapy
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.
epigenetic priming for immune therapy
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.
epigenetic priming for immune therapy
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 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 the difference of tumor gene copy number between pre and post-treatment. Two-sample Wilcoxon signed-rank test will be used to test the gene copy number between tumor responders and nonresponders for pre-treatment, post-treatment, and changes before and after the treatment, separately. Multiple testing adjustment will be done by controlling false positive rate. Nextgeneration 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.
epigenetic priming for immune therapy
8.3.4.2 analysis of immune endpoints

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.
epigenetic priming for immune therapy
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 post-treatment 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.
epigenetic priming for immune therapy
9 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 PI 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 participants before any protocol-related procedures are performed on any participants. 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 FDA has determined that the study is exempt from IND requirements. The PI must comply with the applicable regulations in Title 21 of the Code of Federal Regulations (21 CFR §50, §54, and §312), GCP/ICH guidelines, and all applicable regulatory requirements. The IRB must comply with the regulations in 21 CFR §56 and applicable regulatory requirements.
epigenetic priming for immune therapy
9.2 institutional review board approval

The protocol, the proposed informed consent form, and all forms of participant-facing materials related to the study (e.g., advertisements used to recruit participants) will be reviewed and approved by the UCSF IRB. Prior to obtaining IRB 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.
epigenetic priming for immune therapy
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 IRB-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.
epigenetic priming for immune therapy
9.4 changes in the protocol

Once the protocol has been approved by the UCSF IRB, any changes to the protocol must be documented in the form of an amendment. The amendment must be signed by the PI and approved by PRC and the IRB prior to implementation. If it becomes necessary to alter the protocol to eliminate an immediate hazard to participants, an amendment may be implemented prior to IRB approval. In this circumstance, however, the PI must then notify the IRB according to institutional requirements.
epigenetic priming for immune therapy
9.5 handling and documentation of

The PI will maintain complete records showing the receipt, dispensation, return, or other disposition of all investigational drugs at the site. The date, quantity, and batch or code number of the drug, and the identification of participants to whom the investigational product has been dispensed by participant number and initials will be included. The PI shall not make the investigational drug available to any individuals other than to qualified study participants. Furthermore, the PI will not allow the investigational product to be used in any manner other than that specified in this protocol.
epigenetic priming for immune therapy
9.6 case report forms (crfs)

The PI and/or 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. Study personnel will complete the CRFs; the PI 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 participant's medical records maintained by study personnel. All source documentation should be kept in separate research files for each participant. In accordance with federal regulations, the PI 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. The PI 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 PI and the trial statistician. All source documentation and CTMS data will be available for review/monitoring by the UCSF DSMC and regulatory agencies.
epigenetic priming for immune therapy
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.
epigenetic priming for immune therapy
9.8 record keeping and record

The PI 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 PI 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 including, for example, signed and dated consent forms and medical records including, for example, 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, IRB correspondence and approval, signed participant 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 PI 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.  
Page 73 of 82
epigenetic priming for immune therapy
10 references

1. Sharma D, Blum J, Yang X, Beaulieu N, Macleod AR, Davidson NE. 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.  
2. 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.  
3. Early Breast Cancer Trialists' Collaborative G. 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.  
4. 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.  
5. 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.  
6. Bonneterre J, Buzdar A, Nabholtz J-MA, et al. Anastrozole is superior to tamoxifen as first-line therapy in hormone receptor positive advanced breast carcinoma. *Cancer.*
2001;92(9):2247-2258.  
7. Nabholtz JM, Buzdar A, Pollak M, et al. Anastrozole is superior to tamoxifen as first-line therapy for advanced breast cancer in postmenopausal women: results of a North American multicenter randomized trial. Arimidex Study Group. *J Clin Oncol.*
2000;18(22):3758-3767.  
8. Deschoolmeester V, Baay M, Van Marck E, et al. Tumor infiltrating lymphocytes: an intriguing player in the survival of colorectal cancer patients. *BMC Immunol.* 2010;11:19.  
9. Galon J, Costes A, Sanchez-Cabo F, et al. Type, density, and location of immune cells within human colorectal tumors predict clinical outcome. *Science.* 2006;313(5795):19601964.  
10. Diez M, Pollan M, Enriquez JM, et al. Histopathologic prognostic score in colorectal adenocarcinomas. *Anticancer Res.* 1998;18(1B):689-694.  
11. Giuliano M, Schifp R, Osborne CK, Trivedi MV. Biological mechanisms and clinical implications of endocrine resistance in breast cancer. *Breast.* 2011;20 Suppl 3:S42-49.  
12. Thomas S, Thurn KT, Bicaku E, Marchion DC, Munster PN. Addition of a histone deacetylase inhibitor redirects tamoxifen-treated breast cancer cells into apoptosis, which is opposed by the induction of autophagy. *Breast Cancer Res Treat.*
2011;130(2):437-447.  
13. Munster PN, Thurn KT, Thomas S, et al. A phase II study of the histone deacetylase inhibitor vorinostat combined with tamoxifen for the treatment of patients with hormone therapy-resistant breast cancer. *Br J Cancer.* 2011;104(12):1828-1835.  
14. Wrangle J, Wang W, Koch A, et al. Alterations of immune response of Non-Small Cell Lung Cancer with Azacytidine. *Oncotarget.* 2013;4(11):2067-2079.  
15. Li H, Chiappinelli KB, Guzzetta AA, et al. Immune regulation by low doses of the DNA
methyltransferase inhibitor 5-azacitidine in common human epithelial cancers.  
Oncotarget. 2014;5(3):587-598.  
16. Tao R, de Zoeten EF, Ozkaynak E, et al. Deacetylase inhibition promotes the generation and function of regulatory T cells. *Nat Med.* 2007;13(11):1299-1307.  
17. Licciardi PV, Karagiannis TC. Regulation of immune responses by histone deacetylase inhibitors. *ISRN Hematol.* 2012;2012:690901.  
18. Disis ML. Immune regulation of cancer. *J Clin Oncol.* 2010;28(29):4531-4538.  
19. Dong H, Strome SE, Salomao DR, et al. Tumor-associated B7-H1 promotes T-cell apoptosis: a potential mechanism of immune evasion. *Nat Med.* 2002;8(8):793-800.  
20. Brown JA, Dorfman DM, Ma FR, et al. Blockade of programmed death-1 ligands on dendritic cells enhances T cell activation and cytokine production. *J Immunol.*
2003;170(3):1257-1266.  
21. Francisco LM, Sage PT, Sharpe AH. The PD-1 pathway in tolerance and autoimmunity.  
Immunol Rev. 2010;236:219-242.  
22. Thompson RH, Dong H, Lohse CM, et al. PD-1 is expressed by tumor-infiltrating immune cells and is associated with poor outcome for patients with renal cell carcinoma.  
Clin Cancer Res. 2007;13(6):1757-1761.  
23. Talmadge JE, Donkor M, Scholar E. Inflammatory cell infiltration of tumors: Jekyll or Hyde. *Cancer Metastasis Rev.* 2007;26(3-4):373-400.  
24. Usubutun A, Ayhan A, Uygur MC, Ozen H, Toklu C, Ruacan S. Prognostic factors in renal cell carcinoma. *J Exp Clin Cancer Res.* 1998;17(1):77-81.  
25. Al-Shibli KI, Donnem T, Al-Saad S, Persson M, Bremnes RM, Busund LT. Prognostic effect of epithelial and stromal lymphocyte infiltration in non-small cell lung cancer. *Clin* Cancer Res. 2008;14(16):5220-5227.  
26. Hiraoka N. Tumor-infiltrating lymphocytes and hepatocellular carcinoma: molecular biology. *Int J Clin Oncol.* 2010;15(6):544-551.  
27. Nobili C, Degrate L, Caprotti R, et al. Prolonged survival of a patient affected by pancreatic adenocarcinoma with massive lymphocyte and dendritic cell infiltration after interleukin-2 immunotherapy. Report of a case. *Tumori.* 2008;94(3):426-430.  
28. 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.  
29. 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.  
30. 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.  
31. 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.  
32. 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.  
33. Kelly WK, O'Connor OA, Marks PA. Histone deacetylase inhibitors: from target to clinical trials. *Expert Opin Investig Drugs.* 2002;11(12):1695-1713.  
34. 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.  
35. 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.  
36. Nimmanapalli R, Fuino L, Stobaugh C, Richon V, Bhalla K. Cotreatment with the histone deacetylase inhibitor suberoylanilide hydroxamic acid (SAHA) enhances imatinibinduced apoptosis of Bcr-Abl-positive human acute leukemia cells. *Blood.*
2003;101(8):3236-3239.  
37. Yu C, Rahmani M, Almenara J, et al. Histone deacetylase inhibitors promote STI571mediated apoptosis in STI571-sensitive and -resistant Bcr/Abl+ human myeloid leukemia cells. *Cancer Res.* 2003;63(9):2118-2126.  
38. 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.  
39. Mitsiades CS, Mitsiades N, Richardson PG, Treon SP, Anderson KC. Novel biologically based therapies for Waldenstrom's macroglobulinemia. *Semin Oncol.* 2003;30(2):309312.  
40. Peart MJ, Tainton KM, Ruefli AA, et al. Novel mechanisms of apoptosis induced by histone deacetylase inhibitors. *Cancer Res.* 2003;63(15):4460-4471.  
41. 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.  
42. Huang LL, Pardee AB. Suberoylanilide hydroxamic acid as a potential therapeutic agent for human breast cancer treatment. *Mol Med.* 2000;6(10):849-866.  
43. 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.  
44. 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.  
45. 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.  
46. 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.  
47. Cohen LA, Amin S, Marks PA, Rifkind RA, Desai D, Richon VM. Chemoprevention of carcinogen-induced mammary tumorigenesis by the hybrid polar cytodifferentiation agent, suberanilohydroxamic acid (SAHA). *Anticancer Res.* 1999;19(6B):4999-5005.  
48. 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.  
49. Marks PA, Richon VM, Breslow R, Rifkind RA. Histone deacetylase inhibitors as new cancer drugs. *Current Opinion in Oncology.* 2001;13(6):477-483.  
50. Cress WD, Seto E. Histone deacetylases, transcriptional control, and cancer. J Cell Physiol. 2000;184(1):1-16.  
51. Grunstein M. Histone acetylation in chromatin structure and transcription. *Nature.*
1997;389(6649):349-352.  
52. Yang WM, Tsai SC, Wen YD, Fejer G, Seto E. Functional domains of histone deacetylase-3. *J Biol Chem.* 2002;277(11):9447-9454.  
53. 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.  
54. 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):811814.  
55. Muraoka M, Konishi M, Kikuchi-Yanoshita R, et al. p300 gene alterations in colorectal and gastric carcinomas. *Oncogene.* 1996;12(7):1565-1569.  
56. 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.  
57. 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.  
58. Munster PN, Barberio MT, Pawlowska N, et al. Exhausted CD8+ cells (Tex) to predict response to PD-1 therapy in estrogen receptor (+) hormone therapy resistant breast cancer predictive of response to immune checkpoint inhibitors after epigenetic priming. Paper presented at: ASCO Annual Meeting; June 2, 2018, 2018; Chicago, IL.  
59. Terranova-Barberio M, Thomas S, Ali N, et al. HDAC inhibition potentiates immunotherapy in triple negative breast cancer. *Oncotarget.* 2017;8(69):114156-114172.  
60. Sabatier R, Finetti P, Mamessier E, et al. Prognostic and predictive value of PDL1 expression in breast cancer. *Oncotarget.* 2015;6(7):5449-5464.  
61. Terranova-Barberio M, Thomas S, Munster PN. Epigenetic modifiers in immunotherapy:
a focus on checkpoint inhibitors. *Immunotherapy.* 2016;8(6):705-719.  
62. Shen L, Ciesielski M, Ramakrishnan S, et al. Class I histone deacetylase inhibitor entinostat suppresses regulatory T cells and enhances immunotherapies in renal and prostate cancer models. *PLoS One.* 2012;7(1):e30815.  
63. Daud AI, Loo K, Pauli ML, et al. Tumor immune profiling predicts response to anti-PD-1 therapy in human melanoma. *J Clin Invest.* 2016;126(9):3447-3452.  
64. Kestens L, Vanham G, Gigase P, et al. Expression of activation antigens, HLA-DR and CD38, on CD8 lymphocytes during HIV-1 infection. *AIDS.* 1992;6(8):793-797.  
65. Bates GJ, Fox SB, Han C, et al. Quantification of regulatory T cells enables the identification of high-risk breast cancer patients and those at risk of late relapse. *J Clin* Oncol. 2006;24(34):5373-5380.  
66. Bohling SD, Allison KH. Immunosuppressive regulatory T cells are associated with aggressive breast cancer phenotypes: a potential therapeutic target. *Mod Pathol.*
2008;21(12):1527-1532.  
67. Ohara M, Yamaguchi Y, Matsuura K, Murakami S, Arihiro K, Okada M. Possible involvement of regulatory T cells in tumor onset and progression in primary breast cancer. *Cancer Immunol Immunother.* 2009;58(3):441-447.  
68. Terranova-Barberio M, Thomas S, Munster PN. Host histone acetylation unlocks HDAC
inhibitor potential. *Oncotarget.* 2017;8(63):106161-106162.  
69. Munster PN, Marchion D, Thomas S, et al. Phase I trial of vorinostat and doxorubicin in solid tumours: histone deacetylase 2 expression as a predictive marker. *Br J Cancer.*
2009;101(7):1044-1050.  
70. Eisenhauer EA, Therasse P, Bogaerts J, et al. New response evaluation criteria in solid tumours: revised RECIST guideline (version 1.1). *Eur J Cancer.* 2009;45(2):228-247.  
71. Simon R. Optimal two-stage designs for phase II clinical trials. *Control Clin Trials.*
1989;10(1):1-10.  
72. Chang MN, Wieand HS, Chang VT. The bias of the sample proportion following a group sequential phase II clinical trial. *Statistics in Medicine.* 1989;8(5):563-570.
epigenetic priming for immune therapy
appendix 1 performance status criteria

| ECOG Performance Status Scale                                                                                                         | Karnofsky Performance Scale                |                                                                          |                                                |
|---------------------------------------------------------------------------------------------------------------------------------------|--------------------------------------------|--------------------------------------------------------------------------|------------------------------------------------|
| Grade                                                                                                                                 | Descriptions                               | Percent                                                                  | Description                                    |
| 0                                                                                                                                     | Normal activity                            | 100                                                                      | Normal, no complaints, no evidence  of disease |
| Fully active, able to carry on all  pre-disease performance                                                                           | 90                                         | Able to carry on normal activity;                                        |                                                |
| without restriction                                                                                                                   | minor signs or symptoms of disease         |                                                                          |                                                |
| 1                                                                                                                                     | Symptoms, but ambulatory                   | 80                                                                       | Normal activity with effort; some              |
| Restricted in physically                                                                                                              | signs or symptoms of disease               |                                                                          |                                                |
| strenuous activity, but  ambulatory and able to carry out  work of a light or sedentary  nature (e.g., light housework,  office work) | 70                                         | Cares for self, unable to carry on  normal activity or to do active work |                                                |
| 2                                                                                                                                     | In bed < 50% of the time                   | 60                                                                       | Requires occasional assistance, but            |
| Ambulatory and capable of all                                                                                                         | is able to care for most of his/her  needs |                                                                          |                                                |
| self-care, 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 selfcare, 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                                                |                                                |
| Totally confined to bed or chair                                                                                                      | progressing rapidly                        |                                                                          |                                                |
| 5                                                                                                                                     | Dead                                       | 0                                                                        | Dead                                           |
epigenetic priming for immune therapy
appendix 2 data and safety

Data and Safety Monitoring Plan for a Phase II or III Institutional Trial
epigenetic priming for immune therapy
1. oversight and monitoring plan

The UCSF Helen Diller Family Comprehensive Cancer Center (HDFCCC) Data and Safety Monitoring Committee (DSMC) is responsible for auditing data quality and participant safety for all HDFCCC institutional clinical trials. A summary of DSMC activities for this trial includes:  
Semiannual auditing (depending on trial accrual) Review of serious adverse events Minimum of biennial regulatory auditing
epigenetic priming for immune therapy
2. monitoring and reporting guidelines

Investigators will conduct a continuous review of data and participant safety at monthly site committee meetings where the results of each participant's treatment are discussed and documented in the site committee minutes. All institutional Phase II and III therapeutic trials are audited on a semiannual basis, with all data from twenty percent of the enrolled participants audited by the DSMC Monitor/Auditor. The assigned DSMC Monitor/Auditor will review no more than a total of 10 participant charts during the course of auditing this trial. DSMC Monitor/Auditors will send a follow-up report to the study team within 20 business days after the auditing visit is complete for the PI and the study team to resolve all action items from this report within 20 business days. An abbreviated regulatory review (i.e., reviewing protocol and consent versions, SAEs, PVs, DOA logs, 1572 forms, etc.) will occur at each participant monitoring review; however, a full regulatory review will occur on a biennially basis by the DSMC for regulatory compliance. Auditing of all enrolled participants in these trials will be complete after 20% of enrolled participants have been audited through five cycles of treatment. However, regulatory reviews of the trial, safety reviews (i.e., Serious Adverse Event (SAE) reviews and Protocol Violation (PV) reviews), and audit/inspection preparation (as applicable) will continue until the trial is closed by the IRB.
epigenetic priming for immune therapy
3. review and oversight requirements

All Grade 3-5 adverse events (AEs), whether or not considered to be expected or unexpected and whether or not considered to be associated with the use of the investigational agent(s) or study procedure, will be entered into OnCore®, UCSF's Clinical Trial Management System.  
Adverse events are graded according to the Common Terminology Criteria for Adverse Events (CTCAE) as developed and revised by the Common Therapy Evaluation Program (CTEP) of the National Cancer Institute. Adverse events are further given an assignment of attribution or relationship to investigational agent or study procedure. Attribution categories are:  
- **Definite** - The adverse event is clearly related to the investigational agent(s) or study procedure.  
- **Probable** - The adverse event is likely related to the investigational agent(s) or study procedure.  
- **Possible** - The adverse event may be related to the investigational agent(s) or study procedure.  
- **Unrelated** - the adverse event is clearly not related to the investigational agent(s)
or study procedure.
All Grade 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 attribution assignment.
epigenetic priming for immune therapy
3.2 serious adverse event reporting

By definition, an adverse event is defined as a serious adverse event (SAE) according to the following criteria:  
- Death. - Life-threatening (i.e., results in an immediate risk of death). - Requires inpatient hospitalization or prolongation of existing hospitalization, - Permanent or significant disability/incapacity - Gives rise to a congenital anomaly/birth defect, or cancer, or any experience that suggests a significant hazard, contraindication, side effect, or precaution that may require medical or surgical intervention to prevent one of the outcomes listed above.  
- Event occurring in a gene therapy study. - Event that changes the risk/benefit ratio of a study. - Any other event the Principal Investigator judges to be serious or which would suggest a significant hazard, contraindication, side effect, or precaution.
Serious adverse event reporting will be in accordance with all IRB regulations. For trials conducted under an investigational new drug (IND) application, the SAE will be reported in accordance with Code of Federal Regulation Title 21 Part 312.32 and will be reported on a Med Watch form. UCSF IRB website for guidance in reporting serious adverse events: https://irb.ucsf.edu/adverse-event Med Watch forms and information: www.fda.gov/medwatch/getforms.htm All serious adverse events are entered into OnCore®, as well as submitted to the IRB (per IRB guidelines). The SAEs are 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. The date the SAE is sent to all required reporting agencies will be documented in OnCore®.  
If the SAE involves a subject death, and is determined to be possibly, probably or definitely related to the investigational drug or any research related procedure, the event must be reported to the DSMC Chair (or Vice Chair) and DSMC Director within one business day.
epigenetic priming for immune therapy
1.3 review of adverse event

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 Principal Investigator will notify the DSMC via report 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 Investigator voluntarily holds enrollment or stops the study due to safety issues, the DSMC Chair (or Vice Chair) and the DSMC Director must be notified within one business day and the IRB must be notified as per IRB reporting regulations.
epigenetic priming for immune therapy
appendix 3 prohibited medications list

| Drug                                           | Trade name (if applicable)   |
|------------------------------------------------|------------------------------|
| BCG (Intravesical or vaccine) - ok if on ARM B | Theracys. TICE-BCG           |
| BuPROPion                                      | Wellbutrin                   |
| Cladribine - ok if on ARM B                    | Mavenclad                    |
| Conivaptan                                     | Vaprisol                     |
| Dacomitinib                                    | Vizimpro                     |
| Deferiprone - ok if on ARM B                   | Ferriprox                    |
| Dexamethasone                                  | Prozac                       |
| Fludrocortisone FLUoxetine                     | Prozac                       |
| Hydrocortisone (topical is okay)               | Cortef                       |
| Idelalisib                                     | Zydelig                      |
| PARoxetine                                     | Paxil                        |
| Methylprednisolone                             | Medrol                       |
| Ospemifene                                     | Osphena                      |
| Prednisone                                     | Deltisone                    |
| Tipranavir                                     | Aptivus                      |
| Triamcinolone (topical, inhaled is ok)         | Kenalog                      |