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definitions of adverse events

An AE is any untoward medical occurrence in a patient administered a pharmaceutical product and which does not necessarily have a causal relationship with this treatment. An AE can therefore be any unfavorable and unintended sign (including a clinically significant abnormal laboratory finding, for example), symptom, or disease temporally associated with the use of an investigational study drug, whether or not considered related to the study drug (ICH-E2A, 1995). For the purposes of this clinical study, AEs include events which are either new or represent detectable exacerbations of pre-existing conditions. The term "disease progression" should not be reported as an adverse event term. As an example, "worsening of underlying disease" or the clinical diagnosis that is associated with disease progression should be reported. Adverse events may include, but are not limited to: - Subjective or objective symptoms provided by the patient and/or observed by the Investigator or study staff including laboratory abnormalities of clinical significance.  
- Any AEs experienced by the patient through the completion of final study procedures. - AEs not previously observed in the patient that emerge during the protocol-specified AE
reporting period, including signs or symptoms associated with the underlying disease that were not present before the AE reporting period
- Complications that occur as a result of protocol-mandated interventions (eg, invasive procedures such as biopsies).
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the following are not considered

- Pre-existing condition: A pre-existing condition (documented on the medical history CRF) is not considered an AE unless the severity, frequency, or character of the event worsens during the study period.  
- Pre-planned or elective hospitalization: A hospitalization planned before signing the informed consent form is not considered an SAE, but rather a therapeutic intervention. However, if during the pre-planned hospitalization an event occurs, which prolongs the hospitalization or meets any other SAE criteria, the event will be considered an SAE. Surgeries or interventions that were under consideration, but not performed before enrollment in the study, will not be considered serious if they are performed after enrollment in the study for a condition that has not changed from its baseline level. Elective hospitalizations for social reasons, solely for the administration of chemotherapy, or due to long travel distances are also not SAEs.  
- Diagnostic Testing and Procedures: Testing and procedures should not to be reported as AEs or SAEs, but rather the cause for the test or procedure should be reported.
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recording and reporting of adverse

All AEs of any subject during the course of the study will be recorded in the CRF, and the investigator will give his or her opinion as to the relationship of the AE to the study drug treatment (i.e., whether the event is related or unrelated to study drug administration). All AEs should be documented. A description of the event, including its date of onset and resolution, whether it constitutes an SAE or not, any action taken (e.g., changes to study treatment), and outcome, should be provided, along with the investigator's assessment of causality (i.e., the relationship to the study treatment[s]). For an AE to be a suspected treatment-related event there should be at least a reasonable possibility of a causal relationship between the protocol treatment and the AE. Adverse events will be graded according to the NCI CTCAE 4.03. If the AE is serious, it should be reported immediately to IRB of record. Other untoward events occurring in the framework of a clinical study are also to be recorded as AEs (i.e., AEs that occur prior to assignment of study treatment that are related to a study-mandated intervention, including invasive procedures such as biopsies, medication washout, or no treatment run-in). Any clinically significant signs and symptoms; abnormal test findings; changes in physical examination; hypersensitivity; and other measurements that occur will be reported as an AE, and collected on the relevant CRF. Test findings will be reported as an AE if the test result requires an adjustment in the study drug(s) or discontinuation of treatment; and/ or test findings require additional testing, treatment, or surgical intervention; a test result or finding is associated with accompanying symptoms; or a test result is considered to be an AE by the investigator. All AEs regardless of seriousness or relationship to study treatment, spanning from the start of study treatment, until 30 calendar days after discontinuation or completion of study treatment as defined by the clinical study for that subject, are to be recorded in the CRF.
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handling of adverse events

All AEs resulting in discontinuation from the trial should be followed until resolution or stabilization. Patients must be followed for AEs for 30 calendar days after discontinuation or completion of clinical trial-specific treatment (e.g., chemotherapy, radiation, oral medications, targeted therapy, and surgery). All new AEs occurring during this period must be reported and followed until resolution unless, in the opinion of the investigator, the AE or laboratory abnormality/ies are not likely to improve because of the underlying disease. In this case, the investigators must record his or her reasoning for this decision in the subject's medical record and as a comment on the CRF. After 30 days of completion of study-specific treatment or discontinuation, only AEs, SAEs, or deaths assessed by the investigator as treatment related are to be reported.
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11.2 serious adverse events definitions

The definitions of SAEs are given below. The Principal Investigator is responsible for ensuring that all staff involved in the trial is familiar with the content of this section. A serious adverse event based on ICH and EU Guidelines on Pharmacovigilance for Medicinal Products for Human Use is any untoward medical occurrence that at any dose that:  
Results in death Is a life-threatening adverse event. Life-threatening is defined as an AE in which the patient was at risk of death at the time of the event. It does not refer to an event which hypothetically might have caused death if it were more severe. If either the Investigator or the IND Sponsor believes that an AE meets the definition of life-threatening, it will be considered life threatening.  
Requires at least a 24-hour inpatient hospitalization or prolongation of existing hospitalization Results in persistent or significant incapacity or substantial disruption of the ability to conduct normal life functions Results in a congenital anomaly/birth defect.  
Is an important medical event that may not result in death, be immediately life threatening or require hospitalization, but may be considered an SAE when, based upon appropriate medical judgment, the event may jeopardize the patient or patient may require intervention to prevent one of the other outcomes listed in this definition. Examples of such events are intensive treatment in an emergency department or at home for allergic bronchospasm, blood dyscrasias, or convulsion that does not result in hospitalization; or development of drug dependency or drug abuse.
Treatment within or admission to the following facilities is not considered to meet the criteria of "inpatient hospitalization" (although if any other SAE criteria are met, the event must still be treated as an SAE and immediately reported): - Emergency Department or Emergency Room - Outpatient or same-day surgery units - Observation or short-stay unit - Rehabilitation facility  
- Hospice or skilled nursing facility - Nursing homes, custodial care or respite care facility
Hospitalization during the trial for a pre-planned surgical or medical procedure (one which was planned prior to entry in the trial) does not require reporting as an SAE to the local IRB. Deaths that are attributed by the Investigator solely to the progression of disease do not require reporting as an SAE to the the local IRB.
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serious adverse event reporting by

It is important to distinguish between "serious" and "severe" adverse events, as the terms are not synonymous. Severity is a measure of intensity; however, an AE of severe intensity need not necessarily be considered serious. For example, nausea which persists for several hours may be considered severe nausea, but may not be considered an SAE. On the other hand, a stroke which results in only a limited degree of disability may be considered only a mild stroke, but would be considered an SAE. Severity and seriousness should be independently assessed when recording AEs on the CRF and SAEs on the SAE Report Form. Adverse events classified by the treating investigator as serious require expeditious handling and reporting to the sponsor in order to comply with regulatory requirements. Serious adverse events may occur at any time from the start of study treatment through the 30-day follow-up period after the last study treatment. The sponsor must be notified of all SAEs, regardless of causality, within one business day of the first knowledge of the event by the treating physician or research personnel. To report an SAE, the SAE Report Form should be completed with the necessary information. All SAEs occurring from the start of study treatment, until 30 calendar days of last study treatment must be reported to the chair, Dr. Margaret Tempero as SAEs on the SAE Report Form and followed until resolution (with autopsy report if applicable). Deaths and other SAEs occurring >30 calendar days after last study treatment that are deemed 'possibly' or 'probably' related to study drug must be reported as SAEs on the SAE Report Form within 1 day of first knowledge of the event by the treating physician or research personnel (with an autopsy report if available). Deaths occurring >30 calendar days after last study treatment and not attributed to study treatment (e.g., disease progression) need not be reported as SAEs, but simply captured on the appropriate CRF. To report an SAE, the SAE Report Form should be completed with the necessary information. The SAE report Form should be sent to the study coordination site via e-mail using the following  
 contact information (during both business and non-business hours):  
Emailof the SAE report Form should be confirmed by the site personnel submitting the report.
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reporting to regulatory agencies

Serious adverse events will be forwarded to FDA by the IND Sponsor according to 21 CFR 312.32. It is the responsibility of the Investigator and the research team to ensure that serious adverse events are reported according to the Code of Federal Regulations, Good Clinical Practices (GCP), the protocol guidelines, the sponsor's guidelines, and Institutional Review Board policy.
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severity criteria (grade 1-5)

Definitions found in the Common Terminology Criteria for Adverse Events version 4.03 (CTCAE v4.03) will be used for grading the severity (intensity) of nonhematologic AEs. Refer to http://evs.nci.nih.gov/ftp1/CTCAE/About.html for the grading of hematologic AEs. The CTCAE v4.0 displays Grades 1 through 5 with unique clinical descriptions of severity for each referenced AE. Should a patient experience any AE not listed in the CTCAE v4.03, the following grading system should be used to assess severity:  
  
- Grade 1 (Mild AE) - experiences which are usually transient, requiring no special treatment, and not interfering with the patient's daily activities
- Grade 2 (Moderate AE) - experiences which introduce some level of inconvenience or concern to the patient, and which may interfere with daily activities, but are usually ameliorated by simple therapeutic measures
- Grade 3 (Severe AE) - experiences which are unacceptable or intolerable, significantly interrupt the patient's usual daily activity, and require systemic drug therapy or other treatment
- Grade 4 (Life-threatening or disabling AE) - experiences which cause the patient to be in imminent danger of death
- Grade 5 (Death related to AE) - experiences which result in patient death
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causality (attribution)

The Investigator is to assess the causal relation (ie, whether there is a reasonable possibility that the study drug caused the event) using the following definitions: Not Related: Another cause of the AE is more plausible; a temporal sequence cannot be established with the onset of the AE and administration of the investigational product; or, a causal relationship is considered biologically implausible. Unlikely: The current knowledge or information about the AE indicates that a relationship to the investigational product is unlikely. Possibly Related: There is a clinically plausible time sequence between onset of the AE and administration of the investigational product, but the AE could also be attributed to concurrent or underlying disease, or the use of other drugs or procedures. Possibly related should be used when the investigational product is one of several biologically plausible AE causes. Related: The AE is clearly related to use of the investigational product.
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unexpected adverse events

An "unexpected" AE is an AE that is not listed in the Investigator's Brochure/package insert or is not listed at the specificity or severity that has been observed. For example, hepatic necrosis would be "unexpected" (by virtue of greater severity) if the Investigator's Brochure referred only to elevated hepatic enzymes or hepatitis. Similarly, cerebral thromboembolism and cerebral vasculitis would be "unexpected" (by virtue of greater specificity) if the Investigator's Brochure/package insert listed only cerebral vascular accidents. "Unexpected" also refers to AEs that are mentioned in the Investigator's 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 study drug under investigation.
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documenting and reporting of adverse

Investigators will assess the occurrence of adverse events and serious adverse events at all subject evaluation time points during the study. All adverse events and serious adverse events whether volunteered by the subject, discovered by study personnel during questioning, detected through physical examination, clinically significant laboratory test, or other means, will be recorded. Each recorded adverse event or serious adverse event will be described by its duration (ie, start and end dates), severity, regulatory seriousness criteria (if applicable), suspected relationship to the investigational product, and any actions taken.
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adverse event reporting period

All AEs whether serious or non-serious, will be captured from the time signed and dated ICF is obtained until 30 days following the last dose of study drug. Serious adverse events reported after 30 days following the last dose of study drug should also be reported if considered related to study drug. Resolution information after 30 days should be provided. Progressive disease should NOT be reported as an event term, but instead symptoms/clinical signs of disease progression may be reported. (See Section 11.1.1) All adverse events, regardless of seriousness, severity, or presumed relationship to study drug, must be recorded using medical terminology in the source document. All records will need to capture the details of the duration and the severity of each episode, the action taken with respect to the study drug, investigator's evaluation of its relationship to the study drug, and the event outcome. Whenever possible, diagnoses should be given when signs and symptoms are due to a common etiology (eg, cough, runny nose, sneezing, sore throat, and head congestion should be reported as "upper respiratory infection"). All deaths should be reported with the primary cause of death as the AE term, as death is typically the outcome of the event, not the event itself. If a death occurs within 30 days after the last dose of study drug, the death must be reported as a serious adverse event.
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pregnancy

Before study enrollment, subjects must agree to take appropriate measures to avoid pregnancy. However, should a pregnancy occur in a female study subject, consent to provide follow-up information regarding the outcome of the pregnancy and the health of the infant until 30 days old will be requested. A female subject must immediately inform the Investigator if she becomes pregnant from the time of consent to 30 days after the last dose of study drug. A male subject must immediately inform the Investigator if his partner becomes pregnant from the time of consent to 3 months after the last dose of study drug. Any female subjects receiving study drug(s) who become pregnant must immediately discontinue study drug. The Investigator should counsel the subject, discussing any risks of continuing the pregnancy and any possible effects on the fetus. Although pregnancy itself is not regarded as an adverse event, the outcome will need to be documented. Any pregnancy occurring in a subject or subject's partner from the time of consent to 30 days after the last dose of study drug must be reported. Any occurrence of pregnancy must be reported to Pharmacyclics Drug Safety, or designee, per SAE reporting timelines. All pregnancies will be followed for outcome, which is defined as elective termination of the pregnancy, miscarriage, or delivery of the fetus. For pregnancies with an outcome of live birth, the newborn infant will be followed until 30 days old and this must be reported to Pharmacyclics Drug Safety, or designee, per SAE reporting timelines. Any congenital anomaly/birth defect noted in the infant must be reported as a serious adverse event.
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non-melanoma skin cancer and other

Non-melanoma skin cancer (basal cell carcinoma and squamous cell carcinoma of the skin) have been reported with more frequency and may be related to the use of ibrutinib. Other cancers have been been reported such as solid tumors and hematologic malignancies, and will be reported for the duration of study treatment and during any protocol-specified follow-up periods including post-progression follow-up for overall survival.
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adverse events of special interest

Specific adverse events, or groups of adverse events, will be followed as part of standard safety monitoring activities. These events (regardless of seriousness) will be reported to the local IRB per the SAE reporting timelines.
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major hemorrhage

Major hemorrhage is defined as any of the following: - Any treatment-emergent hemorrhagic adverse events of Grade 3 or higher*. Any treatment-emergent serious adverse events of bleeding of any grade - Any treatment-emergent central nervous system hemorrhage/hematoma of any grade *All hemorrhagic events requiring transfusion of red blood cells should be reported as grade 3 or higher AE per CTCAE v4.02. Events meeting the definition of major hemorrhage will be captured as an event of special interest according to above.
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expediting reporting requirements for serious

All serious adverse events and AESIs (initial and follow-up information) will be reported on FDA Medwatch (Form 3500A) or Suspect Adverse Event Report (CIOMS Form 1) IRB Reporting Form and sent sent via email (AEintakePM@pcyc.com) or fax ((408) 215-3500), to Pharmacyclics Drug Safety, or designee, within 24 hrs of the event. Pharmacyclics may request follow-up and other additional information from the Sponsor Investigator. All serious adverse events that have not resolved by the end of the study, or that have not resolved upon discontinuation of the subject's participation in the study, must be followed until any of the following occurs: - The event resolves - The event stabilizes
- The event returns to baseline, if a baseline value/status is available
- The event can be attributed to agents other than the study drug or to factors unrelated to study conduct
- It becomes unlikely that any additional information can be obtained (subject or health care practitioner refusal to provide additional information, lost to follow up after demonstration of due diligence with follow-up efforts)
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11.3 usage of concurrent/concomitant medications

Ibrutinib is metabolized primarily by CYP3A. Avoid co-administration with strong or moderate CYP3A inhibitors and consider alternative agents with less CYP3A inhibition.  
If a strong CYP3A inhibitor (eg, ketoconazole, indinavir, nelfinavir, ritonavir, saquinavir, clarithromycin, telithromycin, itraconazole, nefazadone, or cobicistat) must be used, reduce ibrutinib dose to 140 mg or withhold treatment for the duration of inhibitor use. Subjects should be monitored for signs of ibrutinib toxicity.  
If a moderate CYP3A inhibitor (eg, voriconazole, erythromycin, amprenavir, aprepitant, atazanavir, ciprofloxacin, crizotinib, darunavir/ritonavir, diltiazem, fluconazole, fosamprenavir, imatinib, verapamil, amiodarone, or dronedarone) must be used, reduce ibrutinib to 140 mg (for 840 mg/day dose, reduce to 280 mg) for the duration of the inhibitor use. Avoid grapefruit and Seville oranges during ibrutinib/placebo treatment, as these contain moderate inhibitors of CYP3A (see Section 5.3.1.2).  
No dose adjustment is required in combination with mild inhibitors.  
Avoid concomitant use of strong CYP3A inducers (eg, carbamazepine, rifampin, phenytoin, and St. John's Wort). Consider alternative agents with less CYP3A induction."A comprehensive list of inhibitors, inducers, and substrates may be found at http://medicine.iupui.edu/clinpharm/ddis/main-table/ This website is continually revised and should be checked frequently for updates.
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11.4 dietary restrictions

Ibrutinib should be taken with water. Seville oranges or grapefruit juice should be avoided
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12 reporting and documentation of

Response and progression in this study will be evaluated using the new international criteria proposed by the Response Evaluation Criteria in Solid Tumors (RECIST) Committee [JNCI 92(3):205-216, 2000]. Changes in only the largest diameter (unidimensional measurement) of the tumor lesions are used in the RECIST v1.1 criteria (or International Workshop on Chronic Lymphocytic Leukemia [IWCLL]).
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12.1.1.1 definitions evaluable for toxicity

All patients will be evaluable for toxicity from the time of their first treatment with the study drug.
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evaluable for objective response

Only those patients 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 patients will have their response classified according to the definitions stated below. (Note: Patients who exhibit objective disease progression prior to the end of Cycle 1 will also be considered evaluable.)
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12.1.1.2 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.
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target lesions

All measurable lesions up to a maximum of 5 lesions total (and a maximum of two lesions per organ) representative of all involved organs should be identified as target lesions and recorded and measured at baseline. Target lesions will be selected on the basis of their size (lesions with the longest diameter) and their suitability for accurate repeated measurements (either by imaging techniques or clinically). A sum of the longest diameter (LD) for all target lesions will be calculated and reported as the baseline sum LD. The baseline sum LD will be used as reference by which to characterize the objective tumor response.
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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 measureable if ≥ 1 cm on MRI. Measurements of these lesions are not required, but the presence or absence of each will be noted throughout follow-up.
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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 techniquesare all nonmeasurable. (e.g. PSA, CA-125, CA19-9, CEA)
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12.2 evaluation of safety

Analyses will be performed for all patients having received at least one dose of study drug. The study will use the CTCAE v4.03 for reporting of non-hematologic adverse events and modified criteria for hematologic adverse events, see Section 6.3.
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12.3 follow-up of adverse events

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

All adverse events, whether or not unexpected, and whether or not considered to be associated with the use of the study drug, will be entered into OnCore®, as noted above.  
The Investigator will assess all adverse events and determine reportability requirements to the UCSF Data and Safety Monitoring Committee (DSMC) and UCSF's Institutional Review Board, the Committee on Human Research (CHR); and, when the study is conducted under an Investigational New Drug Application (IND), to the Food and Drug Administration (FDA) if it meets the FDA reporting criteria..  
All adverse events entered into OnCore® will be reviewed by the Helen Diller Family Comprehensive Cancer Center Site Committee on a weekly basis. The Site Committee will review and discuss at each weekly meeting the selected toxicity, the toxicity grade, and the attribution of relationship of the adverse event to the administration of the study drug(s). In addition, all adverse events and suspected adverse reactions considered "serious," entered into OnCore® will be reviewed and monitored by the Data and Safety Monitoring Committee on an ongoing basis, discussed at DSMC meetings which take place every six (6) weeks, and prior to dose escalation. At the time of dose escalation, a written report will be submitted to the DSMC Chair (or qualified alternate) describing the cohorts, dose levels, adverse events, safety reports, and any Dose Limiting Toxicities observed, in accordance with the protocol. The report will be reviewed by the DSMC Chair (or qualified alternate). Approval for the dose escalation by the DSMC Chair (or qualified alternate) must be obtained prior to implementation. For a detailed description of the Data and Safety Monitoring Plan for a Multicenter Phase 1 Dose Escalation Institutional Study at the Helen Diller Comprehensive Cancer Center please refer Appendix 2 Data and Safety Monitoring Plan for Phase 1 Dose Escalation.
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12.5 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.
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reporting to ucsf committee on

The Principal Investigator must report events meeting the UCSF CHR definition of "Unanticipated Problem" (UP) within 10 business days of his/her awareness of the event.
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expedited reporting to the food

If the study is being conducted under an IND, the Sponsor-Investigator is responsible for determining whether or not the suspected adverse reaction meets the criteria for expedited reporting in accordance with Federal Regulations (21 CFR §312.32). The Investigator must report in an IND safety report any suspected adverse reaction that is both serious and unexpected. The Sponsor-Investigator needs to ensure that the event meets all three definitions:
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suspected adverse reaction (as defined

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
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13 study management 13.1 pre-study

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

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

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

Once the protocol has been approved by the UCSF CHR, any changes to the protocol must be documented in the form of an amendment. The amendment must be signed by the Investigator and approved by PRC and the CHR prior to implementation. Per the IST Agreement, any amendments to the Protocol or Informed Consent Form protocol must be sent to Pharmacyclics for review and approval prior to submission to the IRB. Written verification of IRB approval will be obtained before any amendment is implemented. If it becomes necessary to alter the protocol to eliminate an immediate hazard to patients, an amendment may be implemented prior to CHR approval. In this circumstance, however, the Investigator must then notify the CHR in writing within five (5) working days after implementation. The Study Chair and the UCSF study team will be responsible for updating any participating sites.
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13.5 handling and documentation of

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

The Principal Investigator and/or his/her designee will prepare and maintain adequate and accurate participant case histories with observations and data pertinent to the study. Study specific Case Report Forms (CRFs) will document safety and treatment outcomes for safety monitoring and data analysis. All study data will be entered into OnCore® via standardized CRFs in accordance with the CTMS study calendar, using single data entry with a secure access account. The Clinical Research Coordinator (CRC) will complete the CRFs as soon as possible upon completion of the study visit; the Investigator will review and approve the completed CRFs. The information collected on CRFs shall be identical to that appearing in original source documents. Source documents will be found in the patient's medical records maintained by UCSF personnel. All source documentation should be kept in separate research folders for each patient. In accordance with federal regulations, the Investigator is responsible for the accuracy and authenticity of all clinical and laboratory data entered onto CRFs. The PI will approve all completed CRFs to attest that the information contained on the CRFs is true and accurate. All source documentation and CTMS data will be available for review/monitoring by the UCSF DSMC and regulatory agencies. The Principal Investigator will be responsible for ensuring the accurate capture of study data. At study completion, when the CRFs have been declared to be complete and accurate, the database will be locked. Any changes to the data entered into the CRFs after that time can only be made by joint written agreement among the Study Chair, the Trial Statistician, and the Protocol Project Manager.
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13.7 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 5 Data and Safety Monitoring Plan for Phase 1 Dose Escalation Institutional Study, for additional information.
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13.8 multicenter communication

The UCSF Coordinating Center provides administration, data management, and organizational support for the participating sites in the conduct of a multicenter clinical trial. The UCSF
Coordinating Center for Phase II studies will also coordinate, at minimum, monthly conference calls with the participating sites at the completion of each cohort or more frequently as needed to discuss risk assessment. The following issues will be discussed as appropriate:
Enrollment information Adverse events (i.e. new adverse events and updates on unresolved adverse events and new safety information)
Protocol violations Other issues affecting the conduct of the study.
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13.9 record keeping and record

The Principal Investigator is required to maintain adequate records of the disposition of the drug, including dates, quantity, and use by subjects, as well as written records of the disposition of the drug when the study ends. The Principal Investigator is required to prepare and maintain adequate and accurate case histories that record all observations and other data pertinent to the investigation on each individual administered the investigational drug or employed as a control in the investigation. Case histories include the case report forms and supporting data 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, CHR correspondence and approval, signed patient consent forms). Source documents include all recordings of observations or notations of clinical activities and all reports and records necessary for the evaluation and reconstruction of the clinical research study. In accordance with FDA regulations, the investigator shall retain records for a period of 2 years following the date a marketing application is approved for the drug for the indication for which it is being investigated; or, if no application is to be filed or if the application is not approved for such indication, until 2 years after the investigation is discontinued and FDA is notified.
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13.10 coordinating center documentation of

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

Prior to implementing this protocol at UCSF HDFCCC, the protocol, informed consent form, HIPAA authorization and any other information pertaining to participants must be approved by the UCSF Committee on Human Research (CHR). Prior to implementing this protocol at the participating sites, approval for the UCSF CHR approved protocol must be obtained from the participating site's IRB. The following documents must be provided to UCSF HDFCCC before the participating site can be initiated and begin enrolling participants:
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participating site irb approval(s) for

Participating Site IRB's Federal Wide Assurance number and OHRP Registration number Curriculum vitae and medical license for each investigator and consenting professional Documentation of Human Subject Research Certification training for investigators and key staff members at the Participating Site
**Participating site laboratory certifications and normals**
Upon receipt of the required documents, UCSF HDFCCC will formally contact the site and grant permission to proceed with enrollment.
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14 protection of human subjects

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

Patients will be informed of the extent to which their confidential health information generated from this study may be used for research purposes. Following this discussion, they will be asked to sign the HIPAA form and informed consent documents. The original signed document will become part of the patient's medical records, and each patient will receive a copy of the signed document. The use and disclosure of protected health information will be limited to the individuals described in the informed consent document.  
| Table 11. Schedule of Events and Procedures: Phase Ib Dose escalation  Treatment Cycles 3  and beyondc  End of Study  Treatmentd   | Follow-up   |                    |    |     |     |    |    |     |     |       |       |
|------------------------------------------------------------------------------------------------------------------------------------|-------------|--------------------|----|-----|-----|----|----|-----|-----|-------|-------|
| (Cycle is 28 days)                                                                                                                 |             |                    |    |     |     |    |    |     |     |       |       |
| Treatment Cycles 1-2c                                                                                                              |             |                    |    |     |     |    |    |     |     |       |       |
| Period/Procedure                                                                                                                   | Screeninga  | (Cycle is 28 days) |    |     |     |    |    |     |     |       |       |
| Study Day/Visit Day                                                                                                                | -14 to 0    | D1                 | D8 | D15 | D22 | D1 | D8 | D15 | D22 | Prior | After |
| to PDk                                                                                                                             | PDl         |                    |    |     |     |    |    |     |     |       |       |
| Tests and Observations Informed consent                                                                                            | X           |                    |    |     |     |    |    |     |     |       |       |
| Medical history and Demographic                                                                                                    | X           |                    |    |     |     |    |    |     |     |       |       |
| Physical exam, weight                                                                                                              | X           | Xf                 | X  | X   | X   | X  |    |     |     |       |       |
| Vital signse                                                                                                                       | X           | Xe                 | Xe | Xe  | Xe  | Xe | Xe | X   | X   |       |       |
| Heighte                                                                                                                            | X           |                    |    |     |     |    |    |     |     |       |       |
| ECOG PS                                                                                                                            | X           | Xf                 | X  | X   | X   | X  |    |     |     |       |       |
| Concomitant medications                                                                                                            | X           | X                  | X  | X   | X   | X  |    |     |     |       |       |
| AE assessment                                                                                                                      | X           | X                  | X  | X   | X   | X  | X  | X   | X   | X     |       |
| Archival Tissue Collection (if  available) i                                                                                       | X           |                    |    |     |     |    |    |     |     |       |       |
| 12-lead ECG                                                                                                                        | Xm          | Xn                 |    |     |     |    |    |     |     |       |       |
| Subsequent Cancer Treatment                                                                                                        | X           | X                  |    |     |     |    |    |     |     |       |       |
| Survival Status                                                                                                                    | X           |                    |    |     |     |    |    |     |     |       |       |
| Treatment/Drug Administration Ibrutinibb                                                                                           | X           | X                  | X  | X   | X   | X  | X  | X   |     |       |       |
| Gemcitabine                                                                                                                        | X           | X                  | X  | X   | X   | X  |    |     |     |       |       |
| Nab-Paclitaxel                                                                                                                     | X           | X                  | X  | X   | X   | X  |    |     |     |       |       |
| Laboratory procedures CBC w/ 3 part Diff                                                                                           | X           | Xf                 | X  | X   | X   | X  | X  | X   |     |       |       |
| CMPg                                                                                                                               | X           | Xf                 | X  | X   | X   | X  | X  | X   |     |       |       |
| Urine or serum Pregnancy test                                                                                                      | X           |                    |    |     |     |    |    |     |     |       |       |  
| Treatment Cycles 3  and beyondc                                 | End of Study  Treatmentd   | Follow-up          |      |      |     |    |    |     |     |       |       |
|-----------------------------------------------------------------|----------------------------|--------------------|------|------|-----|----|----|-----|-----|-------|-------|
| (Cycle is 28 days)                                              |                            |                    |      |      |     |    |    |     |     |       |       |
| Treatment Cycles 1-2c                                           |                            |                    |      |      |     |    |    |     |     |       |       |
| Period/Procedure                                                | Screeninga                 | (Cycle is 28 days) |      |      |     |    |    |     |     |       |       |
| Study Day/Visit Day                                             | -14 to 0                   | D1                 | D8   | D15  | D22 | D1 | D8 | D15 | D22 | Prior | After |
| to PDk                                                          | PDl                        |                    |      |      |     |    |    |     |     |       |       |
| o                                                               |                            |                    |      |      |     |    |    |     |     |       |       |
| Hepatitis (HBV, HCV)                                            | X                          |                    |      |      |     |    |    |     |     |       |       |
| Coagulation (INR Pt/PTT)                                        | X                          | Xf                 | X    |      |     |    |    |     |     |       |       |
| CA19-9                                                          | X                          | Xf,f2              | X f2 | X f2 |     |    |    |     |     |       |       |
| Blood collection for correlative  studies, BTK occupancy assays | Xh                         | X                  |      |      |     |    |    |     |     |       |       |
| Imaging procedures Imaging (CT or MRI) every 8 wksj             | X                          | X                  | X    | X    |     |    |    |     |     |       |       |  
a. Pre-treatment assessments will be completed within 14 days of start of therapy. The Informed Consent and scans can be completed within 28 days of start of therapy. The pregnancy test (for women of child-bearing potential) should be completed within 72 hours prior start of therapy.  
b. Daily dosing with ibrutinib should begin day 1 of cycle 1, and should continue through-out the 28 day cycles until patient is off study treatment.  
c. Treatment with gemcitabine and nab-paclitaxel is to be administered on days 1, 8, 15 of each 28 day cycle. Ibrutinib will be taken orally, each day of the 28 day treatment cycle. While every effort should be made to adhere to this schedule, +/- 2 days from any scheduled treatment is acceptable due to holidays, travel issues, or other logistics.  
d. End of study visit should be completed within 30 days of the last dose. In the event that the patient is too ill or frail to return to clinic for this EOT visit, this will not constitute a protocol violation.  
e. Vital signs including BP, pulse and temperature should be documented with each PE. Vital signs should also be documented with any signs or symptoms during or immediately after an infusion. Perform complete physical examination at screening. A limited PE will be repeated on Day 15 of Cycle 1 only. A limited PE related to signs, symptoms and concurrent illnesses is appropriate during Study Treatment. Height only required during Pre-treatment.  
f. These procedures to not need to be repeated if they were performed within the preceding 14 days (eg during the pretreatment period).  
f.2. Only for patients with elevated levels ≥ 2 x ULN at baseline. g. CMP will include measurements of glucose, BUN, creatinine, sodium, potassium, chloride, calcium, CO2, ALP, AST (SGOT),
ALT (SGPT), total bilirubin, total protein, and albumin.  
h. EDTA blood collection for baseline cytokine, B an T cell receptor profiling, and myeloid cell characterization and BTK
occupancy assays should be drawn before beginning combination therapy on day 1 cycle 1, and day 1 of the subsequent cycles before infusion of gemcitabine and nab-paclitaxel . The correlative blood samples will be processed at UCSF before shipping to other sites for analyses.  
i. Archived tumor tissue will be collected for this study. Tissue may be collected at Pre-treatment or at any time during the study.  
j. Tumor assessment occurs at the end of every 2 cycles, during the last week of the cycle. The evaluations should be completed at the end of every 2 cycles regardless of any treatment delays. This typically will consist of CT scans of the chest/abdomen/pelvis. MRI represents an acceptable alternative for patients with increased risk of contrast related nephropathy or other contraindications. Baseline and subsequent imaging must be by the same type of procedure (e.g. CT vs. MRI scan).  
k. Patients who discontinue study treatment prior to the occurrence of disease progression will be followed every 8 weeks from the date of last dose of trial drug until disease progression or for up to 2 years whichever comes first. Any subsequent cancer therapy will be documented.
l. Patients with documented disease progression will be followed every 2 months for survival status (e.g., date and cause of death) for up to 2 years or death whichever comes first. Information on the start date, type and duration of any subsequent anticancer therapy will be collected. Patients may be contacted during outpatient visits, by documented telephone contact with the patient or through contact with the primary practitioner or caregiver m. 12-lead ECGs will be done in triplicate (≥1 minute apart); the calculated QTcF average of the 3 ECGs must be <470 msec for eligibility. Abnormalities noted at Screening should be included in the medical history.  
n. ECGs should be performed at the investigator's discretion, particularly in subjects with arrhythmic symptoms (eg, palpitations, lightheadedness) or new onset of dyspnea.  
o. Screening tests for Hepatitis Virus to include HBsAg, Hepatitis B core antibody (HBcAb), total, and HCV Antibody. If either of the HBV tests are positive, order HBV DNA quantification by PCR. If HBV DNA positive, determine if anti-viral therapy if DNA is necessary.  
| Table 12. Schedule of Events and Procedures: Immune Response Study Ibrutinib Run-in  Periodb Treatment Cycles 1- 2 c  Treatment Cycles 3  and beyondc  (Cycle is 28 days)   | End of  Study   | Follow-up          |       |    |     |     |    |    |     |     |         |            |
|-----------------------------------------------------------------------------------------------------------------------------------------------------------------------------|-----------------|--------------------|-------|----|-----|-----|----|----|-----|-----|---------|------------|
| Treatmentd                                                                                                                                                                  |                 |                    |       |    |     |     |    |    |     |     |         |            |
| Period/Procedure                                                                                                                                                            | Screeninga      | (Cycle is 28 days) | Prior |    |     |     |    |    |     |     |         |            |
| Study Day/Visit Day                                                                                                                                                         | -14 to 0        | Wk1D1              | D1b   | D8 | D15 | D22 | D1 | D8 | D15 | D22 | to  PDk | After  PDl |
| Tests and Observations Informed consent                                                                                                                                     | X               |                    |       |    |     |     |    |    |     |     |         |            |
| Medical history and Demographic                                                                                                                                             | X               |                    |       |    |     |     |    |    |     |     |         |            |
| Physical exam, weight                                                                                                                                                       | X               | Xf                 | X     | X  | X   | X   | X  |    |     |     |         |            |
| Vital signse                                                                                                                                                                | X               | X                  | Xe    | Xe | Xe  | Xe  | Xe | Xe | X   | X   |         |            |
| Heighte                                                                                                                                                                     | X               |                    |       |    |     |     |    |    |     |     |         |            |
| ECOG PS                                                                                                                                                                     | X               | Xf                 | X     | X  | X   | X   | X  |    |     |     |         |            |
| Concomitant medications                                                                                                                                                     | X               | Xf                 | X     | X  | X   | X   | X  |    |     |     |         |            |
| AE assessment                                                                                                                                                               | X               | X                  | X     | X  | X   | X   | X  | X  | X   | X   | X       |            |
| Archival Tissue Collection (if  available) i                                                                                                                                | X               |                    |       |    |     |     |    |    |     |     |         |            |
| 12-lead ECG                                                                                                                                                                 | Xm              | Xf                 | Xn    |    |     |     |    |    |     |     |         |            |
| Subsequent Cancer Treatment                                                                                                                                                 | X               | X                  |       |    |     |     |    |    |     |     |         |            |
| Survival Status                                                                                                                                                             | X               |                    |       |    |     |     |    |    |     |     |         |            |
| EUS-guided biopsy                                                                                                                                                           | Xb              |                    |       |    |     |     |    |    |     |     |         |            |
| Treatment/Drug Administration Ibrutinibb                                                                                                                                    | X               | X                  | X     | X  | X   | X   | X  | X  | X   |     |         |            |
| Gemcitabine                                                                                                                                                                 | X               | X                  | X     | X  | X   | X   |    |    |     |     |         |            |  
Table 12. Schedule of Events and Procedures: Immune Response Study  
| Ibrutinib Run-in  Periodb                                                        | Treatment Cycles 1- 2 c                                                                                               | Treatment Cycles 3  and beyondc  (Cycle is 28 days)   | End of  Study   | Follow-up   |     |     |    |    |     |     |         |            |
|----------------------------------------------------------------------------------|-----------------------------------------------------------------------------------------------------------------------|-------------------------------------------------------|-----------------|-------------|-----|-----|----|----|-----|-----|---------|------------|
| Treatmentd                                                                       |                                                                                                                       |                                                       |                 |             |     |     |    |    |     |     |         |            |
| Period/Procedure                                                                 | Screeninga                                                                                                            | (Cycle is 28 days)                                    | Prior           |             |     |     |    |    |     |     |         |            |
| Study Day/Visit Day                                                              | -14 to 0                                                                                                              | Wk1D1                                                 | D1b             | D8          | D15 | D22 | D1 | D8 | D15 | D22 | to  PDk | After  PDl |
| Nab-Paclitaxel                                                                   | X                                                                                                                     | X                                                     | X               | X           | X   | X   |    |    |     |     |         |            |
| Laboratory procedures CBC w/ 3 part Diff                                         | X                                                                                                                     | Xf                                                    | X               | X           | X   | X   | X  | X  | X   |     |         |            |
| CMPg                                                                             | X                                                                                                                     | Xf                                                    | X               | X           | X   | X   | X  | X  | X   |     |         |            |
| Urine or serum Pregnancy test                                                    | X                                                                                                                     |                                                       |                 |             |     |     |    |    |     |     |         |            |
| Hepatitis (HBV, HCV)                                                             | X                                                                                                                     |                                                       |                 |             |     |     |    |    |     |     |         |            |
| Coagulation (INR, Pt, PTT)                                                       | X                                                                                                                     | Xf                                                    | X               | X           |     |     |    |    |     |     |         |            |
| CA19-9                                                                           | X                                                                                                                     | Xf,f2                                                 | X f2            | X f2        |     |     |    |    |     |     |         |            |
| Blood collection for correlative                                                 | Xh                                                                                                                    | Xh                                                    | Xh              |             |     |     |    |    |     |     |         |            |
| studies,BTK occupancy assays Imaging procedures Imaging (CT or MRI) every 8 wksj | X                                                                                                                     | X                                                     | X               | X           |     |     |    |    |     |     |         |            |
| a.                                                                               | Pre-treatment assessments will be completed within 14 days of start of therapy. The Informed Consent and scans can be |                                                       |                 |             |     |     |    |    |     |     |         |            |  
a. Pre-treatment assessments will be completed within 14 days of start of therapy. The Informed Consent and scans can be completed within 28 days of start of therapy. The pregnancy test (for women of child-bearing potential) should be completed within 72 hours prior start of therapy.  
b. Day 1 of the 7 day ibrutinib-only run-in period should begin at least 5 days after the pretreatment EUS guided biopsy. Dosing with ibrutinib should be stopped for at least 5 day before performing the post-ibrutinib EUS-guided biopsy. Day 1 Cycle 1 of the combination treatment with gemcitabine and nab-paclitaxel may occur at 1-3 days after the post-ibrutinib run-in biopsy, and daily oral dosing with ibrutinib may commence 5-7 days post-biopsy.  
c. Treatment with gemcitabine and nab-paclitaxel is to be administered on days 1, 8, 15 of each 28 day cycle. Ibrutinib will be taken orally, each day of the 28 day treatment cycle. While every effort should be made to adhere to this schedule, +/- 2 days from any scheduled treatment is acceptable due to holidays, travel issues, or other logistics.  
d. End of study visit should be completed within 30 days of the last dose. In the event that the patient is too ill or frail to return to clinic for this EOT visit, this will not constitute a protocol violation.  
e. Vital signs including BP, pulse and temperature should be documented with each PE. Vital signs should also be documented with any signs or symptoms during or immediately after an infusion. Perform complete physical examination at screening. A limited PE will be repeated on Day 15 of Cycle 1 only. A limited PE related to signs, symptoms and concurrent illnesses is appropriate during Study Treatment. Height only required during Pre-treatment.  
f. These procedures to not need to be repeated if they were performed within the preceding 14 days (eg during the pretreatment period).
f.2. Only for patients with elevated levels ≥ 2 x ULN at baseline. g. CMP will include measurements of glucose, BUN, creatinine, sodium, potassium, chloride, calcium, CO2, ALP, AST (SGOT),
ALT (SGPT), total bilirubin, total protein, and albumin.  
h. EDTA Blood collection for baseline cytokine, B and T cell receptor profiling, and myeloid cell characterization and BTK
occupancy assays should be drawn before and after the 7 day ibrutinib run-in, before the EUS-guided biopsies are performed. Blood collection for the correlative analyses will also occur on day 1 of cycle 2 and subsequent cycles of combination therapy before infusion of gemcitabine and nab-paclitaxel begins. The correlative blood samples will be processed at UCSF before shipping to other sites for analyses.  
i. Archived tumor tissue will be collected for this study. Tissue may be collected at Pre-treatment or at any time during the study.
j. Tumor assessment occurs at the end of every 2 cycles, during the last week of the cycle. The evaluations should be completed at the end of every 2 cycles regardless of any treatment delays. This typically will consist of CT scans of the chest/abdomen/pelvis. MRI represents an acceptable alternative for patients with increased risk of contrast related nephropathy or other contraindications. Baseline and subsequent imaging must be by the same type of procedure (e.g. CT vs. MRI scan).  
k. Patients who discontinue study treatment prior to the occurrence of disease progression will be followed every 8 weeks from the date of last dose of trial drug until disease progression or for up to 2 years whichever comes first. Any subsequent cancer therapy will be documented.  
l. Patients with documented disease progression will be followed every 2 months for survival status (e.g., date and cause of death) for up to 2 years or death whichever comes first. Information on the start date, type and duration of any subsequent anticancer therapy will be collected. Patients may be contacted during outpatient visits, by documented telephone contact with the patient or through contact with the primary practitioner or caregiver.  
m. 12-lead ECGs will be done in triplicate (≥1 minute apart); the calculated QTcF average of the 3 ECGs must be <470 msec for eligibility. Abnormalities noted at Screening should be included in the medical history.  
n. ECGs should be performed at the investigator's discretion, particularly in subjects with arrhythmic symptoms (eg, palpitations, lightheadedness) or new onset of dyspnea.  
o. Screening tests for Hepatitis Virus to include HBsAg, Hepatitis B core antibody (HBcAb), total, and HCV Antibody. If either of the HBV tests are positive, order HBV DNA quantification by PCR. If HBV DNA positive, determine if anti-viral therapy is necessary.
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references

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appendices appendix 1 performance status

| ECOG Performance Status Scale                                                                                                         | Karnofsky Performance Scale         |                                                                          |                                                                          |
|---------------------------------------------------------------------------------------------------------------------------------------|-------------------------------------|--------------------------------------------------------------------------|--------------------------------------------------------------------------|
| Grade                                                                                                                                 | Descriptions                        | Percent                                                                  | Description                                                              |
| 100                                                                                                                                   | Normal, no complaints, no evidence  |                                                                          |                                                                          |
| 0                                                                                                                                     | Normal activity                     | 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  is able to care for most of his/her |
| Ambulatory and capable of all                                                                                                         | 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 self-care,  confined to bed or chair more  than 50% of waking hours                                           | 30                                  | Severely disabled, hospitalization indicated Death not imminent          |                                                                          |
| 4                                                                                                                                     | 100% bedridden                      | 20                                                                       | Very sick, hospitalization indicated                                     |
| Completely disabled                                                                                                                   | Death not imminent                  |                                                                          |                                                                          |
| Cannot carry on any self-care                                                                                                         | 10                                  | Moribund, fatal processes                                                |                                                                          |
| Totally confined to bed or chair                                                                                                      | progressing rapidly                 |                                                                          |                                                                          |
| 5                                                                                                                                     | Dead                                | 0                                                                        | Dead                                                                     |
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appendix 2 new york heart

| The following table presents the NYHA classification of cardiac disease. Class Functional Capacity   | Objective  Assessment                                                                                                                                                                                                                                         |                                                                    |
|------------------------------------------------------------------------------------------------------|---------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|--------------------------------------------------------------------|
| I                                                                                                    | Patients with cardiac disease but without resulting limitations of  physical activity. Ordinary physical activity does not cause  undue fatigue, palpitation, dyspnea, or anginal pain.                                                                       | No objective  evidence of cardiovascular  disease.                 |
| II                                                                                                   | Patients with cardiac disease resulting in slight limitation of  physical activity. They are comfortable at rest. Ordinary  physical activity results in fatigue, palpitation, dyspnea, or  anginal pain.                                                     | Objective evidence  of minimal  cardiovascular  disease.           |
| III                                                                                                  | Patients with cardiac disease resulting in marked limitation of  physical activity. They are comfortable at rest. Less than  ordinary activity causes fatigue, palpitation, dyspnea, or  anginal pain.                                                        | Objective evidence  of moderately severe  cardiovascular  disease. |
| IV                                                                                                   | Patients with cardiac disease resulting in inability to carry on  any physical activity without discomfort. Symptoms of heart  failure or the anginal syndrome may be present even at rest. If  any physical activity is undertaken, discomfort is increased. | Objective evidence  of severe  cardiovascular  disease.            |
| Source: The Criteria Committee of New York Heart Association. Nomenclature and Criteria for          |                                                                                                                                                                                                                                                               |                                                                    |
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appendix 3 guidelines for women

Any female who has experienced menarche and does not meet the criteria for
"Women Not of Childbearing Potential".
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women not of childbearing potential

Women who are permanently sterilized (e.g., tubal occlusion, hysterectomy, bilateral salpingectomy, bilateral oophorectomy)
Women who are >45 years of age, not using hormone replacement therapy and who have experienced total cessation of menses for at least 1 year OR
who have a follicle stimulating hormone (FSH) value >40 mIU/mL and an estradiol value <40pg/mL (140 pmol/L)
Women who are >45 years of age, using hormone replacement therapy and who have experienced total cessation of menses for at least 1 year OR who have had documented evidence of menopause based on FSH >40 mIU/mL and estradiol <40 pg/mL prior to initiation of hormone replacement therapy Acceptable Contraception Methods:
Male patients with female partners of child-bearing potential and women patients of childbearing potential are required to use two forms of acceptable contraception, including one barrier method, during their participation in the trial and for 6 months (women) or 6 months (men) following discontinuation of study treatment. Male patients must also refrain from donating sperm for 6 months following discontinuation of study treatment. The following are acceptable forms of barrier contraception:
Latex condom, diaphragm or cervical/vault cap when used with spermicidal foam/gel/film/cream/suppository The following are acceptable forms of secondary contraception, when used with a barrier method and spermicide:
True abstinence. Periodic abstinence (e.g., calendar, ovulation, symptothermal, post-ovulation methods) and withdrawal are not acceptable methods of contraception
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appendix 4 response evaluation criteria

Lesions are either measurable or non-measurable using the criteria provided below. The term "evaluable" in reference to measurability will not be used, as it does not provide additional meaning or accuracy.
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baseline eligibility

| Measurable Disease:     | Tumor lesions: Must be accurately measured in at least one  dimension (longest diameter in the plane of measurement is  to be recorded) with a minimum size of: 10 mm by CT scan (CT scan slice thickness no greater than 5  mm). 10 mm caliper measurement by clinical exam (lesions that  cannot be accurately measured with calipers should be  recorded as non-measurable). 20 mm by chest X-ray. Skin lesions: Documentation by color photography, including  a ruler to estimate the size of the lesion, is recommended. Malignant lymph nodes: To be considered pathologically  enlarged and measurable, a lymph node must be >15 mm in  short axis when assessed by CT scan. At baseline and in  follow-up, only the short axis will be measured and followed.   |
|-------------------------|--------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|
| Non-Measurable Disease: | All other lesions, including small lesions (longest diameter  <10 mm or pathological lymph nodes with >10- to <15-mm  short axis) as well as truly non-measurable lesions. Lesions  considered truly non-measurable include: leptomeningeal  disease, ascites, pleural or pericardial effusion, inflammatory breast disease, lymphangitic involvement of skin or lung,  abdominal masses, and abdominal organomegaly identified by  physical exam that is not measurable by reproducible imaging  requirements.                                                                                                                                                                                                                                                          |  
| Target Lesions:                                 | Selected 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), should be representative  of all involved organs, and in addition should be those that  lend themselves to reproducible repeated measurements.  Pathological nodes which are defined as measurable and that  may be identified as target lesions must meet the criterion or  a short axis of >15 mm by CT scan. 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 as noted above, only the  short axis is added into the sum. The baseline sum diameters  will be used as reference to further characterize any objective  tumor response.   |
|-------------------------------------------------|-----------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|
| Non-Target Lesions:                             | All other lesions should be identified as non-target lesions at  baseline. Measurements of these lesions are not required,  but the presence or absence of each should be noted  throughout follow-up.                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                  |
| Guidelines for Evaluation of Measurable Disease |                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                         |  
All measurements should be taken and recorded in metric notation, using a ruler or calipers. All baseline evaluations should be performed as closely as possible to the beginning of treatment, as per study screening requirements. The same method of assessment and the same technique should 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 anti-tumor 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).  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:   | CT is the best currently available and reproducible method to  measure target lesions selected for response assessment.  This guideline has defined measurability of lesions on CT  scan based on the assumption that CT slice thickness is 5mm  or less. MRI of the chest should only be performed in  extenuating circumstances. Even if IV contract cannot be  administered (for example, in the situation of allergy to  contract), a non-contrast CT of the chest is still preferred over  MRI.   |
|----------------------------|--------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|
| Ultrasound:                | Ultrasound should not be used to measure tumor lesions.  Ultrasound may be useful to confirm the complete  disappearance of superficial lesions usually assessed by  clinical examination.                                                                                                                                                                                                                                                                                                             |
| Endoscopy and              | Use of endoscopy and laparoscopy should not be used to                                                                                                                                                                                                                                                                                                                                                                                                                                                 |
| Laparoscopy:               | measure tumor lesions. Such techniques can be useful in  confirming complete pathological response when biopsies are  obtained.                                                                                                                                                                                                                                                                                                                                                                        |
| Tumor Markers:             | Tumor markers alone cannot be used to assess response. If  markers are initially above the upper limit of normal, they  must normalize for a subject to be considered in complete  clinical response when all lesions have disappeared.                                                                                                                                                                                                                                                                |
| Cytology and Histology:    | Cytology and histology can be used to differentiate between  PR and CR in rare cases (e.g., after treatment to differentiate  between residual benign lesions and residual malignant  lesions in tumor types such as germ cell tumors).                                                                                                                                                                                                                                                                |
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response criteria

Evaluation of Target Lesions  
| Complete Response:   | Complete disappearance of all target lesions. Any  pathological lymph node (target or non-target) must have a  reduction in short axis to < 10 mm).                                                                                                                                                                                           |
|----------------------|-----------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|
| Partial Response:    | A decrease from baseline of ≥30% of the diameter(s) of all  target lesions.                                                                                                                                                                                                                                                                   |
| Stable Disease:      | Neither sufficient shrinkage to qualify for PR nor sufficient  increase to qualify for PD, taking as reference the smallest  (nadir) sum of the diameters of target lesions while on study.                                                                                                                                                   |
| Progressive Disease: | At least a 20% increase in the sum of the diameters of target  lesions, taking as reference the smallest (nadir) sum while on  study (this includes the baseline sum if that is the smallest on  study), or the appearance of one or more new lesions.  Requires not only 20% increase, but absolute increase of a  minimum of 5 mm over sum. |
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evaluation of non-target lesions

| Complete Response:   | Disappearance of all non-target lesions. All lymph nodes  must be non-pathological in size (<10 mm short axis).                                                                                                                                                                                                                                                                                                                                                              |
|----------------------|------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|
| Stable Disease:      | Persistence of one or more non-target lesions.                                                                                                                                                                                                                                                                                                                                                                                                                               |
| Progressive Disease: | Appearance of one or more new lesions and/or unequivocal  progression of existing non-target lesions. When the subject  also has measurable disease, to achieve "unequivocal  progression" on the basis of the non-target disease, there  must be an overall level of substantial worsening in non-target  disease such that, even in presence of SD or PR in the target  disease, the overall tumor burden has increased sufficiently to  merit discontinuation of therapy. |
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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). In general, the subject's best response assignment will depend on the achievement of both measurement and confirmation criteria.  
| Target Lesions                                                                   | Non-Target Lesions   | New Lesions   | Overall   |
|----------------------------------------------------------------------------------|----------------------|---------------|-----------|
| Response                                                                         |                      |               |           |
| CR                                                                               | CR                   | NO            | CR        |
| CR                                                                               | SD                   | NO            | PR        |
| CR                                                                               | NE                   | NO            | PR        |
| PR                                                                               | SD OR NE             | NO            | PR        |
| SD                                                                               | SD OR NE             | NO            | SD        |
| PD                                                                               | ANY                  | YES OR NO     | PD        |
| ANY                                                                              | PD                   | YES OR NO     | PD        |
| ANY                                                                              | ANY                  | YES           | PD        |
| NE                                                                               | SD                   | NO            | NE        |
| Abbreviations: CR=complete response; NE=not evaluable; PD = progressive disease; |                      |               |           |  
Abbreviations: CR=complete response; NE=not evaluable; PD = progressive disease; PR=partial response; SD=stable disease. In some circumstances, it may be difficult to distinguish residual disease from normal tissue. When the evaluation of a CR depends upon this determination, it is recommended that the residual lesion be investigated by fine needle aspirate or biopsy to confirm the CR status. When nodal disease is included in the sum of target lesions, and the nodes decrease to "normal" size (<10 mm), they may still have a measurement reported on scans. This measurement should be recorded even though the nodes are normal in order not to overstate progression, should it be based on increase in size of the nodes. As noted earlier, this means that patients with CR may not have a total sum of "zero" on the CRF.
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appendix 5 data and safety

The UCSF Helen Diller Family Comprehensive Cancer Center (HDFCCC) Data and Safety Monitoring Committee (DSMC) is responsible for monitoring data quality and subject safety for all HDFCCC institutional clinical studies. A summary of DSMC activities for this study includes: - Review of subject data in each cohort - Review of suspected adverse reactions considered "serious" - Approval of dose escalation by DSMC Chair (or qualified alternate) - Monthly monitoring (depending on study accrual) - Minimum of a yearly regulatory audit
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monitoring and reporting guidelines

All institutional Phase 1 therapeutic studies are designated with a high risk assessment. The data is monitored monthly as subjects are enrolled and includes all visits monitored up through the Dose Limiting Toxicity (DLT) period. At the time of dose escalation, a written report will be submitted to the DSMC Chair outlining the cohort dose, all adverse events and suspected adverse reactions considered "serious", and any Dose Limiting Toxicity as described in the protocol. The report will be reviewed by the DSMC Chair or qualified alternate and written authorization to proceed or a request for more information will be issued within 2 business days of the request. The report is then reviewed at the subsequent DSMC meeting. In the event that the committee does not concur with the DSMC Chair's decision, further study accrual is held while further investigation takes place. The Principal Investigator at the UCSF Coordinating Center will hold the role of Study Chair. The Study Chair is responsible for the overall conduct of the study and for monitoring its safety and progress at all participating sites. The Study Chair will conduct continuous review of data and subject safety and discuss each subject's treatment at weekly UCSF Site Committee meetings. The discussions are documented in the UCSF Site Committee meeting minutes. For each dose level, the discussion will include the number of patients, significant toxicities in accordance with the protocol, doses adjustments, and observed responses.
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multicenter communication

The UCSF Coordinating Center provides administration, data management, and organizational support for the participating sites in the conduct of a multicenter clinical trial. The UCSF Coordinating Center will also coordinate, at minimum, monthly conference calls with the participating sites at the completion of each cohort or more frequently as needed to discuss risk assessment. The following issues will be discussed as appropriate:
Enrollment information  
Cohort updates (i.e. DLTs) Adverse events (i.e. new adverse events and updates on unresolved adverse events and new safety information)
Protocol violations Other issues affecting the conduct of the study
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dose level considerations

The PI/Study Chair, participating investigators, and research coordinators from each site will review enrollment for each dose level cohort during the regularly scheduled conference calls.  
The dose level for ongoing enrollment will be confirmed for each subject scheduled to be enrolled at a site. Dose level assignments for any subject scheduled to begin treatment must be confirmed by the UCSF Coordinating Center via fax or e-mail. If a Dose Limiting Toxicity (DLT) arises in a subject treated at a study site, all sites must be notified immediately by the UCSF Coordinating Center. The Study Chair has 1 business day (after first becoming aware of the event at either the UCSF Coordinating Center or the participating site) in which to report the information to all participating sites. If the DLT occurs at a participating site, the local investigator must report it to the UCSF Coordinating Center within 1 business day, after which the UCSF Coordinating Center will notify the other participating sites. Adverse events reporting to the DSMC will include reports from both the UCSF Coordinating Center, as well as the participating sites. The DSMC will be responsible for monitoring all data entered in OnCore® at the UCSF Coordinating Center and the participating sites. The data (i.e. copies of source documents) from the participating sites will be faxed over to the UCSF Coordinating Center prior to the monitoring visits in order for the DSMC to monitor the participating site's compliance with the protocol, patient safety, and to verify data entry. All clinically significant adverse events (AEs), whether or not unexpected, and whether or not considered to be associated with the use of study drug, will be entered into OnCore®, UCSF's Clinical Trial Management System. All clinically significant adverse events entered into OnCore® will be reviewed on a weekly basis at the UCSF Coordinating Center's Site Committee. All clinically significant adverse events must be reported to the UCSF Coordinating Center by the participating sites within 10 business days of becoming aware of the event. 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" are entered into OnCore® and will be reviewed and monitored by the Data and Safety Monitoring Committee on an ongoing basis and discussed at the DSMC meetings, which take place every six (6) weeks.  
All suspected adverse reactions considered "serious" should be reported to the UCSF
Coordinating Center within 1 business day of becoming aware of the event or during the next scheduled conference call, whichever is sooner. If a death occurs during the treatment phase of the study or within 30 days after the last administration of the study drug(s) and is determined to be related either to the investigational drug or any research related procedure, the Study Chair at the UCSF Coordinating Center or the assigned designee must be notified within 1 business day from the participating site(s) and the Study Chair must then notify the DSMC Chair or qualified alternate within 1 business day of this notification. The contact may be by phone or e-mail.
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increase in adverse event rates

If an increase in the frequency of Grade 3 or 4 adverse events (above the rate reported in the Investigator Brochure or package insert), the Study Chair at the UCSF Coordinating Center is responsible for notifying the DSMC at the time the increased rate is identified. The report will indicate if the incidence of adverse events observed in the study is above the range stated in the Investigator Brochure or package insert. If at any time the Study Chair stops enrollment or stops the study due to safety issues, the DSMC Chair and DSMC Manager must be notified within 1 business day via e-mail. The DSMC must receive a formal letter within 10 business days and the CHR must be notified
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data and safety monitoring committee

UCSF Helen Diller Family Comprehensive Cancer Center San Francisco, CA 94143
* DSMP approved by NCI 09/February2012
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appendix 6 ucsf policy/procedure for

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

The International Conference on Harmonization (ICH) Good Clinical Practices (GCP) Guidelines define Essential Regulatory Documents as those documents which individually and collectively permit evaluation of the conduct of a trial and the quality of data produced. These documents serve to demonstrate compliance with standards of GCP and with all applicable regulatory requirements. Filing essential documents in a timely manner can greatly assist in the successful management of a clinical trial.  
The Regulatory Documents will consist of electronic files in both iMedRIS and OnCore®, as well as paper files in the Regulatory Binders for both the Coordinating Site and the Participating Site(s) in the HDFCCC Investigator Initiated Oncology Clinical Trials.
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procedures 1. hdfccc essential regulatory

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

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

Completed Food and Drug Administration (FDA) 1572 document with Principal Investigator's signature For all Principal Investigators and Sub-Investigators listed on the FDA 1572, will need Financial Disclosure Forms, CVs, MD Licenses, Drug Enforcement Agency (DEA) Licenses, and Staff Training Documents (i.e. Collaborative Institute Training Initiative (CITI), etc.)
Site Initiation Visit (SIV) minutes and correspondence with participating site(s).  
As applicable, approvals for Biosafety Committee, Radiation Committee, and Infusion Center Serious Adverse Event (SAE) reports to CHR and sponsor. MedWatch reporting to FDA and sponsor Delegation of Authority Form Drug Destruction Standard Operating Procedure (SOP)
For all laboratories listed on the FDA 1572, will need CLIA certifications, CAP
certifications, lab licenses, CVs of Lab Directors, and laboratory reference ranges
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appendix 7 data and safety

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

All institutional Phase 2 or 3 therapeutic studies are designated with a moderate risk assessment. The data is monitored every six months, with twenty percent of the subjects monitored (or at least three subjects if the calculated value is less than three). The UCSF Coordinating Center provides administration, data management, and organizational support for the participating sites in the conduct of a multicenter clinical trial. The UCSF Coordinating Center will also coordinate quarterly conference calls with the participating sites to communicate the review of adverse events, safety data, and other study matters. The Principal Investigator at the UCSF Coordinating Center will hold the role of Study Chair. The Study Chair is responsible for the overall conduct of the study and for monitoring its safety and progress at all participating sites. The Study Chair will conduct continuous review of data and subject safety and discuss each subject's treatment at monthly UCSF Site Committee meetings. The discussions are documented in the UCSF Site Committee meeting minutes.
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multicenter communication

The UCSF Coordinating Center provides administration, data management, and organizational support for the participating sites in the conduct of a multicenter clinical trial. The UCSF Coordinating Center will also coordinate, at minimum, monthly conference calls with the participating sites at the completion of each cohort or more frequently as needed to discuss risk assessment. The following issues will be discussed as appropriate:
**Enrollment information** **Adverse events (i.e. new adverse events and updates on unresolved adverse events**
and new safety information)
**Protocol violations**
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other issues affecting the conduct

Adverse events reporting to the DSMC will include reports from both the UCSF Coordinating Center, as well as the participating sites. The DSMC will be responsible for monitoring all data entered in OnCore® at the UCSF Coordinating Center and the participating sites. The data (i.e. copies of source documents) from the participating sites will be sent electronically or faxed over to the UCSF Coordinating Center prior to the monitoring visits in order for the DSMC to monitor the participating site's compliance with the protocol, patient safety, and to verify data entry.
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adverse event review and monitoring

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

If an increase in the frequency of Grade 3 or 4 adverse events (above the rate reported in the Investigator Brochure or package insert), the Study Chair at the UCSF Coordinating Center is responsible for notifying the DSMC at the time the increased rate is identified. The report will indicate if the incidence of adverse events observed in the study is above the range stated in the Investigator Brochure or package insert.  
If at any time the Study Chair stops enrollment or stops the study due to safety issues, the DSMC Chair and DSMC Manager must be notified within 1 business day via e-mail. The DSMC must receive a formal letter within 10 business days and the CHR must be notified. Data and Safety Monitoring Committee Contacts:  
  
  
UCSF Helen Diller Family Comprehensive Cancer Center San Francisco, CA 94143
* DSMP approved by NCI 09/February2012
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appendix 8 ucsf policy/procedure for

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

The International Conference on Harmonization (ICH) Good Clinical Practices (GCP) Guidelines define Essential Regulatory Documents as those documents which individually and collectively permit evaluation of the conduct of a trial and the quality of data produced. These documents serve to demonstrate compliance with standards of GCP and with all applicable regulatory requirements. Filing essential documents in a timely manner can greatly assist in the successful management of a clinical trial.  
The Regulatory Documents will consist of electronic files in both iMedRIS and OnCore®, as well as paper files in the Regulatory Binders for both the Coordinating Site and the Participating Site(s) in the HDFCCC Investigator Initiated Oncology Clinical Trials.
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procedures 1. hdfccc essential regulatory

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

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

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

Institutional Review Board (IRB) approval letters, IRB roster, Informed Consent Form
(ICF), and Health Insurance Portability and Accountability Act (HIPAA) Consent Form for the Participating Site(s)
For all Principal Investigators and Sub-Investigators listed on the 1572 at the Participating Site(s) - Financial Disclosure Forms, CVs, MD Licenses, and Staff Training documents (i.e. Collaborative Institute Training Initiative (CITI), etc.) (for Investigational New Drug Application Site Initiation Visit (SIV) minutes and correspondence with Participating Site(s).  
As applicable, approvals for Biosafety Committee, Radiation Committee, and Infusion Center for the Participating Site(s)
Protocol Violations and Single Patient Exception (SPE) reports to IRB with supporting fax documentation for Participating Site(s)
Drug Destruction Standard Operating Procedure (SOP) for the Participating Site(s)
Data and Safety Monitoring Committee (DSMC) monitoring reports for the Participating Site(s)
For all laboratories listed on FDA 1572, will need CLIA certifications, CAP certifications, lab licenses, CVs of Lab Directors, and laboratory reference ranges for the Participating Site(s)
Copy of the Data and Safety Monitoring Plan (DSMP) Monitoring Plan for all participating site(s) in Multicenter studies or Contract Research Organization (CRO) Monitoring Plan (if an outside CRO is used for the study)
Serious Adverse Event (SAE) forms submitted to both the IRB and the sponsor for the Participating Site(s)
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appendix 9 required regulatory documents

Directions:
1) Fax the documents listed below to the UCSF Coordinating center or 2) Scan the documents and upload to OnCore® and create a Note to File for the on-site Regulatory binder to indicate where these documents may be found
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1572

PI and Sub investigators:
CV and Medical license Financial disclosure form NIH or CITI human subject protection training certification Laboratories CLIA and CAP CV of Lab Director and Lab Licenses Laboratory reference ranges
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local institutional review board

IRB Approval letter Reviewed/Approved documents Protocol version date: ___________ Informed consent version date: ___________ Investigator Brochure version date: ___________ HIPAA
Current IRB Roster
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other

Delegation of Authority Log Include NIH or CITI human subject protection training certificates or GCP training certification Pharmacy Drug destruction SOP and Policy Protocol signature page Executed sub contract  
| Strong                                                                        | Moderate inhibitors   | Weak                    | All Other Inhibitors   |
|-------------------------------------------------------------------------------|-----------------------|-------------------------|------------------------|
| inhibitors                                                                    | inhibitors            |                         |                        |
| Indinavir                                                                     | Aprepitant            | Cimetidine              | Chloramphenicol        |
| Nelfinavir                                                                    | Amprenavir            | fluvoxamine             | Delaviridine           |
| Ritonavir                                                                     | Atzanavir             | Diethyl-Dithiocarbamate |                        |
| Clarithromycin                                                                | Ciprofloxacin         | Gestodene               |                        |
| Itraconazole                                                                  | Crizotinib            | Mifepristone            |                        |
| Ketoconazole                                                                  | Darunavir             | Norfloxacin             |                        |
| Nefazodone                                                                    | Diltiazem             | Norfluoxetine           |                        |
| Saquinavir                                                                    | dronedarone           |                         |                        |
| Suboxone                                                                      | Erythromycin          |                         |                        |
| Telithromycin                                                                 | Fluconazole           |                         |                        |
| cobicistat                                                                    | Grapefruit Juice      |                         |                        |
| boceprevir                                                                    | Seville Orange Juice  |                         |                        |
| mibefradil                                                                    | Verapamil             |                         |                        |
| telaprevir                                                                    | Voriconazole          |                         |                        |
| Troeandomycin                                                                 | imatinib              |                         |                        |
| posaconazole Inducers Carbamazepine                                           | Oxcarbarzepine        | Rifabutin               |                        |
| Efavirenz                                                                     | Phenobarbital         | Rifampin                |                        |
| Nevirapine                                                                    | Phenytoin             | St. John's  Wort        |                        |
| Barbiturates                                                                  | Pioglitazone          | Troglitazone            |                        |
| Glucocorticoids Modafinil Oxcarbarzepine Phenobarbital Phenytoin Pioglitazone |                       |                         |                        |