8.0 schedule of assessments
1 2. 7 c orrel

D ue t o t he s mall sa m ple sizes e x pecte d fr o m t he pr o p ose d st u d y desi g n, t he c orrelati ve st u dies will be h y p ot hesis ge nerati n g, b ut will als o hel p pr o vi de pil ot data t o i nf or m eli gi bilit y a n d f oll o w u p of f ut ure trials usi n g a n M O tar geti n g strate g y. C S F 1 le vels will be a nal yze d as a c o nti n u o us varia ble a n d cate g orical varia ble base d o n me dia n C S F c ha n ge wit h treat me nt. Mea n a n d 9 5 % c o nfi de nce i nter vals of C S F 1 le vels will be esti mate d a n d c o m pare d f or differe nces bet wee n d ose c o h orts. As a c o nti n u o us meas ure, A N O V A a n d Pears o n c orrelati o n will c o m pare C S F 1 le vels bet wee n P L X 3 3 8 9 d ose c o h orts a n d res p o nse gr o u ps. As a cate g orical meas ure, C hi-s q uare tests will deter mi ne t he ass ociati o ns bet wee n t u m or s u bt y pe ( m olec ular pr ofile) a n d i m m u ne pr ofile ( dic h ot o m o us varia ble) a n d bet wee n t u m or m olec ular pr ofile a n d C S F 1 gr o u ps.  
F A C S a nal ysis of le u k oc yte p o p ulati o ns as a perce nt of t otal C D 4 5 + cells will be e val uate d a m o n g t he o utc o me gr o u ps, P F S a n d O R R. T he relati o ns hi p bet wee n mea n a n d me dia n i m m u ne i nfiltrate a n d c o nti n u o us q ua ntitati ve meas ure me nts of t u m or classificati o n will be re p orte d usi n g eit her para metric ( Pears o n) a n d Fis her's e xact tests or n o n para metric ( S pear ma n) c orrelati o n c oefficie nts a n d Ra n k tests a n d 9 5 % c o nfi de nce i nter vals f or eac h statistic.
8.0 schedule of assessments
1 3. 0 d at

T he St u d y C hair a n d/ or her desi g nee, will pre pare a n d mai ntai n a de q uate a n d acc urate partici pa nt case hist ories wit h o bser vati o ns a n d data perti ne nt t o t he st u d y. St u d y s pecific Case Re p ort F or ms ( C R Fs) will d oc u me nt safet y a n d treat me nt o utc o mes f or safet y m o nit ori n g a n d data a nal ysis. All st u d y data will be e ntere d i nt o O n C ore via sta n dar dize d C R Fs i n acc or da nce wit h t he C T M S st u d y cale n dar, usi n g si n gle data e ntr y wit h a sec ure access acc o u nt. T he Pr ot o c ol V er si o n \# 1 0 P a g e 5 3 of 8 5 0 3/ 0 3/ 2 0 1 6 Pr ot o c ol \#: 1 2 7 5 1 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. Each participating site will complete study specific CRFs for safety monitoring and data analysis. Each site will enter the study data into OnCore® via standardized CRFs in accordance with the CTMS study calendar, using single data entry with a secure access account. The participating site's Clinical Research Coordinator (CRC) will complete the CRFs; the Investigator will review and approve the completed CRFs - this process must be completed within 3 business days of the visit. Study data from the participating site will be reported and reviewed in aggregate with data from patients enrolled at the coordinating center, UCSF. All source documentation and CTMS data will be available for review/monitoring as needed. 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 Study Chair 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 Plexxikon or the designated CRO and regulatory agencies. The Study Chair 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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14.0 correlative studies 14.1 tumor

Tumor biopsies will be obtained from accessible tumor tissue following the guidelines provided below before treatment start in all eligible patients. Patients enrolled on the Phase II trial will be asked to have a second core biopsy or FNA, depending on ease and site of biopsy. Patients who refuse the second biopsy will be allowed to stay on study treatment. Every attempt will be made to obtain tumor tissue at the time of a clinical procedure, if possible. Patients with lung only metastases will not be required to have biopsies, but will be allowed to enroll on this trial. Core biopsies of the breast will be performed by a qualified radiologist or surgeon, according to institutional guidelines for a diagnostic biopsy. Biopsies of other sites may be done by radiology, pathology or qualified surgeons. When required, radiographic coordination will be arranged. Tissue specimens will be collected from recurrent or metastatic lesions using standard institutional procedures. The goal is to obtain 2 to 4 core needle biopsies using an 18 gauge needle. If a fine needle aspiration is performed, 3-6 passes should be obtained. Less than the goal amount of tissue is acceptable, and should be based upon the clinical judgment of the Investigator and the clinician performing the procedure. The study coordinator will be present at the time of the biopsy to collect and process the tissue samples. Samples will be delivered to the laboratory of . Specific processing and delivery instructions will be provided to all sites in the Laboratory Manual, which contains all details for specimen processing and handling.
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14.2 csf1 levels

Patients on both trials will have CSF1 levels drawn to assess the impact of PLX3397. 5 cc of blood will be obtained in a serum separator tube. For patients on the phase I trial, CSF1 levels will be drawn at Cycle 1, days 1 and 2, and Cycle 2, day 1. For patients on the phase II trial, CSF1 levels will be drawn at the start of the PLX3397 lead-in, at day 5 to 7 before the start of eribulin, at Cycle 1, day 1, and Cycle 2, day 1.
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14.3 blood for leukocyte subtyping

Blood will be drawn for flow cytometric analysis at baseline for patients in phase I, and at day - 7/5 and day 0/1 for patients on the phase II trial. 10 cc of blood will be drawn into an EDTA tube and evaluated by flow cytometry. Processing will take place at each site. See Lab Manual for more details.
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14.4 pharmacokinetic sampling

Limited pharmacokinetic sampling will be performed in the phase I portion of this trial. PK sampling will occur on C1D1 (pre-PLX3397 administration and at 1, 2, 5, and 24 hours post treatment and on C2D1 (pre-PLX3397 administration and at 2 hours post treatment). Serum concentrations of PLX3397 with eribulin will be assessed by ELISA at Plexxikon Inc. and will be used to calculate the values of PK parameters, including maximum serum drug concentration (Cmax), area under the concentration-time curve from time zero to infinity (AUC 0-inf), systemic clearance (CL), volume of distribution (V), and elimination half-life (t1/2). Descriptive statistics (including number, mean and/or median, standard deviation, and coefficient of variation) will be used to describe the concentration time data. Where appropriate, these data may be combined with data from other studies as part of a metaanalysis. The influence of exposure on clinical safety parameters (e.g., selected AEs) will be explored. Results of the PK
analysis will be evaluated in conjunction with available safety and pharmacodynamic data.
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blood collection

Approximately 5 mL of blood will be collected via peripheral venipuncture into a lithium heparin tube. This blood sample will be used to measure concentrations of PLX3397 for each PK blood collection, as noted in the Study Calendar. Samples will be collected, processed and stored according to the study-specific laboratory manual. Blood samples for PK analysis should be collected at the requested time but within a ±15 minute window (or ± 30 minute window where specified) of the requested time. The exact actual time of collection should be noted in the source documents and eCRFs.
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bioanalytical methodology

The plasma samples will be analyzed for PLX3397 by using a validated method (high performance liquid chromatography (HPLC) with tandem quadruple mass spectrometric detection) of appropriate specificity and sensitivity.
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14.5. archival tumor samples

All patients will be asked to provide a sample of their original tumor pathology, if it is available.
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14.6 details of the correlative

The main goal of the correlative studies accompanying this trial will be to identify tissue and serum biomarkers capable of 1) predicting likelihood of response to macrophage-targeted therapy, or 2) providing an early indication of response to PLX3397 treatment likely to be seen at 12 wks of therapy. Both predictive and response biomarker assessment of tissue (core biopsy or FNA) and blood will be conducted as previously described[76, 77]. Phase I studies will be performed on all tumor subtypes, while Phase II studies will be performed on pts with TNBC. The lead-in period in Phase II will allow evaluation of the effect of PLX3397 alone on serum CSF1 levels and leukocyte subsets in blood and tissue prior to administration of eribulin.
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14.6.1 evaluation of baseline biomarkers

We will establish baseline values and variability of immune, and CSF1 measures in pts enrolled in phase I and phase II trials, and correlate these measures to magnitude of change in serum CSF1 levels and clinical response. Pts will be categorized as "good" or "poor" responders based on median change in serum CSF1, clinical response based in RECIST v1.1 imaging criteria at 12 wks and TTP. We will determine whether the tumor phenotype (ER, PR, HER2, and ki67), immune signature (CD68lo/CD4lo/CD8hi vs. CD68hi/CD4hi/CD8lo) and CSF1 signature at initial diagnosis (obtained from archived tumor blocks) correlates with response. In addition, we propose to explore whether the baseline immune and CSF1 signature differ between the early stage setting (derived from ongoing studies) and pts with MBC enrolled on this trial.
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14.6.2 evaluation of dynamic tissue

Identify whether leukocyte subpopulations are altered with PLX3397 treatment alone in a cohort of pts with metastatic TNBC. The lead-in design of the trial will allow evaluation of systemic response to PLX3397 alone in the absence of systemic chemotherapy (CTX). We will determine whether this single-agent therapy modulates leukocyte complexity in blood, with serum CSF1 measured between day -7/-5 and day 0/1. In addition, if ongoing studies demonstrates that core biopsy or FNA can reliably recapitulate the immune signature obtained from surgical samples, repeat biopsies will be used to determine whether immune infiltrate in tissue is modulated with PLX3397 treatment. This will provide confirmation that PLX3397 results in the expected macrophage, DC and T cell modulation at the tissue level.
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14.6.3 determine magnitude of change

Determine whether magnitude of change in serum CSF1 is associated with: 1) dose levels of PLX3397 and 2) response to therapy. For patients on the phase I trial, CSF1 levels will be drawn at Cycle 1, days 1 and 2, and Cycle 2, day 1. For patients on the phase II trial, CSF1 levels will be drawn at the start of the PLX3397 lead-in, at day 5 to 7 before the start of eribulin, at Cycle 1, day 1, and Cycle 2, day 1.. Baseline CSF1 and magnitude of change in CSF1 will be correlated to dose of PLX3397 and treatment response group.
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15.0 reporting adverse drug reactions

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

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

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

An adverse event or suspected adverse reaction is considered *unexpected* if it is not listed in the investigator brochure or package insert(s), or is not listed at the specificity or severity that has been observed, or, if an investigator brochure is not required or available, is not consistent with the risk information described in the general investigational plan or elsewhere in the current application. "Unexpected," as used in this definition, also refers to adverse events or suspected adverse reactions that are mentioned in the investigator brochure as occurring with a class of drugs or as anticipated from the pharmacological properties of the drug, but are not specifically mentioned as occurring with the particular drug under investigation. Adverse events that would be anticipated to occur as part of the disease process are considered unexpected for the purposes of reporting because they would not be listed in the investigator brochure. For example, a certain number of non-acute deaths in a cancer trial would be anticipated as an outcome of the underlying disease, but such deaths would generally not be listed as a suspected adverse reaction in the investigator brochure.  
Page 57 of 85 Some adverse events are listed in the Investigator Brochure as occurring with the same class of drugs, or as anticipated from the pharmacological properties of the drug, even though they have not been observed with the drug under investigation. Such events would be considered unexpected until they have been observed with the drug under investigation. For example, although angioedema is anticipated to occur in some patients exposed to drugs in the ACE inhibitor class and angioedema would be described in the investigator brochure as a class effect, the first case of angioedema observed with the drug under investigation should be considered unexpected for reporting purposes.
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serious

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

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

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

Reportable SAEs are those that occur after the first dose of PLX3397 and until 21 days after the last dose of combined therapy. 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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15.4 adverse events monitoring

The Investigator will assess all adverse events and determine reportability requirements to the UCSF Data and Safety Monitoring Committee (DSMC); UCSF's Institutional Review Board, the Committee on Human Research (CHR); and to the Food and Drug Administration (FDA) if it meets the FDA reporting criteria.  
Adverse events entered into OnCore® will be reviewed by the Helen Diller Family Comprehensive Cancer Center Site Committee on a weekly basis during Phase Ib and on a monthly basis during Phase II. The Site Committee will review and discuss at each 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 Plexxikon or the designated CRO 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 must be obtained prior to implementation. For a detailed description of the Data and Safety Monitoring Plan please see section 16.
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15.5 expedited reporting participating sites

In addition to complying with all applicable regulatory reporting laws and regulations, each site will report the following information in writing to the Sponsor-Investigator within one business day of the Investigator's awareness of occurrence:
All SAEs Reports of pregnancy exposure (pregnancy encompasses the entire course of pregnancy and delivery, perinatal and neonatal outcomes, even if there were no abnormal findings; both maternal and paternal exposure is collected);
Reports of lactation exposure; Overdose (with or without an SAE);
Abuse (use for non-clinical reasons with or without an SAE);
Inadvertent or accidental exposure; and Follow-up information regarding any of the above.  
The participating investigator should include his or her assessment of the causal relationship between each SAE and the Grantor product.  
Reports will include the cover page provided, and reference the Protocol Number. A copy of the report should be sent to the coordinating center CRC at UCSF. Information will be provided.
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sponsor-investigator reporting to the data

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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sponsor-investigator reporting to ucsf committee

The Sponsor-Investigator must report events meeting the UCSF CHR definition of "Unanticipated Problem" (UP) within 5 business days of his/her awareness of the event.
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sponsor-investigator expedited reporting to the

The Sponsor-Investigator is responsible for determining whether or not the suspected adverse reaction meets the criteria for expedited reporting in accordance with Federal Regulations
(21 CFR §312.32).  
The Sponsor-Investigator must report in an IND safety report any suspected adverse reaction that is both serious and unexpected. The Sponsor-Investigator needs to ensure that the event meets all three definitions:
Suspected adverse reaction (as defined in 6.1.30) Unexpected (as defined in 0) Serious (as defined in 6.1.5)
If the adverse event does not meet all three of the definitions, it should not be submitted as an expedited IND safety report.  
The timeline for submitting an IND safety report to FDA is no later than **15 calendar days** after the Investigator determines that the suspected adverse reaction qualifies for reporting (21 CFR 312.32(c)(1)). Any unexpected fatal or life-threatening suspected adverse reaction will be reported to FDA no later than **7 calendar days** after the Investigator's initial receipt of the information (21 CFR
312.32(c)(2)). Any relevant additional information that pertains to a previously submitted IND safety report will be submitted to FDA as a Follow-up IND Safety Report without delay, as soon as the information is available (21 CFR 312.32(d)(2)).
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sponsor-investigator reporting to pharmaceutical companies

The Sponsor-Investigator will report all Serious Adverse Events (SAEs) that occur during the SAE reporting period to the investigational drug manufacturer (Plexxikon) within 24 hours after first becoming aware of the event (immediately if the event is fatal or life-threatening). The Coordinating Center will report the SAE using an FDA MEDWATCH form and the Serious Adverse Event Fax Cover Sheet provided by the pharmaceutical partners for this trial. Events should be reported as soon as they are determined to meet the definition of an SAE, even if complete information is not yet available. The medical monitor contact information for Plexxikon is listed below:  
 Follow-Up Information. Coordinating center and participating sites will assist the pharmaceutical partners in investigating any SAE and will provide any reasonable follow-up information requested.  
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15.6 reporting dlts

The investigator at the originating site must report suspected DLTs to the Study Chair or designee immediately, not more than 24 hours after awareness of the event. The Study Chair will determine whether the event meets the protocol criteria for DLT and may consult with the monitoring CRO, DSMC, UCSF Phase I Site Committee, and/or co-investigators to do so. All investigators and the CRC at both sites will be notified immediately if a DLT determination is made. Dose level assignments for any patients scheduled to begin treatment and cohort expansion must be determined as per protocol criteria by the Study Chair or designee based upon the new DLT results. See Section 5.0 for dose escalation rules and decision process. The coordinating center CRC will utilize the CTMS to track enrollment of subject(s) at each dose level, as well as dose limiting toxicities (DLTs).
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16.0 data safety monitoring plan

Under the IND Transfer of Obligations executed between UCSF and Plexxikon, Plexxikon will monitor all clinical investigations. The UCSF-CCC Data Safety Monitoring Committee (DSMC) will review the monitoring SOPs and subsequent monitoring reports from Plexxikon or the designated CRO. The DSMC will not be involved in the direct monitoring or auditing of this trial. DSMC activities for this study includes:
Review of subject data in each cohort Review of suspected adverse reactions considered "serious"
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16.2 monitoring and reporting guidelines

All institutional Phase Ib therapeutic studies are designated with a high risk assessment. All subject data will be monitored at 6 week intervals data by the designated CRO. 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. Written authorization to proceed will be granted by the DSMC. 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. During Phase 1, the Study Chair will conduct continuous review of data and subject safety and discuss each subject's treatment at weekly UCSF Site Committee meetings. During Phase 2, 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. 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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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.
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16.3 review and oversight requirements

During Phase 1, 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. During Phase 2, all clinically significant grade 3 and above 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.  
During Phase 1, all clinically significant adverse events entered into OnCore® will be reviewed on a weekly basis at the UCSF Coordinating Center's Site Committee. During Phase 2, all clinically significant grade 3 and above adverse events entered into OnCore® will be reviewed on a monthly 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).  
For Phase I patients, toxicity data must be entered into OnCore® by noon (Pacific Standard Time) on Wednesday of each week for review by Site Committee at UCSF.  
For Phase II patients, toxicity data must be entered into OnCore® by noon (Pacific Standard Time) of the second Monday of each month for review by Site Committee at UCSF.  
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. UCSF Data and Safety Monitoring Committee Contacts:
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study management 17.1 pre-study documentation

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. 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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17.2 independent ethics committees/institutional review

This protocol and the informed consent will be approved by the Committee on Human Research (the UCSF IRB). The Principal Investigator is responsible for keeping the IRB advised of the progress of the study and of any changes made in the protocol. The Principal Investigator will also keep the IRB informed of any significant adverse reactions, and any protocol exceptions or deviations. Records of all study review and approval documents must be kept on file by the Principal Investigator and are subject to FDA inspection during or after completion of the study. The IRB will receive notification of the termination of the study.
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17.3 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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17.4 oversight and monitoring plan

This study is a multi-institution, investigator-initiated trial which will be coordinated by UCSF and conducted at both the UCSF Helen Diller Family Comprehensive Cancer Center (HDFCCC) and the participating site. The Principal Investigator at the coordinating center (UCSF) holds the role of Study Chair. The responsibilities of the Study Chair are described in the Code of Federal Regulations (Title 21, Subpart D, 312.50 through 312.69). 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, biweekly (during Phase 1) or monthly (during Phase 2) 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 The coordinating center CRC will insure that participating sites are notified of safety events. Questions regarding the study or reporting of adverse events may be directed to the designated  
 coordinating center (UCSF) CRC (contact information to be provided by the start of study).  
the IND Transfer of Obligations executed between UCSF and Plexxikon, Plexxikon or a designated CRO will monitor all clinical investigations. The DSMC will not be involved in the monitoring and auditing of this trial. Please refer to Section 16.0 for additional details.
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17.5 coordinating center processing and

This study will be conducted under an IND \#114838 held by the Sponsor-Investigator. A copy of all files pertaining to this IND will also be maintained by the centralized regulatory staff of the HDFCCC. It is the responsibility of the Study Chair to relay to HDFCCC centralized regulatory staff any correspondence to or from the FDA regarding the IND.
8.0 schedule of assessments
17.6 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.
8.0 schedule of assessments
17.7 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:
Participating Site IRB approval(s) for the protocol, appendices, informed consent form and HIPAA authorization Participating Site IRB approved consent form Participating Site IRB membership list Participating Site IRB's Federal Wide Assurance number and OHRP Registration number Page 66 of 85  
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.
8.0 schedule of assessments
17.8 patient enrollment

Patients can be registered only after the pretreatment evaluation is complete and all eligibility criteria have been met. Patients must meet all inclusion criteria and no exclusion criteria should apply. The patient must have signed and dated an approved, current version of all applicable consent forms. The participating site should fax a completed eligibility checklist and all supporting source documentation to the designated coordinating center CRC at UCSF (contact information to be provided by the start of study). The CRC will check the forms for completeness and contact the participating site with any discrepancies. Eligibility must be confirmed by the Study Chair, or designee before patient ID number is assigned. The coordinating center will provide a study-specific patient ID number to the participating site. All future study documentation related to that patient should include the assigned patient ID number.
8.0 schedule of assessments
17.9 study drug supply and

Study drug will be shipped directly to the participating site from Plexxikon for direct distribution of the drugs to the study patients in accordance with the IND Transfer of Obligations executed between UCSF and Plexxikon. The participating site will be responsible for drug accountability at their site. Plexxikon CRAs will monitor the participating sites to ensure that appropriate records are kept regarding drug accountability. All documentation will be provided by Plexxikon CRA to the coordinating center. See Section 11 for specific instructions regarding study drug availability. Eribulin is FDA approved and should be available through the infusion center at each institution.
8.0 schedule of assessments
17.10 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.
8.0 schedule of assessments
17.10.1 approval of protocol and

All protocol amendments must be approved by the participating sites' IRBs within 90 days of receipt. Failure to do so can result in the suspension of study activities at that site. Upon approval of the protocol or amendment by a participating site's IRB, a copy of the approval documentation must be submitted (electronically or in hard form) to the office of the Study Chair. Documentation of participating sites' protocol approvals will be maintained in the correspondence files by the Study Chair or his/her designee.
8.0 schedule of assessments
18.0 references

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40. Yang, L., et al., *Expansion of myeloid immune suppressor Gr+CD11b+ cells in tumorbearing host directly promotes tumor angiogenesis.* Cancer Cell, 2004. 6(4): p. 409-21.  
41. Yang, L., et al., *Abrogation of TGF beta signaling in mammary carcinomas recruits Gr1+CD11b+ myeloid cells that promote metastasis.* Cancer Cell, 2008. 13(1): p. 23-35.  
42. Tang, R., et al., M-CSF (monocyte colony stimulating factor) and M-CSF receptor expression by breast tumour cells: M-CSF mediated recruitment of tumour infiltrating monocytes? J Cell Biochem, 1992. 50(4): p. 350-356.  
43. Wei, S., et al., *Functional overlap but differential expression of CSF-1 and IL-34 in their* CSF-1 receptor-mediated regulation of myeloid cells. J Leukoc Biol, 2010. 88(3): p. 495505.  
44. Chihara, T., et al., IL-34 and M-CSF share the receptor Fms but are not identical in biological activity and signal activation. Cell Death Differ, 2010.  
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48. Nowicki, A., et al., *Impaired tumor growth in colony-stimulating factor 1 (CSF-1)-*
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50. Manthey, C.L., et al., JNJ-28312141, a novel orally active colony-stimulating factor-1 receptor/FMS-related receptor tyrosine kinase-3 receptor tyrosine kinase inhibitor with potential utility in solid tumors, bone metastases, and acute myeloid leukemia. Mol Cancer Ther, 2009. 8(11): p. 3151-61.  
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| Strong Inhibitors                                                                                                                     | Strong Inducers                                 |                                           |               |
|---------------------------------------------------------------------------------------------------------------------------------------|-------------------------------------------------|-------------------------------------------|---------------|
| Protease inhibitors                                                                                                                   | Anticonvulsants, mood stabilizers               |                                           |               |
|                                                                                                                                      | Ritonavir                                       |                                          | Phenytoin     |
|                                                                                                                                      | Indinavir                                       |                                          | Carbamazepine |
|                                                                                                                                      | Nelfinavir                                      |                                          | Oxcarbazepine |
| Macrolide antibiotics                                                                                                                 | Non-nucleoside reverse transcriptase inhibitors |                                           |               |
|                                                                                                                                      | Erythromycin                                    |                                          | Efavirenz     |
|                                                                                                                                      | Telithromycin                                   |                                          | Nevirapine    |
|                                                                                                                                      | Clarithromycin                                  |                                          | Etravirine    |
| Azole antifungals                                                                                                                     | Phenobarbital (barbiturate)                     |                                           |               |
|                                                                                                                                      | Fluconazole                                     | Rifampicin (bactericidal)                 |               |
|                                                                                                                                      | Ketoconazole                                    | Modafinil (stimulant)                     |               |
|                                                                                                                                      | Itraconazole                                    | Hyperforin (constituent of St Johns Wort) |               |
| Chloramphenicol (antibiotic)                                                                                                          | Cyproterone (antiandrogen, progestin)           |                                           |               |
| Nefazodone (antidepressant) Bergamottin (constituent of grapefruit juice) Aprepitant (antiemetic) Verapamil (calcium channel blocker) |                                                 |                                           |               |  
| Appendix 2: Drugs With A Risk Of Torsades De Pointes Generic Name Brand Name Class/Clinical Use   | Comments                                                                                         |                                                      |                                                       |
|---------------------------------------------------------------------------------------------------|--------------------------------------------------------------------------------------------------|------------------------------------------------------|-------------------------------------------------------|
| Amiodarone                                                                                        | Cordarone®                                                                                       | Anti-arrhythmic / abnormal heart                     | Females>Males,TdP risk regarded                       |
| rhythm                                                                                            | as low                                                                                           |                                                      |                                                       |
| Amiodarone                                                                                        | Pacerone®                                                                                        | Anti-arrhythmic / abnormal heart                     | Females>Males,TdP risk regarded                       |
| rhythm                                                                                            | as low                                                                                           |                                                      |                                                       |
| Arsenic trioxide                                                                                  | Trisenox®                                                                                        | Anti-cancer / Leukemia                               |                                                       |
| Bepridil                                                                                          | Vascor®                                                                                          | Anti-anginal / heart pain                            | Females>Males                                         |
| Chloroquine                                                                                       | Aralen®                                                                                          | Anti-malarial / malaria infection                    |                                                       |
| Chlorpromazine                                                                                    | Thorazine®                                                                                       | Anti-psychotic/ Anti-emetic /  schizophrenia/ nausea |                                                       |
| Cisapride                                                                                         | Propulsid®                                                                                       | GI stimulant / heartburn                             | No longer available in the U.S.;  available in Mexico |
| Citalopram                                                                                        | Celexa®                                                                                          | Anti-depressant / depression                         |                                                       |
| Clarithromycin                                                                                    | Biaxin®                                                                                          | Antibiotic / bacterial infection                     |                                                       |
| Disopyramide                                                                                      | Norpace®                                                                                         | Anti-arrhythmic / abnormal heart                     | Females>Males                                         |
| rhythm                                                                                            |                                                                                                  |                                                      |                                                       |
| Dofetilide                                                                                        | Tikosyn®                                                                                         | Anti-arrhythmic / abnormal heart  rhythm             |                                                       |
| Droperidol                                                                                        | Inapsine®                                                                                        | Sedative;Anti-nausea / anesthesia  adjunct, nausea   |                                                       |
| Erythromycin                                                                                      | Erythrocin®                                                                                      | Antibiotic;GI stimulant / bacterial                  | Females>Males                                         |
| infection; increase GI motility                                                                   |                                                                                                  |                                                      |                                                       |
| Erythromycin                                                                                      | E.E.S.®                                                                                          | Antibiotic;GI stimulant / bacterial                  | Females>Males                                         |
| infection; increase GI motility                                                                   |                                                                                                  |                                                      |                                                       |
| Flecainide                                                                                        | Tambocor®                                                                                        | Anti-arrhythmic / abnormal heart  rhythm             |                                                       |
| Halofantrine                                                                                      | Halfan®                                                                                          | Anti-malarial / malaria infection                    | Females>Males                                         |
| Haloperidol                                                                                       | Haldol®                                                                                          | Anti-psychotic / schizophrenia,                      | When given intravenously or at                        |
| agitation                                                                                         | higher-than- recommended doses,  risk of sudden death, QT  prolongation and torsades  increases. |                                                      |                                                       |
| Ibutilide                                                                                         | Corvert®                                                                                         | Anti-arrhythmic / abnormal heart                     | Females>Males                                         |
| rhythm                                                                                            |                                                                                                  |                                                      |                                                       |
| Mesoridazine                                                                                      | Serentil®                                                                                        | Anti-psychotic / schizophrenia                       |                                                       |
| Methadone                                                                                         | Methadose®                                                                                       | Opiate agonist / pain control,                       | Females>Males                                         |
| narcotic dependence                                                                               |                                                                                                  |                                                      |                                                       |
| Methadone                                                                                         | Dolophine®                                                                                       | Opiate agonist / pain control,                       | Females>Males                                         |
| narcotic dependence                                                                               |                                                                                                  |                                                      |                                                       |
| Moxifloxacin                                                                                      | Avelox®                                                                                          | Antibiotic / bacterial infection                     |                                                       |
| Pentamidine                                                                                       | Pentam®                                                                                          | Anti-infective / pneumocystis                        | Females>Males                                         |
| pneumonia                                                                                         |                                                                                                  |                                                      |                                                       |
| Pentamidine                                                                                       | NebuPent®                                                                                        | Anti-infective / pneumocystis                        | Females>Males                                         |
| pneumonia                                                                                         |                                                                                                  |                                                      |                                                       |
| Pimozide                                                                                          | Orap®                                                                                            | Anti-psychotic / Tourette's tics                     | Females>Males                                         |
| Procainamide                                                                                      | Pronestyl®                                                                                       | Anti-arrhythmic / abnormal heart  rhythm             |                                                       |
| Procainamide                                                                                      | Procan®                                                                                          | Anti-arrhythmic / abnormal heart                     |                                                       |
| Protocol Version #10                                                                              | Page 75 of 85                                                                                    | 03/03/2016                                           |                                                       |
| Protocol #: 12751                                                                                 |                                                                                                  |                                                      |                                                       |
8.0 schedule of assessments
appendix 2 drugs with a

| Generic Name   | Brand Name                  | Class/Clinical Use                       | Comments      |
|----------------|-----------------------------|------------------------------------------|---------------|
| rhythm         |                             |                                          |               |
| Quinidine      | Cardioquin®                 | Anti-arrhythmic / abnormal heart         | Females>Males |
| rhythm         |                             |                                          |               |
| Quinidine      | Quinaglute®                 | Anti-arrhythmic / abnormal heart         | Females>Males |
| rhythm         |                             |                                          |               |
| Sotalol        | Betapace®                   | Anti-arrhythmic / abnormal heart         | Females>Males |
| rhythm         |                             |                                          |               |
| Sparfloxacin   | Zagam®                      | Antibiotic / bacterial infection         |               |
| Thioridazine   | Mellaril®                   | Anti-psychotic / schizophrenia           |               |
| Vandetanib     | Caprelsa®                   | Anti-cancer / Thyroid cancer             |               |
| Fluconazole    | Diflucan®                   | Anti-arrhythmic / abnormal heart  rhythm |               |
| Ciprofloxacin  | Ciloxan,  Cipro,  Neofloxin | Anti-arrhythmic / abnormal heart  rhythm |               |
8.0 schedule of assessments
appendix 2 drugs with a

CC\#12751: Enhancing Efficacy of Chemotherapy in Triple Negative/Basal-Like Breast Cancer by Targeting Macrophages: A Phase Ib/II study of PLX 3397 and Eribulin in Patients with Metastatic Breast Cancer
8.0 schedule of assessments
study subject id # patient

Current Assigned dose: ______________________ **Start Date:**__________________
Reminders:
Study medication should be stored at room temperature (Temperature storage range 15-30 oC or 59-86 oF). Take your dose of study medication every24 hours (± 2 hours) If it is after 2 hours from when your dose was due, skip that dose and continue with the subsequent dose.Fast for at least 1 hour prior to taking the study medication and 1 hour after you take the study medication. You are allowed to have a low-fat, bland snack (crackers, toast, tea, etc.) if needed (if you are feeling nauseous or weak) during this 2 hour period.  
Medication should be taken with at least 8 ounces (1 cup) of room temperature water. Missed doses should be skipped and not taken as a double dose at the next dosing timepoint. If you vomit your dose, you should not make-up that dose or take extra study drug at the next dosing timepoint.  
Write down the time each dose is taken. Bring your study medication and study diary with you every time you visit the clinic. Contact your study doctor if you have any questions/concerns.  
| Patient Signature:   | Were you fasting before  and after to your  dose?(circle one)   | # of       |              |         |        |
|----------------------|-----------------------------------------------------------------|------------|--------------|---------|--------|
| capsules  taken      | Reason for  missed  dose                                        |            |              |         |        |
| Date                 |                                                                 |            |              |         |        |
| Cycle #              | Day                                                             | mm/dd/yyyy | Time of Dose | Before: | After: |
| Cycle __             | Day 1*                                                          | /          | /            | Yes/No  | Yes/No |
| Before:              | After:                                                          |            |              |         |        |
| Cycle __             | Day 2**                                                         | /          | /            | Yes/No  | Yes/No |
| Before:              | After:                                                          |            |              |         |        |
| Cycle __             | Day 3                                                           | /          | /            | Yes/No  | Yes/No |
| Before:              | After:                                                          |            |              |         |        |
| Cycle __             | Day 4                                                           | /          | /            | Yes/No  | Yes/No |
| Before:              | After:                                                          |            |              |         |        |
| Cycle __             | Day 5                                                           | /          | /            | Yes/No  | Yes/No |
| Before:              | After:                                                          |            |              |         |        |
| Cycle __             | Day 6                                                           | /          | /            | Yes/No  | Yes/No |
| Before:              | After:                                                          |            |              |         |        |
| Cycle __             | Day 7                                                           | /          | /            | Yes/No  | Yes/No |
| Before:              | After:                                                          |            |              |         |        |
| Cycle __             | Day 8                                                           | /          | /            | Yes/No  | Yes/No |
| Before:              | After:                                                          |            |              |         |        |
| Cycle __             | Day 9                                                           | /          | /            | Yes/No  | Yes/No |
| Before:              | After:                                                          |            |              |         |        |
| Cycle __             | Day 10                                                          | /          | /            | Yes/No  | Yes/No |
| Before:              | After:                                                          |            |              |         |        |
| Cycle __             | Day 11                                                          | /          | /            | Yes/No  | Yes/No |
| Before:              | After:                                                          |            |              |         |        |
| Cycle __             | Day 12                                                          | /          | /            | Yes/No  | Yes/No |
8.0 schedule of assessments
plx3397 qd - patient drug

CC\#12751: Enhancing Efficacy of Chemotherapy in Triple Negative/Basal-Like Breast Cancer by Targeting Macrophages: A Phase Ib/II study of PLX 3397 and Eribulin in Patients with Metastatic Breast Cancer
8.0 schedule of assessments
study subject id # patient

Reminders:
Study medication should be stored at room temperature (Temperature storage range 15-30 oC or 59-86 oF).  
Take your dose of study medication every24 hours (± 2 hours) If it is after 2 hours from when your dose was due, skip that dose and continue with the subsequent dose.Fast for at least 1 hour prior to taking the study medication and 1 hour after you take the study medication. You are allowed to have a low-fat, bland snack (crackers, toast, tea, etc.) if needed (if you are feeling nauseous or weak) during this 2 hour period.  
Medication should be taken with at least 8 ounces (1 cup) of room temperature water. Missed doses should be skipped and not taken as a double dose at the next dosing timepoint. If you vomit your dose, you should not make-up that dose or take extra study drug at the next dosing timepoint.  
Write down the time each dose is taken. Bring your study medication and study diary with you every time you visit the clinic. Contact your study doctor if you have any questions/concerns.  
| Patient Signature:                                                                                                                      | Were you fasting before  and after to your  dose?(circle one)   | # of       |              |         |        |
|-----------------------------------------------------------------------------------------------------------------------------------------|-----------------------------------------------------------------|------------|--------------|---------|--------|
| capsules taken                                                                                                                          | Reason for  missed  dose                                        |            |              |         |        |
| Date                                                                                                                                    |                                                                 |            |              |         |        |
| Cycle #                                                                                                                                 | Day                                                             | mm/dd/yyyy | Time of Dose | Before: | After: |
| Cycle __                                                                                                                                | Day 13                                                          | /          | /            | Yes/No  | Yes/No |
| Before:                                                                                                                                 | After:                                                          |            |              |         |        |
| Cycle __                                                                                                                                | Day 14                                                          | /          | /            | Yes/No  | Yes/No |
| Before:                                                                                                                                 | After:                                                          |            |              |         |        |
| Cycle __                                                                                                                                | Day 15                                                          | /          | /            | Yes/No  | Yes/No |
| Before:                                                                                                                                 | After:                                                          |            |              |         |        |
| Cycle __                                                                                                                                | Day 16                                                          | /          | /            | Yes/No  | Yes/No |
| Before:                                                                                                                                 | After:                                                          |            |              |         |        |
| Cycle __                                                                                                                                | Day 17                                                          | /          | /            | Yes/No  | Yes/No |
| Before:                                                                                                                                 | After:                                                          |            |              |         |        |
| Cycle __                                                                                                                                | Day 18                                                          | /          | /            | Yes/No  | Yes/No |
| Before:                                                                                                                                 | After:                                                          |            |              |         |        |
| Cycle __                                                                                                                                | Day 19                                                          | /          | /            | Yes/No  | Yes/No |
| Before:                                                                                                                                 | After:                                                          |            |              |         |        |
| Cycle __                                                                                                                                | Day 20                                                          | /          | /            | Yes/No  | Yes/No |
| Before:                                                                                                                                 | After:                                                          |            |              |         |        |
| Cycle __                                                                                                                                | Day 21                                                          | /          | /            | Yes/No  | Yes/No |
| * For Cycle 1 and Cycle 2, Day 1, do not take your morning dose of PLX3397 until you are instructed to do so during your clinic  visit. |                                                                 |            |              |         |        |  
* For Cycle 1 and Cycle 2, Day 1, do not take your morning dose of PLX3397 until you are instructed to do so during your clinic  
visit.  
** For Day 2 of Cycle 1 ONLY, do not take your morning dose of PLX3397 until you are instructed to so during your clinic visit.
plx3397 bid - patient drug
study subject id # patient

CC\#12751: Enhancing Efficacy of Chemotherapy in Triple Negative/Basal-Like Breast Cancer by Targeting Macrophages: A Phase Ib/II study of PLX 3397 and Eribulin in Patients with Metastatic Breast Cancer
plx3397 bid - patient drug
study subject id # patient

Current Assigned dose: ______________________ **Start Date:**__________________
Reminders:
Study medication should be stored at room temperature (Temperature storage range 15-30 oC or 59-86 oF).  
Take your dose of study medication every 12 hours (± 2 hours). If it is after 2 hours from when your dose was due, skip that dose and continue with your next scheduled dose.  
Fast for at least 1 hour prior to taking the study medication and 1 hour after you take the study medication. You are allowed to have a low-fat, bland snack (crackers, toast, tea, etc.) if needed (if you are feeling nauseous or weak) during this 2 hour period.  
Medication should be taken with at least 8 ounces (1 cup) of room temperature water. Missed doses should be skipped and not taken as a double dose at the next dosing timepoint. If you vomit your dose, you should not make-up that dose or take extra study drug at the next dosing timepoint.  
Write down the time each dose is taken. Bring your study medication and study diary with you every time you visit the clinic. Contact your study doctor if you have any questions/concerns.  
| Patient Signature:   | Were you fasting before  and after to your  dose?(circle one)   | # of       |        |         |        |        |        |
|----------------------|-----------------------------------------------------------------|------------|--------|---------|--------|--------|--------|
| capsule s taken      | Reason for  missed  dose                                        |            |        |         |        |        |        |
| Date                 | Time of                                                         |            |        |         |        |        |        |
| Cycle #              | Day                                                             | mm/dd/yyyy | Dose** | Before: | After: |        |        |
| Cycle __             | Day 1*                                                          | :          | AM     | Yes/No  | Yes/No |        |        |
| Before:              | After:                                                          |            |        |         |        |        |        |
| Cycle __             | Day 1                                                           | /          | /      | :       | PM     | Yes/No | Yes/No |
| Before:              | After:                                                          |            |        |         |        |        |        |
| Cycle __             | Day 2**                                                         | /          | /      | :       | AM     | Yes/No | Yes/No |
| Before:              | After:                                                          |            |        |         |        |        |        |
| Cycle __             | Day 2                                                           | /          | /      | :       | PM     | Yes/No | Yes/No |
| Before:              | After:                                                          |            |        |         |        |        |        |
| Cycle __             | Day 3                                                           | /          | /      | :       | AM     | Yes/No | Yes/No |
| Before:              | After:                                                          |            |        |         |        |        |        |
| Cycle __             | Day 3                                                           | /          | /      | :       | PM     | Yes/No | Yes/No |
| Before:              | After:                                                          |            |        |         |        |        |        |
| Cycle __             | Day 4                                                           | /          | /      | :       | AM     | Yes/No | Yes/No |
| Before:              | After:                                                          |            |        |         |        |        |        |
| Cycle __             | Day 4                                                           | /          | /      | :       | PM     | Yes/No | Yes/No |
| Before:              | After:                                                          |            |        |         |        |        |        |
| Cycle __             | Day 5                                                           | /          | /      | :       | AM     | Yes/No | Yes/No |
| Before:              | After:                                                          |            |        |         |        |        |        |
| Cycle __             | Day 5                                                           | /          | /      | :       | PM     | Yes/No | Yes/No |
| Before:              | After:                                                          |            |        |         |        |        |        |
| Cycle __             | Day 6                                                           | /          | /      | :       | AM     | Yes/No | Yes/No |
| Before:              | After:                                                          |            |        |         |        |        |        |
| Cycle __             | Day 6                                                           | /          | /      | :       | PM     | Yes/No | Yes/No |
| Before:              | After:                                                          |            |        |         |        |        |        |
| Cycle __             | Day 7                                                           | /          | /      | :       | AM     | Yes/No | Yes/No |
| Before:              | After:                                                          |            |        |         |        |        |        |
| Cycle __             | Day 7                                                           | /          | /      | :       | PM     | Yes/No | Yes/No |
| Protocol Version #10 | Page 79 of 85                                                   | 03/03/2016 |        |         |        |        |        |
| Protocol #: 12751    |                                                                 |            |        |         |        |        |        |
plx3397 bid - patient drug
study subject id # patient

| Patient Signature:   | Were you fasting before  and after to your  dose?(circle one)   | # of       |        |         |        |        |        |
|----------------------|-----------------------------------------------------------------|------------|--------|---------|--------|--------|--------|
| capsule s taken      | Reason for  missed  dose                                        |            |        |         |        |        |        |
| Date                 | Time of                                                         |            |        |         |        |        |        |
| Cycle #              | Day                                                             | mm/dd/yyyy | Dose** | Before: | After: |        |        |
| Cycle __             | Day 8                                                           | /          | /      | :       | AM     | Yes/No | Yes/No |
| Before:              | After:                                                          |            |        |         |        |        |        |
| Cycle __             | Day 8                                                           | /          | /      | :       | PM     | Yes/No | Yes/No |
| Before:              | After:                                                          |            |        |         |        |        |        |
| Cycle __             | Day 9                                                           | /          | /      | :       | AM     | Yes/No | Yes/No |
| Before:              | After:                                                          |            |        |         |        |        |        |
| Cycle __             | Day 9                                                           | /          | /      | :       | PM     | Yes/No | Yes/No |
| Before:              | After:                                                          |            |        |         |        |        |        |
| Cycle __             | Day 10                                                          | /          | /      | :       | AM     | Yes/No | Yes/No |
| Before:              | After:                                                          |            |        |         |        |        |        |
| Cycle __             | Day 10                                                          | /          | /      | :       | PM     | Yes/No | Yes/No |
| Before:              | After:                                                          |            |        |         |        |        |        |
| Cycle __             | Day 11                                                          | /          | /      | :       | AM     | Yes/No | Yes/No |
| Before:              | After:                                                          |            |        |         |        |        |        |
| Cycle __             | Day 11                                                          | /          | /      | :       | PM     | Yes/No | Yes/No |
| Before:              | After:                                                          |            |        |         |        |        |        |
| Cycle __             | Day 12                                                          | /          | /      | :       | AM     | Yes/No | Yes/No |
| Before:              | After:                                                          |            |        |         |        |        |        |
| Cycle __             | Day 12                                                          | /          | /      | :       | PM     | Yes/No | Yes/No |
| Before:              | After:                                                          |            |        |         |        |        |        |
| Cycle __             | Day 13                                                          | /          | /      | :       | AM     | Yes/No | Yes/No |
| Before:              | After:                                                          |            |        |         |        |        |        |
| Cycle __             | Day 13                                                          | /          | /      | :       | PM     | Yes/No | Yes/No |
| Before:              | After:                                                          |            |        |         |        |        |        |
| Cycle __             | Day 14                                                          | /          | /      | :       | AM     | Yes/No | Yes/No |
| Before:              | After:                                                          |            |        |         |        |        |        |
| Cycle __             | Day 14                                                          | /          | /      | :       | PM     | Yes/No | Yes/No |
| Before:              | After:                                                          |            |        |         |        |        |        |
| Cycle __             | Day 15                                                          | /          | /      | :       | AM     | Yes/No | Yes/No |
| Before:              | After:                                                          |            |        |         |        |        |        |
| Cycle __             | Day 15                                                          | /          | /      | :       | PM     | Yes/No | Yes/No |
| Protocol Version #10 | Page 80 of 85                                                   | 03/03/2016 |        |         |        |        |        |
| Protocol #: 12751    |                                                                 |            |        |         |        |        |        |
plx3397 bid - patient drug
reminders

Study medication should be stored at room temperature (Temperature storage range 15-30 oC or 59-86 oF).  
Take your dose of study medication every 12 hours (± 2 hours). If it is after 2 hours from when your dose was due, skip that dose and continue with your next scheduled dose.  
Fast for at least 1 hour prior to taking the study medication and 1 hour after you take the study medication. You are allowed to have a low-fat, bland snack (crackers, toast, tea, etc.) if needed (if you are feeling nauseous or weak) during this 2 hour period.  
Medication should be taken with at least 8 ounces (1 cup) of room temperature water. Missed doses should be skipped and not taken as a double dose at the next dosing timepoint. If you vomit your dose, you should not make-up that dose or take extra study drug at the next dosing timepoint.  
Write down the time each dose is taken. Bring your study medication and study diary with you every time you visit the clinic.  
Contact your study doctor if you have any questions/concerns.
plx3397 bid - patient drug
study subject id # patient

Reminders:
Study medication should be stored at room temperature (Temperature storage range 15-30 oC or 59-86 oF).  
Take your dose of study medication every 12 hours (± 2 hours). If it is after 2 hours from when your dose was due, skip that dose and continue with your next scheduled dose.  
Fast for at least 1 hour prior to taking the study medication and 1 hour after you take the study medication. You are allowed to have a low-fat, bland snack (crackers, toast, tea, etc.) if needed (if you are feeling nauseous or weak) during this 2 hour period.  
Medication should be taken with at least 8 ounces (1 cup) of room temperature water. Missed doses should be skipped and not taken as a double dose at the next dosing timepoint. If you vomit your dose, you should not make-up that dose or take extra study drug at the next dosing timepoint.  
Write down the time each dose is taken. Bring your study medication and study diary with you every time you visit the clinic.  
Contact your study doctor if you have any questions/concerns.  
| Patient Signature:                                                                                                                     | Were you fasting before  and after to your  dose?(circle one)   | # of       |        |         |        |        |        |
|----------------------------------------------------------------------------------------------------------------------------------------|-----------------------------------------------------------------|------------|--------|---------|--------|--------|--------|
| capsule s taken                                                                                                                        | Reason for  missed  dose                                        |            |        |         |        |        |        |
| Date                                                                                                                                   | Time of                                                         |            |        |         |        |        |        |
| Cycle #                                                                                                                                | Day                                                             | mm/dd/yyyy | Dose** | Before: | After: |        |        |
| Cycle __                                                                                                                               | Day 16                                                          | /          | /      | :       | AM     | Yes/No | Yes/No |
| Before:                                                                                                                                | After:                                                          |            |        |         |        |        |        |
| Cycle __                                                                                                                               | Day 16                                                          | /          | /      | :       | PM     | Yes/No | Yes/No |
| Before:                                                                                                                                | After:                                                          |            |        |         |        |        |        |
| Cycle __                                                                                                                               | Day 17                                                          | /          | /      | :       | AM     | Yes/No | Yes/No |
| Before:                                                                                                                                | After:                                                          |            |        |         |        |        |        |
| Cycle __                                                                                                                               | Day 17                                                          | /          | /      | :       | PM     | Yes/No | Yes/No |
| Before:                                                                                                                                | After:                                                          |            |        |         |        |        |        |
| Cycle __                                                                                                                               | Day 18                                                          | /          | /      | :       | AM     | Yes/No | Yes/No |
| Before:                                                                                                                                | After:                                                          |            |        |         |        |        |        |
| Cycle __                                                                                                                               | Day 18                                                          | /          | /      | :       | PM     | Yes/No | Yes/No |
| Before:                                                                                                                                | After:                                                          |            |        |         |        |        |        |
| Cycle __                                                                                                                               | Day 19                                                          | /          | /      | :       | AM     | Yes/No | Yes/No |
| Before:                                                                                                                                | After:                                                          |            |        |         |        |        |        |
| Cycle __                                                                                                                               | Day 19                                                          | /          | /      | :       | PM     | Yes/No | Yes/No |
| Before:                                                                                                                                | After:                                                          |            |        |         |        |        |        |
| Cycle __                                                                                                                               | Day 20                                                          | /          | /      | :       | AM     | Yes/No | Yes/No |
| Before:                                                                                                                                | After:                                                          |            |        |         |        |        |        |
| Cycle __                                                                                                                               | Day 20                                                          | /          | /      | :       | PM     | Yes/No | Yes/No |
| Before:                                                                                                                                | After:                                                          |            |        |         |        |        |        |
| Cycle __                                                                                                                               | Day 21                                                          | /          | /      | :       | AM     | Yes/No | Yes/No |
| Before:                                                                                                                                | After:                                                          |            |        |         |        |        |        |
| Cycle __                                                                                                                               | Day 21                                                          | /          | /      | :       | PM     | Yes/No | Yes/No |
| *For Cycle 1 and Cycle 2, Day 1, do not take your morning dose of PLX3397 until you are instructed to do so during your  clinic visit. |                                                                 |            |        |         |        |        |        |  
*For Cycle 1 and Cycle 2, Day 1, do not take your morning dose of PLX3397 until you are instructed to do so during your clinic visit. **For Day 2 of Cycle 1 ONLY, do not take your morning dose of PLX3397 until you are instructed to so during your clinic visit.
plx3397 bid - patient drug
study subject id # patient

CC\#12751: Enhancing Efficacy of Chemotherapy in Triple Negative/Basal-Like Breast Cancer by Targeting Macrophages: A Phase Ib/II study of PLX 3397 and Eribulin in Patients with Metastatic Breast Cancer Study Subject ID \#:____________ _______ **Patient Name**: _______________________
Current Assigned dose: ______________________ **Start Date:**__________________
Reminders:
Study medication should be stored at room temperature (Temperature storage range 15-30 oC or 59-86 oF).  
Take your dose of study medication every 12 hours (± 2 hours). If it is after 2 hours from when your dose was due, skip that dose and continue with your next scheduled dose.  
Take your study medication daily for 5 days, followed by 2 days off, then restart each week with the same schedule Fast for at least 1 hour prior to taking the study medication and 1 hour after you take the study medication. You are allowed to have a low-fat, bland snack (crackers, toast, tea, etc.) if needed (if you are feeling nauseous or weak) during this 2 hour period.  
Medication should be taken with at least 8 ounces (1 cup) of room temperature water. Missed doses should be skipped and not taken as a double dose at the next dosing timepoint. If you vomit your dose, you should not make-up that dose or take extra study drug at the next dosing timepoint. If you miss or hold a dose, maintain the 5 days on/2 days off schedule marked on the study calendar.  
Write down the time each dose is taken. Bring your study medication and study diary with you every time you visit the clinic. Contact your study doctor if you have any questions/concerns.  
Patient Signature:  
| Patient Signature:                                                                                     | Were you fasting before  and after to your dose?  (circle one)   | # of       |              |                        |        |        |        |
|--------------------------------------------------------------------------------------------------------|------------------------------------------------------------------|------------|--------------|------------------------|--------|--------|--------|
| capsules  taken                                                                                        | Reason for  missed  dose                                         |            |              |                        |        |        |        |
| Date                                                                                                   |                                                                  |            |              |                        |        |        |        |
| Cycle #                                                                                                | Day                                                              | mm/dd/yyyy | Time of Dose |                        |        |        |        |
| In Cycle 1, you will start taking PLX3397 six to seven days before starting eribulin.  Before:  After: |                                                                  |            |              |                        |        |        |        |
| Cycle 1                                                                                                | Day -7                                                           | :          | AM           | Yes/No                 | Yes/No |        |        |
| Before:                                                                                                | After:                                                           |            |              |                        |        |        |        |
| Cycle 1                                                                                                | Day-7                                                            | /          | /            | :                      | PM     | Yes/No | Yes/No |
| Before:                                                                                                | After:                                                           |            |              |                        |        |        |        |
| Cycle 1                                                                                                | Day-6                                                            | /          | /            | :                      | AM     | Yes/No | Yes/No |
| Before:                                                                                                | After:                                                           |            |              |                        |        |        |        |
| Cycle 1                                                                                                | Day-6                                                            | /          | /            | :                      | PM     | Yes/No | Yes/No |
| Before:                                                                                                | After:                                                           |            |              |                        |        |        |        |
| Cycle 1                                                                                                | Day-5                                                            | /          | /            | :                      | AM     | Yes/No | Yes/No |
| Before:                                                                                                | After:                                                           |            |              |                        |        |        |        |
| Cycle 1                                                                                                | Day-5                                                            | /          | /            | :                      | PM     | Yes/No | Yes/No |
| Before:                                                                                                | After:                                                           |            |              |                        |        |        |        |
| Cycle 1                                                                                                | Day-4                                                            | /          | /            | :                      | AM     | Yes/No | Yes/No |
| Before:                                                                                                | After:                                                           |            |              |                        |        |        |        |
| Cycle 1                                                                                                | Day-4                                                            | /          | /            | :                      | PM     | Yes/No | Yes/No |
| Before:                                                                                                | After:                                                           |            |              |                        |        |        |        |
| Cycle 1                                                                                                | Day-3                                                            | /          | /            | :                      | AM     | Yes/No | Yes/No |
| Before:                                                                                                | After:                                                           |            |              |                        |        |        |        |
| Cycle 1                                                                                                | Day-3                                                            | /          | /            | :                      | PM     | Yes/No | Yes/No |
| DO NOT TAKE                                                                                            |                                                                  |            |              |                        |        |        |        |
| Cycle 1                                                                                                | Day-2                                                            | /          | /            | STUDY DRUG DO NOT TAKE |        |        |        |
| Cycle 1                                                                                                | Day-2                                                            | /          | /            | STUDY DRUG             |        |        |        |  
Page 82 of 85
plx3397 bid - patient drug
study subject id # patient

Study medication should be stored at room temperature (Temperature storage range 15-30 oC or 59-86 oF). Take your dose of study medication every 12 hours (± 2 hours). If it is after 2 hours from when your dose was due, skip that dose and continue with your next scheduled dose.  
Take your study medication daily for 5 days, followed by 2 days off, then restart each week with the same schedule Fast for at least 1 hour prior to taking the study medication and 1 hour after you take the study medication. You are allowed to have a low-fat, bland snack (crackers, toast, tea, etc.) if needed (if you are feeling nauseous or weak) during this 2 hour period.  
Medication should be taken with at least 8 ounces (1 cup) of room temperature water.  
Missed doses should be skipped and not taken as a double dose at the next dosing timepoint. If you vomit your dose, you should not make-up that dose or take extra study drug at the next dosing timepoint. If you miss or hold a dose, maintain the 5 days on/2 days off schedule marked on the study calendar.  
Write down the time each dose is taken. Bring your study medication and study diary with you every time you visit the clinic. Contact your study doctor if you have any questions/concerns.  
Patient Signature:  
| Patient Signature:   | Were you fasting before  and after to your dose?  (circle one)   | # of       |                          |                        |         |        |        |
|----------------------|------------------------------------------------------------------|------------|--------------------------|------------------------|---------|--------|--------|
| capsules  taken      | Reason for  missed  dose                                         |            |                          |                        |         |        |        |
| Date                 |                                                                  |            |                          |                        |         |        |        |
| Cycle #              | Day                                                              | mm/dd/yyyy | Time of Dose DO NOT TAKE |                        |         |        |        |
| Cycle 1              | Day-1                                                            | /          | /                        | STUDY DRUG DO NOT TAKE |         |        |        |
| Cycle 1              | Day-1                                                            | /          | /                        | STUDY DRUG             | Before: | After: |        |
| Cycle __             | Day 1                                                            | /          | /                        | :                      | AM      | Yes/No | Yes/No |
| Before:              | After:                                                           |            |                          |                        |         |        |        |
| Cycle __             | Day 1                                                            | /          | /                        | :                      | PM      | Yes/No | Yes/No |
| Before:              | After:                                                           |            |                          |                        |         |        |        |
| Cycle __             | Day 2                                                            | /          | /                        | :                      | AM      | Yes/No | Yes/No |
| Before:              | After:                                                           |            |                          |                        |         |        |        |
| Cycle __             | Day 2                                                            | /          | /                        | :                      | PM      | Yes/No | Yes/No |
| Before:              | After:                                                           |            |                          |                        |         |        |        |
| Cycle __             | Day 3                                                            | /          | /                        | :                      | AM      | Yes/No | Yes/No |
| Before:              | After:                                                           |            |                          |                        |         |        |        |
| Cycle __             | Day 3                                                            | /          | /                        | :                      | PM      | Yes/No | Yes/No |
| Before:              | After:                                                           |            |                          |                        |         |        |        |
| Cycle __             | Day 4                                                            | /          | /                        | :                      | AM      | Yes/No | Yes/No |
| Before:              | After:                                                           |            |                          |                        |         |        |        |
| Cycle __             | Day 4                                                            | /          | /                        | :                      | PM      | Yes/No | Yes/No |
| Before:              | After:                                                           |            |                          |                        |         |        |        |
| Cycle __             | Day 5                                                            | /          | /                        | :                      | AM      | Yes/No | Yes/No |
| Before:              | After:                                                           |            |                          |                        |         |        |        |
| Cycle __             | Day 5                                                            | /          | /                        | :                      | PM      | Yes/No | Yes/No |
| DO NOT TAKE          |                                                                  |            |                          |                        |         |        |        |
| Cycle __             | Day 6                                                            | /          | /                        | STUDY DRUG DO NOT TAKE |         |        |        |
| Cycle __             | Day 6                                                            | /          | /                        | STUDY DRUG DO NOT TAKE |         |        |        |
| Cycle __             | Day 7                                                            | /          | /                        | STUDY DRUG             |         |        |        |  
Study medication should be stored at room temperature (Temperature storage range 15-30 oC or 59-86 oF). Take your dose of study medication every 12 hours (± 2 hours). If it is after 2 hours from when your dose was due, skip that dose and continue with your next scheduled dose.  
Take your study medication daily for 5 days, followed by 2 days off, then restart each week with the same schedule Fast for at least 1 hour prior to taking the study medication and 1 hour after you take the study medication. You are allowed to have a low-fat, bland snack (crackers, toast, tea, etc.) if needed (if you are feeling nauseous or weak) during this 2 hour period.  
Medication should be taken with at least 8 ounces (1 cup) of room temperature water.  
Missed doses should be skipped and not taken as a double dose at the next dosing timepoint. If you vomit your dose, you should not make-up that dose or take extra study drug at the next dosing timepoint. If you miss or hold a dose, maintain the 5 days on/2 days off schedule marked on the study calendar.  
Write down the time each dose is taken. Bring your study medication and study diary with you every time you visit the clinic. Contact your study doctor if you have any questions/concerns.  
Patient Signature:  
| Patient Signature:   | Were you fasting before  and after to your dose?  (circle one)   | # of       |                          |                        |         |        |        |
|----------------------|------------------------------------------------------------------|------------|--------------------------|------------------------|---------|--------|--------|
| capsules  taken      | Reason for  missed  dose                                         |            |                          |                        |         |        |        |
| Date                 |                                                                  |            |                          |                        |         |        |        |
| Cycle #              | Day                                                              | mm/dd/yyyy | Time of Dose DO NOT TAKE |                        |         |        |        |
| Cycle __             | Day 7                                                            | /          | /                        | STUDY DRUG             | Before: | After: |        |
| Cycle __             | Day 8                                                            | /          | /                        | :                      | AM      | Yes/No | Yes/No |
| Before:              | After:                                                           |            |                          |                        |         |        |        |
| Cycle __             | Day 8                                                            | /          | /                        | :                      | PM      | Yes/No | Yes/No |
| Before:              | After:                                                           |            |                          |                        |         |        |        |
| Cycle __             | Day 9                                                            | /          | /                        | :                      | AM      | Yes/No | Yes/No |
| Before:              | After:                                                           |            |                          |                        |         |        |        |
| Cycle __             | Day 9                                                            | /          | /                        | :                      | PM      | Yes/No | Yes/No |
| Before:              | After:                                                           |            |                          |                        |         |        |        |
| Cycle __             | Day 10                                                           | /          | /                        | :                      | AM      | Yes/No | Yes/No |
| Before:              | After:                                                           |            |                          |                        |         |        |        |
| Cycle __             | Day 10                                                           | /          | /                        | :                      | PM      | Yes/No | Yes/No |
| Before:              | After:                                                           |            |                          |                        |         |        |        |
| Cycle __             | Day 11                                                           | /          | /                        | :                      | AM      | Yes/No | Yes/No |
| Before:              | After:                                                           |            |                          |                        |         |        |        |
| Cycle __             | Day 11                                                           | /          | /                        | :                      | PM      | Yes/No | Yes/No |
| Before:              | After:                                                           |            |                          |                        |         |        |        |
| Cycle __             | Day 12                                                           | /          | /                        | :                      | AM      | Yes/No | Yes/No |
| Before:              | After:                                                           |            |                          |                        |         |        |        |
| Cycle __             | Day 12                                                           | /          | /                        | :                      | PM      | Yes/No | Yes/No |
| DO NOT TAKE          |                                                                  |            |                          |                        |         |        |        |
| Cycle __             | Day 13                                                           | /          | /                        | STUDY DRUG DO NOT TAKE |         |        |        |
| Cycle __             | Day 13                                                           | /          | /                        | STUDY DRUG DO NOT TAKE |         |        |        |
| Cycle __             | Day 14                                                           | /          | /                        | STUDY DRUG DO NOT TAKE |         |        |        |
| Cycle __             | Day 14                                                           | /          | /                        | STUDY DRUG             |         |        |        |
plx3397 bid - patient drug
study subject id # patient

Reminders:
Study medication should be stored at room temperature (Temperature storage range 15-30 oC or 59-86 oF). Take your dose of study medication every 12 hours (± 2 hours). If it is after 2 hours from when your dose was due, skip that dose and continue with your next scheduled dose.  
Take your study medication daily for 5 days, followed by 2 days off, then restart each week with the same schedule Fast for at least 1 hour prior to taking the study medication and 1 hour after you take the study medication. You are allowed to have a low-fat, bland snack (crackers, toast, tea, etc.) if needed (if you are feeling nauseous or weak) during this 2 hour period.  
Medication should be taken with at least 8 ounces (1 cup) of room temperature water.  
Missed doses should be skipped and not taken as a double dose at the next dosing timepoint. If you vomit your dose, you should not make-up that dose or take extra study drug at the next dosing timepoint. If you miss or hold a dose, maintain the 5 days on/2 days off schedule marked on the study calendar.  
Write down the time each dose is taken. Bring your study medication and study diary with you every time you visit the clinic. Contact your study doctor if you have any questions/concerns.  
Patient Signature:  
| Patient Signature:   | Were you fasting before  and after to your dose?  (circle one)   | # of       |              |                        |        |        |        |
|----------------------|------------------------------------------------------------------|------------|--------------|------------------------|--------|--------|--------|
| capsules  taken      | Reason for  missed  dose                                         |            |              |                        |        |        |        |
| Date                 |                                                                  |            |              |                        |        |        |        |
| Cycle #              | Day                                                              | mm/dd/yyyy | Time of Dose | Before:                | After: |        |        |
| Cycle __             | Day 15                                                           | /          | /            | :                      | AM     | Yes/No | Yes/No |
| Before:              | After:                                                           |            |              |                        |        |        |        |
| Cycle __             | Day 15                                                           | /          | /            | :                      | PM     | Yes/No | Yes/No |
| Before:              | After:                                                           |            |              |                        |        |        |        |
| Cycle __             | Day 16                                                           | /          | /            | :                      | AM     | Yes/No | Yes/No |
| Before:              | After:                                                           |            |              |                        |        |        |        |
| Cycle __             | Day 16                                                           | /          | /            | :                      | PM     | Yes/No | Yes/No |
| Before:              | After:                                                           |            |              |                        |        |        |        |
| Cycle __             | Day 17                                                           | /          | /            | :                      | AM     | Yes/No | Yes/No |
| Before:              | After:                                                           |            |              |                        |        |        |        |
| Cycle __             | Day 17                                                           | /          | /            | :                      | PM     | Yes/No | Yes/No |
| Before:              | After:                                                           |            |              |                        |        |        |        |
| Cycle __             | Day 18                                                           | /          | /            | :                      | AM     | Yes/No | Yes/No |
| Before:              | After:                                                           |            |              |                        |        |        |        |
| Cycle __             | Day 18                                                           | /          | /            | :                      | PM     | Yes/No | Yes/No |
| Before:              | After:                                                           |            |              |                        |        |        |        |
| Cycle __             | Day 19                                                           | /          | /            | :                      | AM     | Yes/No | Yes/No |
| Before:              | After:                                                           |            |              |                        |        |        |        |
| Cycle __             | Day 19                                                           | /          | /            | :                      | PM     | Yes/No | Yes/No |
| DO NOT TAKE          |                                                                  |            |              |                        |        |        |        |
| Cycle __             | Day 20                                                           | /          | /            | STUDY DRUG DO NOT TAKE |        |        |        |
| Cycle __             | Day 20                                                           | /          | /            | STUDY DRUG DO NOT TAKE |        |        |        |
| Cycle __             | Day 21                                                           | /          | /            | STUDY DRUG DO NOT TAKE |        |        |        |
| Cycle __             | Day 21                                                           | /          | /            | STUDY DRUG             |        |        |        |