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6.1.5 long term/survival follow-up procedures

The Investigator will withdraw a patient whenever continued participation is no longer in the patient's best interests. Reasons for withdrawing a patient include, but are not limited to, disease progression, the occurrence of an adverse event or a concurrent illness, a patient's request to end participation, a patient's non-compliance or simply significant uncertainty on the part of the Investigator that continued participation is prudent. There may also be administrative reasons to terminate participation, such as concern about a patient's compliance with the prescribed treatment regimen.  
| Table 6.1                                        | Schedule of Study Procedures and Assessments   | End of   |                           |                 |         |         |                 |         |         |    |    |
|--------------------------------------------------|------------------------------------------------|----------|---------------------------|-----------------|---------|---------|-----------------|---------|---------|----|----|
| Period/Procedure                                 | Screeninga                                     | Cycle 1  | Cycle 2 and future Cycles | Treatment visit | Followup visits FU every 3 months (+/- 14d)         |         |                 |         |         |    |    |
| 30d after last dose of study drug                |                                                |          |                           |                 |         |         |                 |         |         |    |    |
| Study Day/Visit Day                              | -28 to 0                                       | 1        | 8                         | 15              | 22      | 29      | 1               | 8       | 15      | 22 | 29 |
| (+/- 3)                                          | (+/- 3)                                        | (+/- 3)  | (+/- 3)                   | (+/- 3)         | (+/- 3) | (+/- 3) | (+/- 3) (+/- 3) | (+/- 3) | (+/- 3) |    |    |
| Informedconsent                                  | X                                              |          |                           |                 |         |         |                 |         |         |    |    |
| Baselineconditionsb                              | X                                              |          |                           |                 |         |         |                 |         |         |    |    |
| AEassessment                                     | X                                              | X        | X                         | X               | X       | X       |                 |         |         |    |    |
| Concomitant medications                          | X                                              | X        | X                         | X               | X       | X       | X               |         |         |    |    |
| Blood collection for biomarkers                  | X                                              | X        | X                         | X               | X       | X       |                 |         |         |    |    |
| Required Research Biopsy)c                       | X                                              |          |                           |                 |         |         |                 |         |         |    |    |
| OptionalResearch                                 | X +/- 7d (C2only)                              | X        |                           |                 |         |         |                 |         |         |    |    |
| Biopsy Treatment/Drug Administration Trametinibd | X                                              | X        | X                         | X               |         |         |                 |         |         |    |    |
| Clinicalprocedures Physical exam                 | X                                              | X        | X                         | X               | X       |         |                 |         |         |    |    |
| Vital signs                                      | X                                              | X        | X                         | X               | X       |         |                 |         |         |    |    |
| Medicalhistorye                                  | X                                              | X        | X                         | X               |         |         |                 |         |         |    |    |
| Diseaseassessmentf                               | X                                              | X        | X                         | X               |         |         |                 |         |         |    |    |
| Performancestatus                                | X                                              | X        | X                         | X               | X       |         |                 |         |         |    |    |
| Laboratory proceduresg CBC w/ Diff               | X                                              | X        | X                         | X               | X       |         |                 |         |         |    |    |
| Bloodchemistry                                   | X                                              | X        | X                         | X               | X       |         |                 |         |         |    |    |  
| End of                                  |                                                                                                                                        |         |                           |                 |         |         |         |         |         |         |    |
|-----------------------------------------|----------------------------------------------------------------------------------------------------------------------------------------|---------|---------------------------|-----------------|---------|---------|---------|---------|---------|---------|----|
| Period/Procedure                        | Screeninga                                                                                                                             | Cycle 1 | Cycle 2 and future Cycles | Treatment visit | Followup visits FU every 3 months (+/- 14d)         |         |         |         |         |         |    |
| 30d after last dose of study drug       |                                                                                                                                        |         |                           |                 |         |         |         |         |         |         |    |
| Study Day/Visit Day                     | -28 to 0                                                                                                                               | 1       | 8                         | 15              | 22      | 29      | 1       | 8       | 15      | 22      | 29 |
| (+/- 3)                                 | (+/- 3)                                                                                                                                | (+/- 3) | (+/- 3)                   | (+/- 3)         | (+/- 3) | (+/- 3) | (+/- 3) | (+/- 3) | (+/- 3) | (+/- 3) |    |
| Coagulation                             | X                                                                                                                                      | X       | X                         | X               | X       |         |         |         |         |         |    |
| Urinalysis                              | X                                                                                                                                      | X       | X                         | X               |         |         |         |         |         |         |    |
| Pregnancy test (HCG)                    | X                                                                                                                                      | X       | X                         |                 |         |         |         |         |         |         |    |
| Imagingprocedureh Imaging (CT or MRI) h | X                                                                                                                                      | X       | X                         | X               |         |         |         |         |         |         |    |
| CardiacAssessment (ECHO,MUGA)           | X                                                                                                                                      | X       |                           |                 |         |         |         |         |         |         |    |
| ECG/EKG (in triplicate)                 | X                                                                                                                                      | X       | X                         | X               |         |         |         |         |         |         |    |
| OphthalmologyExam                       | X                                                                                                                                      | X       |                           |                 |         |         |         |         |         |         |    |
| a.                                      | Screening procedures and assessments must be completed -28d of Day 1 visit. Screening labs completed within 3 days of C1D1 need not be |         |                           |                 |         |         |         |         |         |         |    |  
a. Screening procedures and assessments must be completed -28d of Day 1 visit. Screening labs completed within 3 days of C1D1 need not be repeated.  
b. Baseline conditions include all ongoing medical conditions at time of consent.  
c. Archival tissue **collection** and research biopsy during screening and for exploratory biomarker assessments. Biopsy will be CT guided (or via bronchoscopy if unable to obtain) unless deemed medically unsafe.  
Optional tumor **biopsy**: for exploratory analyses, best response and resistance (C2D1 +/- 7d and at end of treatment visit).  
d. Trametinib will be taken with a full glass of water, without food, at least 1 hour before or 2 hours after a meal, 2mg, once a day. See section 5.0 Table 5.1 for treatment regimen details. Safety assessments (AE assessments and concomitant medication check) to be completed during clinic visits.  
e. Medical history documentation of past conditions or procedures that have been resolved.  
f. Disease assessment documentation at screening (presence of measurable disease) and on trial includes restaging (per RECIST), which will occur q2 cycles beginning cycle \#3. During Follow-up visits, scans would only be completed in follow-up for patients whose disease has not yet progressed since entering the study g. Blood chemistry **labs**: alkaline phosphatase, ALT/AST, total bilirubin, calcium, phosphorus, (BUN), creatinine, total protein, albumin, fasting glucose, potassium, sodium, chloride, bicarbonate  
Coagulation **labs**: PT/PTT/INR
Serum or urine pregnancy test must be negative within 3 days prior to start of C1D1.  
h. Imaging **exams**: if known lesions, brain imaging every other cycle starting with cycle \#3.  
Cardiac **assessments** to be completed every 3 months after cycle \#2.  
Ophthalmology **exams** to be completed prior to cycle 2 day 1, again at 6 months, and then annually thereafter unless clinically indicated sooner.
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6.2 usage of concurrent/concomitant medications

No formal drug interaction studies have been conducted with trametinib. There is a low likelihood of drug-drug interactions with trametinib.  
Trametinib has a high passive permeability and is eliminated primary via deacetylation, which is mediated by hydrolytic enzymes that are generally not associated with drug interaction risks. It is also not an in vitro substrate for human Pgp, BCRP, MRP2 and MATE1. In addition, due to trametinib's low efficacious dose and low systemic maximal concentration (22 ng/mL or 0.04 μM) relative to its in vitro CYP inhibition/induction potency. Therefore, the risk of a drug-drug interaction by trametinib as both perpetrator or as a victim is low. See also Section 4.3.6 for detailed discussion.
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6.3 dietary restrictions

Trametinib should be taken with a full glass of water, without food, at least 1 hour before or 2 hours after a meal. If a dose of trametinib is missed, the dose can be taken if it is more than 12 hours until the next scheduled dose.  
Administration of a single dose of trametinib with a high-fat, high-calorie meal resulted in a 70%, 24%, and 10% decrease in Cmax, AUC(0-t), and AUC(0-∞), respectively compared to fasted conditions.
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6.4 prohibited medications

All treatments that the investigator considers necessary for a subject's welfare may be administered at the discretion of the investigator in keeping with the community standards of medical care. Palliative and supportive care is permitted during the course of the trial for underlying medical conditions and management of symptoms. Surgery or radiotherapy for tumor controls not permitted during the study; however, radiotherapy or procedures for symptom management is allowed. Subjects are prohibited from receiving antineoplastic systemic chemotherapy or biological therapy not specified in this protocol.  
Bisphosphonates or denosumab are allowed for patients with bone metastases.  
Growth factor support may be considered for patients with neutropenia after discussion with the study PI.  
Avoid concurrent use of strong CYP3A inhibitors during treatment.  
Medications known to produce QT prolongation should be avoided during treatment of patients with and trametinib. See http://crediblemeds.org/ for the most up-to-date reference lists of QT-prolonging medications. Please note that the lists contain common supportive medications, such as anti-emetics (ondansetron [and other 5HT3 antagonists], metoclopramide, hydroxyzine), antibiotics (azithromycin, ciprofloxacin, metronidazole) and anti-depressants
(escitalopram).  
Medications to consider for nausea that are not associated with QT prolongation include:  
- Steroids (dexamethasone, methylprednisolone) - Benzodiazepines - Aprepitant - Select anticholinergic agents (scopolamine) - Trimethobenzamide - Cannabinoids 7 Reporting and Documentation of **Results**
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7.1 evaluation of efficacy (or

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

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

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

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

All measurable lesions up to a maximum of 5 lesions total (and a maximum of two lesions per organ) representative of all involved organs should be identified as target lesions and recorded and measured at baseline. Target lesions will be selected on the basis of their size (lesions with the longest diameter) and their suitability for accurate repeated measurements (either by imaging techniques or clinically). A sum of the longest diameter (LD) for all target lesions will be calculated and reported as the baseline sum LD. The baseline sum LD will be used as reference by which to characterize the objective tumor response.
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non-target lesions

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

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

All measurements will be taken and recorded in metric notation using a ruler or calipers. All baseline evaluations will be performed as closely as possible to the beginning of treatment and never more than 28 days before the beginning of the treatment. The same method of assessment and the same technique will be used to characterize each identified and reported lesion at baseline and during follow-up. Imaging-based evaluation is preferred to evaluation by clinical examination when both methods have been used to assess the antitumor effect of a treatment.
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conventional ct and mri

Spiral CT scans should be performed using a 5 mm contiguous reconstruction algorithm.
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7.1.1.3 response criteria evaluation of

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

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

At least a 20% increase in the sum of the SLD of target lesions, taking as reference the smallest sum SLD recorded since the treatment started and minimum 5 mm increase over the nadir, or the appearance of one or more new lesions.
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stable disease (sd)

Neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD, taking as reference the smallest sum LD since the treatment started.
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evaluation of non-target lesions complete

Disappearance of all non-target lesions and normalization of tumor marker level. All lymph nodes must be non-pathological in size (< 10 mm short axis).
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incomplete response/stable disease (sd)

Persistence of one or more non-target lesion(s) and/or maintenance of tumor marker level above the normal limits.
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progressive disease (pd)

Appearance of one or more new lesions and/or unequivocal progression of existing non-target lesions.
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evaluation of best overall response

The best overall response is the best response recorded from the start of the treatment until disease progression/recurrence (taking as reference for progressive disease the smallest measurements recorded since the treatment started). The patient's best response assignment will depend on the achievement of both measurement and confirmation criteria.
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table 7.1 response criteria

Target Lesions Non-Target Lesions New Lesions Overall Response Best Response forthis **Category** Also **Requires**  
| CR                                                                                                       | CR                    | No                      | CR   | > 4 weeks confirmation                           |
|----------------------------------------------------------------------------------------------------------|-----------------------|-------------------------|------|--------------------------------------------------|
| CR                                                                                                       | Non-CR/ Non-PD Non-PD | No                      | PR   | > 4 weeks confirmation                           |
| PR                                                                                                       |                       |                         |      |                                                  |
| PR                                                                                                       | No                    |                         |      |                                                  |
| SD                                                                                                       | Non-PD                | No                      | SD   | documented at least once > 4 weeks from baseline |
| PD Any Any                                                                                               | Any                   | Yes or No Yes or No Yes | PD   |                                                  |
| PD* Any                                                                                                  | PD                    | no prior SD, PR or CR   |      |                                                  |
| PD                                                                                                       |                       |                         |      |                                                  |
| * In exceptional circumstances, unequivocal progression in non-target lesions may be accepted as disease |                       |                         |      |                                                  |  
* In exceptional circumstances, unequivocal progression in non-target lesions may be accepted as disease progression
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duration of response duration of

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

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

Progression-free survival (PFS) is defined as the duration of time from start of treatment to time of progression.
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7.2 evaluation of safety

Analyses will be performed for all patients having received at least one dose of study drug. The study will use the CTCAE v4.03 for reporting of non-hematologic adverse events and modified criteria for hematologic adverse events, For multicenter studies, the Principal Investigator at the UCSF Coordinating Center will hold the role of Study Chair. The Study Chair is responsible for the overall conduct of the study and for monitoring its safety and progress at all participating sites.
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7.3 definitions of adverse events

An adverse event (also known as an adverse experience) is defined as any untoward medical occurrence associated with the use of a drug in humans, whether or not considered 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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7.3.2 adverse reaction

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

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

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

An adverse event or suspected adverse reaction is considered *serious* if, in the view of either the investigator- 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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7.3.2.4 life-threatening

An adverse event or suspected adverse reaction is considered *life-threatening* if, in the view of either the investigator- 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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7.4 recording of an adverse

All grade 3 and above adverse events will be entered into OnCore®, whether or not the event is believed to be associated with use of the study drug. Data about these events and their severity will be recorded using the NCI CTCAE v4.03.  
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 The AE is clearly NOT related to the   |
|----------------------------------------------|--------------------------------------------------|----------------------------------------------------|
| Unrelated to investigational                 | Unrelated                                        | intervention                                       |
| drug/intervention                            | 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     |                                                    |
| Definite                                     | The AE is clearly related to the intervention    |                                                    |
| Unlikely                                     |                                                  |                                                    |
| Related to investigational drug/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 selfcare ADL
Grade 4: Life-threatening consequences; urgent intervention indicated Grade 5: Death related to AE
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7.5 follow-up of adverse events

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

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

If a death occurs during the treatment phase of the study or within 30 days after the last administration of the study drug(s) and it is determined to be related either to the study drug(s) or to a study procedure, the Investigator or his/her designee must notify the DSMC Chair (or qualified alternate) within 1 business day of knowledge of the event. The contact may be by phone or e-mail.
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reporting to ucsf committee on

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

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

To ensure patient safety, every SAE, regardless of suspected causality, occurring after the patient has provided the main informed consent and until at least 30 days after the patient has stopped study treatment must be reported to Novartis within 24 hours of learning of its occurrence. Any SAEs experienced after this 30 days period should only be reported to Novartis if the investigator suspects a causal relationship to the study treatment. Recurrent episodes, complications, or progression of the initial SAE must be reported as follow-up to the original episode within 24 hours of the investigator receiving the follow-up information. An SAE occurring at a different time interval or otherwise considered completely unrelated to a previously reported one should be reported separately as a new event.  
Information about all SAEs is collected and recorded on the Serious Adverse Event Report Form; all applicable sections of the form must be completed in order to provide a clinically thorough report. The investigator must assess and record the relationship of each SAE to each specific study treatment (if there is more than one study treatment), complete the SAE Report Form in English, and send the completed, signed form by fax within 24 hours to the oncology Novartis Drug Safety and Epidemiology (DS&E) department - Fax: (877-778-9739). The original copy of the SAE Report Form and the fax confirmation sheet must be kept with the case report form documentation at the study site. Follow-up information is sent to the same contact(s) to whom the original SAE Report Form was sent, using a new SAE Report Form stating that this is a follow-up to the previously reported SAE and giving the date of the original report. Each re-occurrence, complication, or progression of the original event should be reported as a follow-up to that event regardless of when it occurs. The follow-up information should describe whether the event has resolved or continues, if and how it was treated, whether the blind was broken or not, and whether the patient continued or withdrew from study participation.  
If the SAE is not previously documented in the Investigator's Brochure or Package Insert (new occurrence) and is thought to be related to the Novartis study treatment, an oncology Novartis Drug Safety and Epidemiology (DS&E) department associate may urgently require further information from the investigator for Health Authority reporting. Novartis may need to issue an Investigator Notification (IN), to inform all investigators involved in any study with the same drug that this SAE has been reported. Suspected Unexpected Serious Adverse Reactions (SUSARs) will be collected and reported to the competent authorities and relevant ethics committees in accordance with Directive 2001/20/EC or as per national regulatory requirements in participating countries.  
Pregnancies To ensure patient safety, each pregnancy occurring while the patient is on study treatment must be reported to Novartis within 24 hours of learning of its occurrence. The pregnancy should be followed up to determine outcome, including spontaneous or voluntary termination, details of the birth, and the presence or absence of any birth defects, congenital abnormalities, or maternal and/or newborn complications.  
Pregnancy should be recorded on a Clinical Trial Pregnancy Form and reported by the investigator to the oncology Novartis Drug Safety and Epidemiology Department (DS&E). Pregnancy follow-up should be recorded on the same form and should include an assessment of the possible relationship to the study treatment any pregnancy outcome. Any SAE
experienced during pregnancy must be reported on the SAE Report Form.  
Warnings and precautions Additional safety information collected between IB updates will be communicated in the form of Investigator Notifications. This information will be included in the patient informed consent and should be discussed with the patient during the study as needed
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8 statistical considerations and evaluation

See Section 2.4 for study endpoints. This is a Phase II, open-label, multicenter clinical trial evaluating the efficacy and safety of trametinib monotherapy in patients with advanced non-squamous NSCLC whose tumors harbor a non-synonymous NF1 mutation and are wildtype for KRAS. Patients will receive trametinib monotherapy in 28 day cycles.
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8.1.1 randomization

This is a single-arm, open-label phase II study without any randomization.
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8.1.2 unblinding subjects

Study is open-label so unblinding subjects is not applicable.  
8.1.3
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8.2 determination of sample size

The primary endpoint is objective response rate (ORR). To provide 80% power to detect a 30% ORR compared to the null hypothesis of a 10% ORR in each cohort, 27 patients will be enrolled, with the goal of obtaining 24 evaluable patients. Using a Simon 2-stage design, if we do not observe at least 2 responses within the first 15 patients, enrollment will be stopped due to lack of efficacy. The primary efficacy analysis will be based on one-sided exact binomial test comparison of the observed ORR in patients receiving at least one dose of study treatment to the nullhypothesized value of 10%, using the 5% significance level. Secondary time-to-event endpoints
(DR, PFS and OS) will be summarized using Kaplan-Meier estimates with associated 95%
confidence limits. The secondary DCR endpoint will be summarized as a proportion with an exact binomial 95% confidence interval. Safety analyses will be descriptive summaries of AEs by patient and type.
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8.2.2 replacement policy

All patients who receive a dose of trametinib will be analyzed for safety and efficacy. Subjects who discontinue from study participation prior to receiving any dose of study therapy may be replaced after discussion with the Principal Investigator. Patients removed from study for unacceptable treatment related adverse event(s) will be followed until resolution or stabilization of all treatment related AEs to grade 2 or lower; however, they will not be replaced.
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8.2.3 accrual estimates

At UCSF, UC Davis, and UC San Diego we see > 200 patients per month with advanced NSCLC, 80% of whom have non-squamous histology. Based on The Cancer Genome Atlas
(TCGA) Research Network studies described in Section 1.1, we predict that about,11% of lung adenocarcinomas will harbor *NF1* mutations.17 Conservatively, we expect that 10 patients per month will harbor one of these mutations and that 1-2 patients per month will be eligible and will consent to participate in the study. Interim Analyses and Stopping Rules Using a Simon 2-stage design, if we do not observe at least 2 responses within the first 15 patients in a given cohort, enrollment to that arm would be stopped due to lack of efficacy.
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8.3 analyses plans 8.3.1 analysis

All patients who receive a dose of trametinib will be analyzed for safety and efficacy. Subjects who discontinue from study participation prior to receiving any dose of study therapy may be replaced after discussion with the investigator sponsor. Subjects who have received any dose of study therapy will not be replaced. Demographic and baseline characteristics will be summarized by each cohort and overall. In general, frequency distribution and percentage will be used to summarize categorical measurements, while mean with standard deviation and median with interquartile range will be used to describe symmetric and skewed continuous measurements, respectively. Univariate analysis among variables will be assessed using the two-sample t-test, Wilcoxon-rank-sum test, Chi-square test, as appropriate.
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8.3.2 primary analysis (or analysis

The ORR is defined as the best overall response recorded from the start of the treatment until disease progression or recurrence as assessed over a 1-year period from the start of treatment. The frequency and percentages of patients with a best overall response rate of complete response (CR), partial response (PR), stable disease (SD), or progressive disease (PD) will be determined. We will test the hypothesis that the ORR is greater than the null hypothesis of 10% using the Fisher's exact test.  
8.3.3
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secondary analysis (or analysis of

(a) Duration of response **(DR):** The DR for CR and PR will be measured from the date that the best response if first recorded until the date that PD is documented over the period of 1 year. For patients who continue treatment post progression, the date of PD documentation will be used for analysis. The DR will be summarized using descriptive statistics (N, mean, standard deviation, minimum, and maximum).  
(b) Disease control rate **(DCR):** DCR will be defined as the percentage of patients who have achieved CR, PR, or SD for at least 12 weeks. The DCR will be summarized using descriptive statistics (N, mean, standard deviation, minimum, and maximum).  
(c) Progression-free Survival **(PFS):** PFS will be calculated as 1+ the number of days from the first dose of study drugs to documented radiographic progression or death due to any cause over a period of 1 year. For patients who continue treatment post-progression, the date of radiographic progression will be used for PFS analysis. The Kaplan-Meier analysis will be used to calculate the median PFS with 95% confidence interval.  
(d) Overall Survival **(OS):** OS will be calculated as 1+ the number of days from the first dose of study drugs to death due to any cause over a period of 1 year. The Kaplan-Meier analysis will be used to calculate the median OS with 95% confidence interval.  
(3) Definition and analytical plan for safety and tolerability **endpoints:** The safety population will consist of all subjects who receive any amount of study treatment. Safety will be assessed by evaluation of AEs. All safety analyses will be performed using the safety population. Adverse event terms recorded on the CRFs will be mapped to preferred terms using the Medical Dictionary for Regulatory Activities (MedDRA). Seriousness, severity grade and relationship to study treatment will be assessed by the investigator. Severity grade will be defined by the National Cancer Institute (NCI) CTCAE v4.03. Listings of AEs will be provided.  
Separate tables will present the following by dose group and study phase:  
- All treatment-emergent AEs
- Treatment-emergent AEs by CTCAE grade
- Grade 3 or greater treatment-emergent AEs - Treatment-related, treatment-emergent AEs - Dose-limiting toxicity AEs - Serious treatment-emergent AEs
- Treatment-emergent AEs with an outcome of death
- Treatment-emergent AEs leading to discontinuation of trametinib.  
- Treatment-emergent AEs resulting in interruption or reduction or delay of trametinib.
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8.3.4 other analyses/assessments

Exploratory **Analysis:** Understanding the mechanisms of response and resistance to trametinib therapy will be critical to identifying patients who may preferentially benefit the most from this therapy. We propose to investigate this by:
(a) Assess pre-treatment, at time of first scan to assess response, trametinib resistant tumors V(i en rso iop nti do an ta e:l 0b 2i
-o 1p 5s
-2y 01s 8pecimens) for evidence MAPK pathway activation. IHC wiPll rboteocpoelrCfCor
\#m: 1e6d*6521* to assess ERK1/2 phosphorylation. Phosphorylation will be scored in a continuous manner, and difference in phosphorylation between pre-treatment, best response, and post-resistant specimens will be determined by a two-tailed T-test.  
(b) We will use whole exome and transcriptome deep sequencing (WES; RNAseq) in the pretreatment, at time of first scan to assess response (optional), and post- progression (optional)
tumor biopsy samples to uncover somatic genetic alterations (mutations and copy number alterations) and transcriptional events associated with clinical resistance (either de novo or acquired), with a minimum depth of WES coverage of 100X to capture events occurring down to ~10% frequency. We will use tumor microdissection to maximize tumor purity and peripheral leukocytes as normal/germline controls, with appropriate standard correction of the genetic findings for cancer cell fraction. This unbiased analysis is warranted to ensure we capture resistance events that are anticipated (e.g. secondary BRAF or MEK pathway mutations or ERK1/2 upregulation, or HIPPO-YAP pathway upregulation32,35 and unexpected and coordinated changes (e.g. genomic amplification + concordant RNA overexpression of a resistance gene). This approach will enable identification and/or validation of RNA signatures of potential resistance events (such as ERK1/2 transcriptional output). The analysis of samples from patients with de novo resistance and of matched paired tumor samples acquired from individual patients before treatment and at acquired resistance will be prioritized for study to facilitate the clinical correlation of the genetic findings with bona fide clinical resistance. For instance, we may find that genetic mutation/amplification or transcriptional upregulation of ERK1/2 is present in tumors from patients with de novo or acquired trametinib resistance. All statistical and genomic analyses will be done with custom scripts and extensively developed pipelines in the R statistical computing framework ). Descriptive statistics and graphical methods will be used to analyze the data. Orthogonal validation of specific findings will be done using individualized assays in the clinical specimens (e.g. direct sequencing, SNP arrays, fluorescence in situ hybridization for DNA alterations; q-RT-PCR, IHC for RNA and protein abundance changes) and associated circulating free DNA, where feasible.  
(c) When possible, we will generate patient-derived organoids and/or patient-derived xenografts from biopsy specimens from patients that participate in the trial in order to fully interrogate pathways of response and resistance in a highly clinically relevant system. We will use these models to perform pre-clinical trials aimed at overcoming mechanisms of resistance with rationally designed polytherapy.  
(d) Circulating cell free DNA (cfDNA) will be assessed for biomarkers of resistance that are identified above. Descriptive statistics and graphical methods will be used to analyze the data.
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8.4 evaluation of safety

Analyses will be performed for all patients having received at least one dose of study drug. The frequencies of individual toxicities thought to be probably, possible, or definitely related to study drug will be reported as well as the incidence of any grade 3, 4, and 5 toxicities regardless of attribution. Analyses will be performed for all patients having received at least one dose of study drug. The study will use the NCI CTCAE v4.03.
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9 study management 9.1 pre-study

This study will be conducted in accordance with the ethical principles that have their origin in the Declaration of Helsinki as stated in 21 CFR §312.120(c)(4); consistent with GCP and all applicable regulatory requirements.  
Before initiating this trial, the Investigator will have written and dated approval from the Institutional Review Board for the protocol, written informed consent form, subject recruitment materials, and any other written information to be provided to subjects before any protocol related procedures are performed on any subjects.  
The clinical investigation will not begin until either FDA has determined that the study under the Investigational Drug Application (IND) is allowed to proceed or the Investigator has received a letter from FDA stating that the study is exempt from IND requirements.  
The Investigator must comply with the applicable regulations in Title 21 of the Code of Federal Regulations (21 CFR §50, §54, and §312), GCP/ICH guidelines, and all applicable regulatory requirements. The IRB must comply with the regulations in 21 CFR §56 and applicable regulatory requirements.
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9.2 institutional review board approval

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

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

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

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

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

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

The UCSF Coordinating Center provides administration, data management, and organizational support for the participating sites in the conduct of a multicenter clinical trial. The UCSF Coordinating Center for Phase II studies will also coordinate, at minimum, monthly conference calls with the participating sites at the completion of each cohort or more frequently as needed to discuss risk assessment. The following issues will be discussed as appropriate: Enrollment information
- Adverse events (i.e., new adverse events and updates on unresolved adverse events and new safety information)
- Protocol violations - Other issues affecting the conduct of the study Record Keeping and Record Retention 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, IRB correspondence and approval, signed patient consent forms). Source documents include all recordings of observations or notations of clinical activities and all reports and records necessary for the evaluation and reconstruction of the clinical research study.  
In accordance with FDA regulations, the investigator shall retain records for a period of 2 years following the date a marketing application is approved for the drug for the indication for which it is being investigated; or, if no application is to be filed or if the application is not approved for such indication, until 2 years after the investigation is discontinued and FDA is notified.
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9.9 coordinating center documentation of

It is the responsibility of the Study Chair to maintain adequate files documenting the distribution of study documents as well as their receipt (when possible). The HDFCCC recommends that the Study Chair maintain a correspondence file and log for each segment of distribution (e.g., FDA, drug manufacturer, participating sites, etc.).  
Correspondence file: should contain copies (paper or electronic) of all protocol versions, cover letters, amendment outlines (summary of changes), etc., along with distribution documentation and (when available) documentation of receipt.  
Correspondence log: should be a brief list of all documents distributed including the date sent, recipient(s), and (if available) a tracking number and date received. At a minimum, the Study Chair must keep documentation of when and to whom the protocol, its updates and safety information are distributed.
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9.10 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 Institutional Review Board (IRB). Prior to implementing this protocol at the participating sites, approval for the UCSF IRB 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
- Curriculum vitae and medical license for each investigator and consenting professional
- Documentation of Human Subject Research Certification training for investigators and key staff members at the Participating Site
- Participating site laboratory certifications and normals Upon receipt of the required documents, UCSF HDFCCC will formally contact the site and grant permission to proceed with enrollment.
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10 protection of human subjects

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

Patients will be informed of the extent to which their confidential health information generated from this study may be used for research purposes. Following this discussion, they will be asked to sign the HIPAA form and informed consent documents. The original signed document will become part of the patient's medical records, and each patient will receive a copy of the signed document. The use and disclosure of protected health information will be limited to the individuals described in the informed consent document. References 1. Cancer Genome Atlas Research Network: Comprehensive molecular profiling of lung adenocarcinoma. Nature 511:543-50, 2014 2. Davies H, Bignell GR, Cox C, et al: Mutations of the BRAF gene in human cancer. Nature 417:949-54, 2002 3. Comprehensive molecular profiling of lung adenocarcinoma. Nature 511:543-50, 2014 4. Chapman PB, Hauschild A, Robert C, et al: Improved survival with vemurafenib in melanoma with BRAF V600E mutation. N Engl J Med 364:2507-16, 2011 5. Pratilas CA, Hanrahan AJ, Halilovic E, et al: Genetic predictors of MEK
dependence in non-small cell lung cancer. Cancer Res 68:9375-83, 2008 6. Trejo CL, Juan J, Vicent S, et al: MEK1/2 inhibition elicits regression of autochthonous lung tumors induced by KRASG12D or BRAFV600E. Cancer Res 72:3048-59, 2012 7. Xu GF, O'Connell P, Viskochil D, et al: The neurofibromatosis type 1 gene encodes a protein related to GAP. Cell 62:599-608, 1990 8. Xu GF, Lin B, Tanaka K, et al: The catalytic domain of the neurofibromatosis type 1 gene product stimulates ras GTPase and complements ira mutants of S. cerevisiae. Cell 63:835-41, 1990 9. Martin GA, Viskochil D, Bollag G, et al: The GAP-related domain of the neurofibromatosis type 1 gene product interacts with ras p21. Cell 63:843-9, 1990 10. Patil S, Chamberlain RS: Neoplasms associated with germline and somatic NF1 gene mutations. Oncologist 17:101-16, 2012 11. Imielinski M, Berger AH, Hammerman PS, et al: Mapping the hallmarks of lung adenocarcinoma with massively parallel sequencing. Cell 150:1107-20, 2012 12. Nissan MH, Pratilas CA, Jones AM, et al: Loss of NF1 in cutaneous melanoma is associated with RAS activation and MEK dependence. Cancer Res 74:2340-50, 2014 13. Verhaak RG, Hoadley KA, Purdom E, et al: Integrated Genomic Analysis Identifies Clinically Relevant Subtypes of Glioblastoma Characterized by Abnormalities in PDGFRA, IDH1, EGFR, and NF1. Cancer Cell 17:98-110, 2010 14. Side LE, Emanuel PD, Taylor B, et al: Mutations of the NF1 gene in children with juvenile myelomonocytic leukemia without clinical evidence of neurofibromatosis, type 1. Blood 92:267-72, 1998 15. Chang T, Krisman K, Theobald EH, et al: Sustained MEK inhibition abrogates myeloproliferative disease in Nf1 mutant mice. J Clin Invest 123:335-9, 2013 16. Falchook GS, Lewis KD, Infante JR, et al: Activity of the oral MEK inhibitor trametinib in patients with advanced melanoma: a phase 1 dose-escalation trial. Lancet Oncol 13:782-9, 2012 17. Cancer Genome Atlas Research N: Comprehensive molecular profiling of lung adenocarcinoma. Nature 511:543-50, 2014 18. Redig AJ, Capelletti M, Dahlberg SE, et al: Clinical and Molecular Characteristics of NF1-Mutant Lung Cancer. Clin Cancer Res 22:3148-56, 2016 19. Shannon KM, O'Connell P, Martin GA, et al: Loss of the normal NF1 allele from the bone marrow of children with type 1 neurofibromatosis and malignant myeloid disorders. N Engl J Med 330:597-601, 1994 20. Bollag G, Clapp DW, Shih S, et al: Loss of NF1 results in activation of the Ras signaling pathway and leads to aberrant growth in haematopoietic cells. Nat Genet 12:144-8, 1996 21. Ingram DA, Yang FC, Travers JB, et al: Genetic and biochemical evidence that haploinsufficiency of the Nf1 tumor suppressor gene modulates melanocyte and mast cell fates in vivo. J Exp Med 191:181-8, 2000 22. McGillicuddy LT, Fromm JA, Hollstein PE, et al: Proteasomal and genetic inactivation of the NF1 tumor suppressor in gliomagenesis. Cancer Cell 16:44-54, 2009 23. Malone CF, Fromm JA, Maertens O, et al: Defining key signaling nodes and therapeutic biomarkers in NF1-mutant cancers. Cancer Discov 4:1062-73, 2014 24. Kris MG, Johnson BE, Berry LD, et al: Using multiplexed assays of oncogenic drivers in lung cancers to select targeted drugs. JAMA 311:1998-2006, 2014 25. Comprehensive genomic characterization of squamous cell lung cancers. Nature 489:519-25, 2012 26. Stieger B: Role of the bile salt export pump, BSEP, in acquired forms of cholestasis. Drug Metab Rev 42:437-45, 2010 27. Hillgren KM, Keppler D, Zur AA, et al: Emerging transporters of clinical importance: an update from the International Transporter Consortium. Clin Pharmacol Ther 94:52-63, 2013 28. Hotta K, Fujiwara Y, Kiura K, et al: Relationship between response and survival in more than 50,000 patients with advanced non-small cell lung cancer treated with systemic chemotherapy in 143 phase III trials. J Thorac Oncol 2:402-7, 2007 29. Wan PT, Garnett MJ, Roe SM, et al: Mechanism of activation of the RAF-ERK
signaling pathway by oncogenic mutations of B-RAF. Cell 116:855-67, 2004 30. Andreadi C, Cheung LK, Giblett S, et al: The intermediate-activity (L597V)BRAF
mutant acts as an epistatic modifier of oncogenic RAS by enhancing signaling through the RAF/MEK/ERK pathway. Genes Dev 26:1945-58, 2012 31. Chang T, Krisman K, Theobald EH, et al: Sustained MEK inhibition abrogates myeloproliferative disease in Nf1 mutant mice. J Clin Invest 126:404, 2016 32. Lin L, Sabnis AJ, Chan E, et al: The Hippo effector YAP promotes resistance to RAF- and MEK-targeted cancer therapies. Nat Genet, 2015 33. Balagula Y, Barth Huston K, Busam KJ, et al: Dermatologic side effects associated with the MEK 1/2 inhibitor selumetinib (AZD6244, ARRY-142886). Invest New Drugs 29:1114-21, 2011 34. Lacouture ME, Anadkat MJ, Bensadoun RJ, et al: Clinical practice guidelines for the prevention and treatment of EGFR inhibitor-associated dermatologic toxicities. Support Care Cancer 19:1079-95, 2011 35. Lin L, Asthana S, Chan E, et al: Mapping the molecular determinants of BRAF
oncogene dependence in human lung cancer. Proc Natl Acad Sci U S A 111:E748-57, 2014
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appendices appendix 1 qt interval

Bazett's formula used to correct QT interval for heart rate is:
QTcB QT
RR
where QTcB is the QT interval corrected for heart rate, RR is the interval from the onset of one QRS complex to the onset of the next QRS complex, measured in seconds, often derived from the heart rate (HR) as 60/HR, and QT is the QT interval measured in milliseconds. Reference Bazett HC. An analysis of the time-relations of electrocardiograms. Heart 1920; 7: 353-370.
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appendix 2 performance status criteria

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

This policy defines the required Regulatory Documents for Single Site and Multicenter Investigator Initiated Oncology Clinical Trials at the Helen Diller Family Comprehensive Cancer Center (HDFCCC) for both IND and IND-exempt trials.
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background

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

- Current and prior versions of the Informed Consent Form(s) (ICFs).  
- IRB approvals for initial submission of application, all modifications, and continuing annual renewals.  
- Current and prior approved protocol versions.  
- Current IRB roster - Current and prior versions of the Investigator Brochure (IB).  
- Serious Adverse Event (SAE) Reports. - Subject diary and handouts (if applicable).  
- Single Patient Exception (SPE) Report(s) to the IRB with Approval Letter(s) from IRB.  
- Protocol Violation (PV) Reports with acknowledgement from the IRB.
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documents filed in oncore

- Package Insert (if the study drug is commercial). - Protocol signature page(s) with Pl signature(s) for all protocol versions.  
- Protocol Review Committee (PRC) approved protocols, protocol amendments and Summary of Changes (SOC) document.  
- Screening/enrollment log.  
- Data and Safety Monitoring Committee (DSMC) monitoring reports. - DSMC dose escalation approvals with study status summary forms.  
- Case Report Form (CRF) completion manual.  
- Drug Destruction Standard Operating Procedure (SOP).  
- Completed Food and Drug Administration (FDA) 1572 document with Principal Investigator's signature.  
- For all Principal Investigators and Sub-Investigators listed on the FDA 1572, will need Financial Disclosure Forms, CVs, MD Licenses, and Staff Training Documents (i.e., Collaborative Institute Training Initiative (CITI), etc.).  
- As applicable, approvals for Biosafety Committee, Radiation Committee, and Infusion Center.  
- Serious Adverse Event (SAE) reports to IRB and sponsor.  
- MedWatch reporting to FDA and sponsor.  
- Drug Destruction Standard Operating Procedure (SOP).  
- For all laboratories listed on the FDA 1572, will need CUA certifications, CAP
certifications, lab licenses, CV(s) and Medical License(s) of Lab Director(s), and laboratory reference ranges.
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documents filed in regulatory binder

- Delegation of Authority Log with signatures (to be scanned in OnCore once the trial is complete).
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2. additional essential documents for

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

- For IND Exempt studies, the Essential Regulatory Documents for UCSF would include all documents in Section \#1 of this policy. The Essential Regulatory Documents from the participating site(s) for Multicenter Trials when UCSF is the Coordinating Center would only include the signed protocol signature page, CV of the Pl, and the IRB approval letters. All other documents in Section \#2 of this policy would be the responsibility of the Participating Site(s).
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5. required essential regulatory documents

- For Single Site non-therapeutic trials, all Regulatory Documents in Section \#1 of this policy are required except for: current and prior versions of the Investigator Brochure (IB), package insert (if the study drug is commercial), DSMC dose escalation approvals with study status summary forms, approvals for Biosafety Committee, Radiation Committee, and Infusion Center, and drug destruction SOPs.
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6. required essential regulatory documents

- For Multicenter non-therapeutic trials with UCSF as the Coordinating Site, all required Regulatory Documents listed above in Section \#5 for Single Site non-therapeutic trials are required for the Coordinating Site. The only required Regulatory Documents from the Participating Site(s) will be: IRB approval letters, IRB roster, and ICF and HIPAA consent forms, the Delegation of Authority Log (with NIH or CITI human subject protection training certificates or GCP training certification), Protocol Violations and Single Patient Exception (SPE) reports to the IRB with supporting fax documentation (if applicable),
Serious Adverse Event (SAE) forms submitted to both the IRB and the sponsor, and the Data and Safety Monitoring Committee (DSMC) monitoring reports for the Participating Site(s). If applicable, a copy of the Data and Safety Monitoring Plan (DSMP) Monitoring Plan for all participating site(s) in Multicenter studies or Contract Research Organization (CRO) Monitoring Plan (if an outside CRO is used for the study) will be required.
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alternate procedures

There are no alternate procedures to the HDFCCC policy for requirements for Essential Regulatory Documents for Multicenter Investigator-Initiated Oncology Clinical Trials.
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references

- ICH Guidance for Industry: E6 Good Clinical Practice: Consolidated Guidance (current version).
- International Conference on Harmonization: Good Clinical Practice: Consolidated Guideline (current version).  
- International Conference on Harmonization: Essential Documents for the Conduct of a Clinical Trial (current version).  
- 21CFR50 - 21 CFR56.11 - 45CFR46 - 21 CFR312 Required Regulatory Documents for Sub-sites Participating in Therapeutic UCSF Investigator Initiated Multicenter trial Directions: Scan the documents in a zip drive and upload to OnCore.
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1572

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

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

Delegation of Authority Log
- Include NIH or CITI human subject protection training certificates or GCP training certification Pharmacy
- Drug destruction SOP and Policy Protocol signature page Executed sub contract
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appendix 4 data safety monitoring

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

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

The UCSF Coordinating Center provides administration, data management, and organizational support for the participating sites in the conduct of a multicenter clinical trial. The UCSF
Coordinating Center will also coordinate monthly conference calls with the participating sites. The following issues will be discussed as appropriate:  
- Enrollment information. - Adverse Events (i.e., new adverse events and updates on unresolved adverse events and new safety information).  
- Protocol Violations.  
- Other issues affecting the conduct of the study.
Adverse events reporting to the DSMC will include reports from both the UCSF Coordinating Center, as well as the participating sites. The DSMC will be responsible for monitoring all data entered in OnCore® at the UCSF Coordinating Center and the participating sites as per the study-specific guidelines listed in Appendix H. The data (i.e., copies of source documents) from the participating sites will be downloaded into the PC console of OnCore prior to the monitoring visits in order for the DSMC to monitor the participating site's compliance with the protocol and FDA regulations.
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3. review and oversight requirements

All Grade 3-5 Adverse Events (AEs), regardless of being unexpected or considered to be associated with the use of the study drug will be entered into OnCore®, UCSF's Clinical Trial Management System. Adverse Events are graded according to the Common Terminology Criteria for Adverse Events (CTCAE) as developed and revised by the Common Therapy Evaluation Program (CTEP) of the National Cancer Institute. Adverse Events are further given an assignment of attribution or relationship to treatment or medical procedure. Attribution categories are:
- **Definite** - The adverse event is clearly related to the investigational agent(s) or medical procedure.  
- **Probable** - The adverse event is likely related to the investigational agent(s) or medical procedure.  
- **Possible** - The adverse event may be related to the investigational agent(s) or medical procedure.  
- **Unlikely** - The adverse event is doubtfully related to the investigational agent(s)
or medical procedure.  
- **Unrelated** - the adverse event is clearly not related to the investigational agent(s)
or medical procedure.  
All Grade 3-5 adverse events entered into OnCore® will be reviewed on a monthly basis at the UCSF Site Committee meetings. All adverse events entered into OnCore® will be reviewed on a monthly basis at the UCSF Coordinating Center Site Committee meetings. All clinically significant adverse events must be reported to the UCSF Coordinating Center by the participating sites within 10 business days of becoming aware of the event or during the next scheduled monthly conference call, whichever is sooner. The UCSF Site Committee will review and discuss the selected toxicity, the toxicity grade, and the attribution of relationship of the adverse event to the administration of the study drug(s) from the UCSF Coordinating Center and the participating sites.
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3.2 serious adverse event reporting

By definition, an Adverse Event is defined as a Serious Adverse Event (SAE) according to the following criteria: - Death.  
- Life-threatening (i.e. results in an immediate risk of death).  
- Requires inpatient hospitalization or prolongation of existing hospitalization.  
- Permanent or significant disability/incapacity.  
- Gives rise to a congenital anomaly/birth defect, or cancer, or any experience that suggests a significant hazard, contraindication, side effect, or precaution that may require medical or surgical intervention to prevent one of the outcomes listed above.  
- Event occurring in a gene therapy study. - Event that changes the risk/benefit ratio of a study.  
- Any other event the Principal Investigator judges to be serious or which would
*02-15-2018*
suggest a significant hazard, contraindication, side effect, or precaution.  
Serious Adverse Event reporting will be in accordance with the UCSF IRB Regulations and Code of Federal Regulation Title 21 Part 312.32. The SAE will be reported on a Med Watch form.  
UCSF IRB website for guidance in reporting serious adverse events:
https://irb.ucsf.edu/adverse-event FDA website for guidance in reporting serious adverse events: www.fda.gov/Safety/MedWatch/HowToReport/default.htm Med Watch forms and information:
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www.fda.gov/medwatch/getforms.htm

All Serious Adverse Events are entered into OnCore®, as well as submitted to the IRB (per IRB guidelines) via iRIS®. All SAEs, whether expected or unexpected, must be reported to the UCSF Coordinating Center within 1 business days of becoming aware of the event. The SAEs are reviewed and monitored by the UCSF Data and Safety Monitoring Committee on an ongoing basis and discussed at DSMC meetings, which take place every six weeks. The date the SAE
was sent to all required reporting agencies will be documented in OnCore®.  
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 possibly, probably, or definitely 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 reporting procedure is by communication via phone or in person with written documentation of the one-on-one communication via e-mail, with a copy of the e- mail to the DSMC Manager.
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3.3 review of adverse event

If an increase in the frequency of Grade 3 or 4 adverse events (above the rate reported in the Investigator Brochure or package insert) is noted in the study, the Study Chair at the UCSF
Coordinating Center is responsible for notifying the DSMC at the time the increased rate is identified. The report will indicate if the incidence of adverse events observed in the study is above the range stated in the Investigator Brochure or package insert.  
If at any time the Study Chair stops enrollment or stops the study due to safety issues, the DSMC Chair and DSMC Manager must be notified within 1 business day and the IRB must be notified within 10 business days via an iRIS Reporting Form. Data and Safety Monitoring Committee **Contacts:**  
  
DSMC Monitors Box 0128 UCSF HDFCCC
San Francisco, CA 94143
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appendix 5 prohibited medications medications

The following is a list of medications to avoid while you are participating in this study. If you go to any medical visit, please take this list with you for the doctor's reference.  
Before you begin treatment, Dr. Blakely or one of his associates will review all medications you are taking. Make sure you talk with Dr. Blakely before you start or stop taking any medications.  
This list contains only the most common drugs that are known to interact with the drugs used in this study. It is very important to discuss all medications that you are taking with your study doctor. This information will be reviewed at each study visit.  
| Strong inducers of CYP3A or CYP2C8   | Strong inhibitors of CYP3A                |                          |                 |
|--------------------------------------|-------------------------------------------|--------------------------|-----------------|
| Generic Name                         | Brand Names ®                             | Generic Name             | Brand Names ®   |
| Rifampin                             | Rifadin                                   | Clarithromycin           | Biaxin          |
| Rifabutin                            | Mycobutin                                 | Telithromycin            | Ketek           |
| Rifapentine                          | Priftin                                   | Troleandomycin           |                 |
| Carbamazepine                        | Tegretol, Carbatrol, Equetro              | Nefazodone               | Serzone         |
| Oxcarbazepine                        | Trileptal                                 | Itraconazole             | Sporanox, Onmel |
| Phenobarbital                        | Ketoconazole                              | Nizoral, Xolegel, Extina |                 |
| Phenytoin                            | Dilantin, Phenytek, Dilantin-125, Cerebyx | Posaconazole             | Noxafil         |
| s-mephenytoin                        | Voriconazole                              | Vfend                    |                 |
| Bosentan                             | Ritonavir                                 | Norvir                   |                 |
| St. John's Wort                      | Saguinavir Atazanavir                     | Reyataz                  |                 |
| Gemfibrozil                          | Lopid                                     |                          |                 |
| Conivaptan                           | Vaprisol                                  |                          |                 |
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appendix 6 specimen collection sampling

For the purposes of this study, a whole blood sample is collected by standard phlebotomy procedures. Blood should be drawn in the morning prior to drug administration. Aliquots of 5-10 ml of venous blood will be drawn from each patient using PPT and SST vacutainers and or PAXGene tubes.  
1) Two Plasma Preparation (EDTA) Tubes (PPT, 6-10ml) 2) One Serum Separator Tube (SST, 8.5ml)
3) In cases in which sequencing to be performed immediately by the Bivona lab, one PAXGene tube will be collected for transport
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these samples will be used

1) 6 x 300 µl of plasma aliquots, frozen at -80o Celsius 2) 6 x 300 µl of sera aliquots, frozen at -80o Celsius 3) 4 x 1.5ml whole blood aliquots, frozen at -80o Celsius 4) Two "Crude Buffy Coat" aliquots
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processing of the samples will

- Gently inverts the Plasma Preparation Tube 8 -10 times following venipuncture
- The sample will be hold at room temperature (RT) until processing.  
Processing should occur within 2 hours of the blood draw.  
- The sample will be centrifuged at 1,100 x g for 10 minutes at RT in a swing out rotor.  
- Plasma aliquots will be transferred from the vacutainer to cryo vials
- Plasma samples will be frozen and archived at -80Co Celsius.  
- The "Crude" Buffy Coat is removed with a transfer pipette and two equal aliquots are generated in 1.8 ml cryovial.  
- The cryo vials are immediately placed in a –800 Celsius freezer (no transfer in slow freezing chamber).  
- The clinical coordinator transfers samples into a Tissue Core–800 Celsius freezer for temporary storage, the time when the samples have been frozen will be noted.
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serum preparation sop

- Inverts the Serum Preparation Tube 5 times following venipuncture and records the blood draw time
- Hold sample at room temperature. Wait for blood to clot 30 - 45 minutes after blood collection in order to ensure that proper blood clotting occurred. Blood processing should occur within 2 hours of blood draw.  
- Centrifuge at 1,100 x g for 10 minutes at room temperature in a swing out rotor.  
- Serum aliquots will be transferred from the vacutainer to the cryo vials using a 200 µl transfer pipette.  
- Serum samples will be frozen and archived at -80o Celsius.
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whole blood preparation sop

- The EDTA tube is inverted 5 - 10 times before 4 x 1500 µl aliquots are transferred into 1.8 ml cryo vials.  
- The vials are immediately placed in a –800 Celsius freezer (no transfer in slow freezing chamber).
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paxgene tube blood preparation sop

If not picked up or delivered to the Bivona lab within 2 hours, the tube is temporarily stored at –
20 Celsius freezer for up to 72 hours
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sample shipment instructions

For each shipment, an inventory of the samples should accompany the shipment. This inventory should include the study ID, subject ID, sample number, visit number scheduled time of collection.  
Clearly indicate any missing specimens. The original inventory will be retained at the site in the Investigator's file. All samples will be kept at the temperature specified up to and during the shipment. Unless instructed otherwise, the samples will be packed carefully with suitable packing material and dry ice to keep them frozen.  
All shipments should be sent (Monday through Wednesday **only**) by a carrier guaranteeing overnight delivery. The following items should be considered:  
- Advise the carrier of the type of service desired, need for personalized door-to-door pickup, and delivery guaranteed within 24 hours.  
- Advise the carrier of the nature of the shipment's contents (human biological specimens)
and label the package accordingly.  
- Indicate Novartis drug code and Study No. on the face of the parcel to be shipped. The parcel also must carry a "dangerous goods" label because of the dry ice (labels supplied by the courier).  
- The carrier must be asked to store the parcel(s) in a freezer if shipment is delayed and to replace exhausted dry ice before transportation continues.
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instructions for shipment of biological

Samples have to be packed according to the ICAO/IATA-Packing-Instructions in an insulated box. To guarantee that the samples remain deep frozen during transport, use about 10 kg of dry ice per box which will keep the samples frozen during the whole duration of the transport
(air freight). Send the parcel to the following. A shipping log must be included with the shipment. Ship to:
Helen Diller Family Comprehensive Cancer Center Tissue Core C/O Collin Blakely  
 Please notify the addressee in *advance* of the shipment and **indicate:**
- Number of the airbill  
- The time and date of shipping and approximate time of arrival
- To whom the shipment is addressed, the study number, carrier and the shipping form number (or equivalent airbill number)
- The sender's name, telephone number and alternative contact personnel - The total number of cartons and unit weight of each carton
Also notify the Clinical Trial Leader when a shipment has been scheduled.