a phase 1/2 trial of
3.3.7.1 drugs that are prohibited

Other investigational therapies must not be used while the patient is on the study.  
Systemic anticancer therapy (chemotherapy or biologic therapy) other than the study treatments must not be given to patients while the patient is on the study. If such agents are required for a patient then the patient must be discontinued from the study.  
In *vitro* metabolism studies suggest that oxidative metabolism of BKM120 is predominantly mediated by CYP3A4 (fm>0.9), with only minor contributions of CYP1A1. As BKM120 is a sensitive CYP3A4 substrate, co-administration of BKM120 with strong and moderate CYP3A4 inhibitors and CYP3A4 inducers is prohibited. Refer to *Table A4* for a list of prohibited drugs. Please note this list may not be comprehensive. Based on in vitro studies, co-administration of BKM120 with CYP3A4 inducers is predicted to decrease the systemic exposure to BKM120, thereby increasing the risk of exposing the patient to subtherapeutic drug levels. Refer to *Table A4* for a list of prohibited CYP3A inducers. Please note that this list may not be comprehensive. Therapeutic doses of warfarin sodium (Coumadin®) or any other coumadin-derivative anticoagulants are not permitted.  
If a patient requires the concomitant use of any medication included in *Table A4* entitled
"List of Prohibited QT prolonging drugs" (i.e., drugs that are generally accepted by the Qtdrugs.org Advisory Board of the Arizona CERT to have a risk of causing Torsades des de Pointes), study treatment administration must be interrupted as long as the patient requires therapy with the QT prolonging agent. Herbal preparations/medications are not allowed throughout the study. These herbal medications include, but are not limited to St. John"s Wort, Kava, ephedra (ma huang), ginkobiloba, dehydroepiandrosterone (DHEA), yohimbe, saw palmetto, ginseng. Patients should stop using these herbal medications 7 days prior to first dose of study drug. Hormonal contraceptives may be affected by cytochrome P450 interactions, and are therefore not considered effective in this study.
a phase 1/2 trial of
3.3.7.2 drugs to be used

Preliminary in vitro metabolism studies suggest that BKM120 is a weak, reversible inhibitor CYP3A4/5 (Ki=13.6 μM, [I]/Ki= 0.4 where [I] is the average Cmax at steady-state following 100 mg daily dose) and a weak reversible inhibitor of CYP2C8/2C9/2C19 (IC50=34 μM, [I]/IC50=0.15). Note: that with the data available, we are not able to confirm whether such interactions will occur in patients. Therefore, investigators, at their discretion, may administer concomitant medications known to be metabolized by CYP3A4/5, CYP2C8, CYP2C9 and CYP2C19. Patients receiving such medications must be carefully monitored for potentiation of toxicity due to any individual concomitant medications, and may require dose titration or reduction of the drug substrate. Please refer to *Table A5* for a list of CYP450 substrates and carefully consider their co-administration with BKM120. Particularly, caution is advised when BKM120 is co-administered with:  
Drugs which are substrates for CYP3A4, CYP2C8, CYP2C9 or CYP2C19 and which have a narrow therapeutic index.
Oral anti-diabetics which are metabolized by CYP2C8 or CYP2C9 can possibly result in hypoglycemia. Patients who develop diabetes mellitus during the study should be treated according to the American Diabetes Association guidance. It is recommended that treatment start with metformin. Note that the use of troglitazone and pioglitazone is prohibited due to possible induction of CPY3A4 which can be expected to decrease BKM120 exposure to subtherapeutic levels.  
Concomitant treatment with corticosteroids and BKM120 should be avoided, whenever possible, during this study. If a patient, after study enrollment, requires the concomitant use of any medication which may cause QT prolongation and/or torsade de pointes then the investigators, at their discretion, may co-administer such medications. Patients receiving such medications must be monitored. Refer to *Tables A6 and A7* for a list of medications which may prolong QT.  
Please refer to *Table A5* for a list of CYP450 substrates and carefully consider their coadministration with BKM120.  
A short duration (< 2 weeks) of systemic corticosteroids is allowed (e.g. for chronic obstructive pulmonary disease, or as an anti-emetic). Chronic dosing of corticosteroids is known to induce CYP3A enzymes, thereby increasing the risk or reducing BKM120 overall exposure to sub-therapeutic levels.
a phase 1/2 trial of
3.4 visit schedule and assessments

+ / - 1 day window is allowed for cycle 1 procedures. + / - 3 days window is allowed for all subsequent cycles unless otherwise noted.  
| Future Cycles              |                                                                                                                                                |         |         |         |         |        |       |             |    |    |    |    |
|----------------------------|------------------------------------------------------------------------------------------------------------------------------------------------|---------|---------|---------|---------|--------|-------|-------------|----|----|----|----|
| Assessment                 | Screening13                                                                                                                                    | Cycle 0 | Cycle 1 | Cycle 2 | Cycle 3 | (even) | (odd) | Progression |    |    |    |    |
| Study Day/Visit Day        | -7                                                                                                                                             | -4      | 1       | 8       | 15      | 2214   | 1     | 15          | 1  | 1  | 1  |    |
| Informed consent           | X                                                                                                                                              |         |         |         |         |        |       |             |    |    |    |    |
| Background information     | X                                                                                                                                              |         |         |         |         |        |       |             |    |    |    |    |
| Serum Pregnancy Test       | X                                                                                                                                              |         |         |         |         |        |       |             |    |    |    |    |
| (WOCBP) Physical Exam      | X                                                                                                                                              | X       | X       | X       | X       | X      | X     | X           | X  | X  | X  |    |
| Dermatology Exam           | X                                                                                                                                              | X       | X       | X       |         |        |       |             |    |    |    |    |
| Vitals                     | X                                                                                                                                              | X       | X       | X       | X       | X      | X     | X           | X  | X  | X  |    |
| ECOG PS                    | X                                                                                                                                              | X       | X       | X       | X       | X      | X     | X           | X  | X  | X  |    |
| Neuropsychiatric           | X                                                                                                                                              | X       | X       | X       | X       | X      | X     | X           |    |    |    |    |
| Assessment1 Adverse Event  | X                                                                                                                                              | X       | X       | X       | X       | X      | X     | X           | X  | X  |    |    |
| Assessment Hematology2     | X                                                                                                                                              | X       | X       | X       | X       | X      | X     | X           | X  | X  | X  |    |
| HbA1c and C-peptide3       | X                                                                                                                                              | X       | (X)     | (X)     |         |        |       |             |    |    |    |    |
| Chemistry4                 | X                                                                                                                                              | X       | X       | X       | X       | X      | X     | X           | X  | X  | X  | X  |
| Coagulation5               | X                                                                                                                                              | X       | X       | X       |         |        |       |             |    |    |    |    |
| Fasting Blood Glucose6     | X                                                                                                                                              | X       | X       | X       | X       | X      | X     | X           |    |    |    |    |
| Urinalysis7                | X                                                                                                                                              | X       |         |         |         |        |       |             |    |    |    |    |
| Radiographic Tumor         | X                                                                                                                                              | X       | X       | X       |         |        |       |             |    |    |    |    |
| Assessment8 RECIST reading | X                                                                                                                                              | X       | X       |         |         |        |       |             |    |    |    |    |
| Tumor Biopsy9              | X                                                                                                                                              | X       | X       |         |         |        |       |             |    |    |    |    |
| BRAF Testing               | X                                                                                                                                              |         |         |         |         |        |       |             |    |    |    |    |
| MUGA/Echo10                | X                                                                                                                                              | (X)     |         |         |         |        |       |             |    |    |    |    |
| ECG11                      | X                                                                                                                                              | X       | X       | X       | (X)     | (X)    | X     |             |    |    |    |    |
| PK12                       | X                                                                                                                                              | X       | X       | X       | X       | X      | (X)   |             |    |    |    |    |
| 1                          | Symptomatic patients (≥ CTCAE grade 1) must continue with questionnaires on a weekly basis while active on the treatment portion of the study. |         |         |         |         |        |       |             |    |    |    |    |  
RECIST reading X X X  
Tumor Biopsy9 X X X  
BRAF Testing X  
MUGA/Echo10 X (X)  
ECG11 X X X X (X) (X) X  
PK12 X X X X X X (X)  
1Symptomatic patients (≥ CTCAE grade 1) must continue with questionnaires on a weekly basis while active on the treatment portion of the study. 2Hematology - WBC plus differential (neutrophil including bands, lymphocyte, monocyte, eosinophil, basophil and other counts, hemoglobin and platelets.  
3HbA1c and C-peptide will be measured at screening and on Day 1 of every third treatment cycle starting with Cycle 2 Day 1 and at EOT.  
4Biochemistry - K+, Na+, Ca++, Mg++, LDH, ALT, AST, total bilirubin (direct and indirect), creatinine, amylase, GGT, lipase, alkaline phosphatase (fractionated if alkaline  
phosphatase is grade 2 or higher), bicarbonate, phosphorus, uric acid, total cholesterol, HDL, LDL, triglycerides, glucose, urea or BUN, albumin, and total protein are  
required at baseline and at end of treatment. Subsequent assessments always include K+, Na+, Ca++, ALT, AST, total bilirubin (direct and indirect), creatinine, alkaline  
phosphatase, bicarbonate, phosphorus, glucose, urea or BUN, albumin, and total protein BUT, lipase, total cholesterol, HDL, LDL, triglycerides should be obtained on the  
first day of odd numbered cycles only. C1D-7 assessments may be performed up to 72 hours prior to the scheduled visit.  
5Coagulation - PT or INR, PTT. Patient entering the study while receiving anti-coagulation therapy or those who have the initiation of an anti-coagulation therapy should  
have their coagulation test performed on a weekly basis.  
6Patients must be fasting overnight for at least 8 hours. Additional measurements may be performed as clinically indicated.  
7Urinalysis includes macroscopic (protein, glucose, ketones, blood, and specific gravity). A microscopic (WBC/HPF, RBC/HPF, and any additional findings) exam need  
only be performed if the urinalysis result is abnormal.  
8Screening radiological assessments should be performed within 4 weeks of the first dose. Radiological tumor assessment should be performed at baseline within 28 days  
before start of treatment and subsequently every 8 weeks of combination therapy (first restaging at the end of week 8), until progression of disease or end of treatment. All assessments should be performed within ±7 days of the scheduled day of assessment. The assessment at the end of treatment visit is only to be performed if the prior  
assessment occurred ≥ 21 days before.  
9Biopsies will be done at Screening, Cycle 1 Day 15, and within 14 days of any radiographic examination documenting disease progression by RECIST from all patients  
with visible or palpable disease unless the PI determines thata biopsy would pose an unacceptable risk to the patient.  
10 Echo/MUGA will be performed at baseline and every 4 cycles, or more often as clinically indicated.  
11 ECG will be performed at baseline and (+/- 2 days) on cycle 1 day 15, on cycle 2, 3, and 4 day 1, and every 3 months thereafter in accordance with the manufacturer"s  
standard-of-care recommendations for vemurafenib  
12 PK analysis will only be performed during the phase 1 portion of the study. See section 3.4.6 for schedule.  
13 Laboratory assessments including hematology, blood chemistries, and fasting blood glucose do not need to be repeated prior to the first dose of BKM120 if screening  
laboratories were performed within 14 days of this date.  
14 If toxicity is present at C1D15, C1D22 visit may be done at the discretion of the physician.  
Note: A Brain MRI may be performed at screening and/or at any time during the study as clinically indicated  
| + / - 1 day window is allowed for cycle 1 procedures. + / - 3 days window is allowed for all subsequent cycles unless otherwise noted. Future Cycles Assessment Screening Cycle 1 Cycle 2 Cycle 3 (even)(odd)   | Progression   |    |      |     |     |     |    |    |    |    |    |
|-----------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|---------------|----|------|-----|-----|-----|----|----|----|----|----|
| 13                                                                                                                                                                                                              | 8             | 15 | 2214 | 1   | 15  | 1   | 1  | 1  |    |    |    |
| Study Day/Visit Day                                                                                                                                                                                             | 1             |    |      |     |     |     |    |    |    |    |    |
| Informed consent                                                                                                                                                                                                | X             |    |      |     |     |     |    |    |    |    |    |
| Background information                                                                                                                                                                                          | X             |    |      |     |     |     |    |    |    |    |    |
| Serum Pregnancy Test                                                                                                                                                                                            | X             |    |      |     |     |     |    |    |    |    |    |
| (WOCBP) Physical Exam                                                                                                                                                                                           | X             | X  | X    | X   | X   | X   | X  | X  | X  | X  | X  |
| Dermatology Exam                                                                                                                                                                                                | X             | X  | X    | X   |     |     |    |    |    |    |    |
| Vitals                                                                                                                                                                                                          | X             | X  | X    | X   | X   | X   | X  | X  | X  | X  | X  |
| ECOG PS                                                                                                                                                                                                         | X             | X  | X    | X   | X   | X   | X  | X  | X  | X  | X  |
| Neuropsychiatric Assessment1                                                                                                                                                                                    | X             | X  | X    | X   | X   | X   | X  | X  |    |    |    |
| Adverse Event Assessment                                                                                                                                                                                        | X             | X  | X    | X   | X   | X   | X  | X  | X  | X  |    |
| Hematology2                                                                                                                                                                                                     | X             | X  | X    | X   | X   | X   | X  | X  | X  | X  | X  |
| HbA1c and C-peptide3                                                                                                                                                                                            | X             | X  | (X)  | (X) |     |     |    |    |    |    |    |
| Chemistry4                                                                                                                                                                                                      | X             | X  | X    | X   | X   | X   | X  | X  | X  | X  | X  |
| Coagulation5                                                                                                                                                                                                    | X             | X  | X    | X   |     |     |    |    |    |    |    |
| Fasting Blood Glucose6                                                                                                                                                                                          | X             | X  | X    | X   | X   | X   | X  | X  |    |    |    |
| Urinalysis7                                                                                                                                                                                                     | X             | X  |      |     |     |     |    |    |    |    |    |
| Radiographic Tumor                                                                                                                                                                                              | X             | X  | X    | X   |     |     |    |    |    |    |    |
| Assessment8 RECIST reading                                                                                                                                                                                      | X             | X  | X    |     |     |     |    |    |    |    |    |
| Tumor Biopsy9                                                                                                                                                                                                   | X             | X  | X    |     |     |     |    |    |    |    |    |
| BRAF Testing                                                                                                                                                                                                    | X             |    |      |     |     |     |    |    |    |    |    |
| MUGA/Echo10                                                                                                                                                                                                     | X             |    |      |     |     |     |    |    |    |    |    |
| ECG11                                                                                                                                                                                                           | X             | X  | X    | X   | (X) | (X) | X  |    |    |    |    |
| PK12                                                                                                                                                                                                            | X             | X  | X    | X   | (X) |     |    |    |    |    |    |
| 1 Symptomatic patients (≥ CTCAE grade 1) must continue with questionnaires on a weekly basis while active on the treatment portion of the study.                                                                |               |    |      |     |     |     |    |    |    |    |    |  
RECIST reading X X X  
Tumor Biopsy9 X X X  
BRAF Testing X  
MUGA/Echo10 X  
ECG11 X X X X (X) (X) X PK12 X X X X (X)  
1Symptomatic patients (≥ CTCAE grade 1) must continue with questionnaires on a weekly basis while active on the treatment portion of the study. 2Hematology - WBC plus differential (neutrophil including bands, lymphocyte, monocyte, eosinophil, basophil and other counts, hemoglobin and platelets.  
3HbA1c and C-peptide will be measured at screening and on Day 1 of every third treatment cycle starting with Cycle 2 Day 1 and at EOT.  
4Biochemistry - K+, Na+, Ca++, Mg++, LDH, ALT, AST, total bilirubin (direct and indirect), creatinine, amylase, GGT, lipase, alkaline phosphatase (fractionated if alkaline  
phosphatase is grade 2 or higher), bicarbonate, phosphorus, uric acid, total cholesterol, HDL, LDL, triglycerides, glucose, urea or BUN, albumin, and total protein are required at baseline and at end of treatment. Subsequent assessments always include K+, Na+, Ca++, ALT, AST, total bilirubin (direct and indirect), creatinine, alkaline phosphatase, bicarbonate, phosphorus, glucose, urea or BUN, albumin, and total protein BUT, lipase, total cholesterol, HDL, LDL, triglycerides should be obtained on the first day of odd numbered cycles only.  
5Coagulation - PT or INR, PTT. Patient entering the study while receiving anti-coagulation therapy or those who have the initiation of an anti-coagulation therapy should  
have their coagulation test performed on a weekly basis.  
6Patients must be fasting overnight for at least 8 hours. Additional measurements may be performed as clinically indicated.  
7Urinalysis includes macroscopic (protein, glucose, ketones, blood, and specific gravity). A microscopic (WBC/HPF, RBC/HPF, and any additional findings) exam need  
only be performed if the urinalysis result is abnormal.  
8Screening radiological assessments should be performed within 4 weeks of the first dose. Radiological tumor assessment should be performed at baseline within 28 days  
before start of treatment and subsequently every 8 weeks of combination therapy (first restaging at the end of week 8), until progression of disease or end of treatment. All assessments should be performed within ±7 days of the scheduled day of assessment. The assessment at the end of treatment visit is only to be performed if the prior  
assessment occurred ≥ 21 days before.  
9Biopsies will be done at Screening, Cycle 1 Day 15, and within 14 days of any radiographic examination documenting disease progression by RECIST from all patients  
with visible or palpable disease unless the PI determines that a biopsy would pose an unacceptable risk to the patient.  
10 Echo/MUGA will be performed at baseline and every 4 cycles, or more often as clinically indicated.  
11 ECG will be performed at baseline and (+/- 2 days) on cycle 1 day 15, on cycle 2, 3, and 4 day 1, and every 3 months thereafter in accordance with the manufacturer"s  
standard-of-care recommendations for vemurafenib  
12 PK analysis will only be performed during the phase 1 portion of the study. See section 3.4.6 for schedule.  
13 Laboratory assessments including hematology, blood chemistries, and fasting blood glucose do not need to be repeated prior to the first dose of BKM120 if screening  
laboratories were performed within 72 hours of C1D1.  
14 If toxicity is present at C1D15, C1D22 visit may be done at the discretion of the physician.  
Note: A Brain MRI may be performed at screening and/or at any time during the study as clinically indicated
a phase 1/2 trial of
table 11b. evaluation and visit

| FutureCycles                                                                                                                                     |           |         |         |         |             |             |    |    |    |    |    |
|--------------------------------------------------------------------------------------------------------------------------------------------------|-----------|---------|---------|---------|-------------|-------------|----|----|----|----|----|
| Assessment                                                                                                                                       | Screening | Cycle 1 | Cycle 2 | Cycle 3 | (even)(odd) | Progression |    |    |    |    |    |
| Study Day/Visit Day                                                                                                                              | 1 12      | 8       | 15      | 2213    | 1           | 15          | 1  | 1  | 1  |    |    |
| Informed consent                                                                                                                                 | X         |         |         |         |             |             |    |    |    |    |    |
| Background information                                                                                                                           | X         |         |         |         |             |             |    |    |    |    |    |
| Serum Pregnancy Test                                                                                                                             | X         |         |         |         |             |             |    |    |    |    |    |
| (WOCBP) Physical Exam                                                                                                                            | X         | X       | X       | X       | X           | X           | X  | X  | X  | X  | X  |
| Dermatology Exam                                                                                                                                 | X         | X       | X       | X       |             |             |    |    |    |    |    |
| Vitals                                                                                                                                           | X         | X       | X       | X       | X           | X           | X  | X  | X  | X  | X  |
| ECOG PS                                                                                                                                          | X         | X       | X       | X       | X           | X           | X  | X  | X  | X  | X  |
| Neuropsychiatric                                                                                                                                 | X         | X       | X       | X       | X           | X           | X  | X  |    |    |    |
| Assessment1 Adverse Event                                                                                                                        | X         | X       | X       | X       | X           | X           | X  | X  | X  | X  |    |
| Assessment Hematology2                                                                                                                           | X         | X       | X       | X       | X           | X           | X  | X  | X  | X  | X  |
| HbA1c and C-peptide3                                                                                                                             | X         | X       | (X)     | (X)     |             |             |    |    |    |    |    |
| Chemistry4                                                                                                                                       | X         | X       | X       | X       | X           | X           | X  | X  | X  | X  | X  |
| Coagulation5                                                                                                                                     | X         | X       | X       | X       |             |             |    |    |    |    |    |
| Fasting Blood Glucose6                                                                                                                           | X         | X       | X       | X       | X           | X           | X  | X  |    |    |    |
| Urinalysis7                                                                                                                                      | X         | X       |         |         |             |             |    |    |    |    |    |
| Radiographic Tumor                                                                                                                               | X         | X       | X       | X       |             |             |    |    |    |    |    |
| Assessment8 RECIST reading                                                                                                                       | X         | X       | X       |         |             |             |    |    |    |    |    |
| Tumor Biopsy9                                                                                                                                    | X         | X       | X       |         |             |             |    |    |    |    |    |
| BRAF Testing                                                                                                                                     | X         |         |         |         |             |             |    |    |    |    |    |
| MUGA/Echo10                                                                                                                                      | X         | (X)     |         |         |             |             |    |    |    |    |    |
| ECG11                                                                                                                                            | X         | X       | X       | X       | (X)         | (X)         | X  |    |    |    |    |
| 1 Symptomatic patients (≥ CTCAE grade 1) must continue with questionnaires on a weekly basis while active on the treatment portion of the study. |           |         |         |         |             |             |    |    |    |    |    |
a phase 1/2 trial of
table 11c. evaluation and visit

+ / - 1 day window is allowed for cycle 1 procedures. + / - 3 days window is allowed for all subsequent cycles.  
RECIST reading X X X
Tumor Biopsy9 X X X
BRAF Testing X
MUGA/Echo10 X (X)
ECG11 X X X X (X) (X) X
1Symptomatic patients (≥ CTCAE grade 1) must continue with questionnaires on a weekly basis while active on the treatment portion of the study.  
2Hematology - WBC plus differential (neutrophil including bands, lymphocyte, monocyte, eosinophil, basophil and other counts, hemoglobin and platelets.  
3HbA1c and C-peptide will be measured at screening and on Day 1 of every third treatment cycle starting with Cycle 2 Day 1 and at EOT.  
4Biochemistry - K+, Na+, Ca++, Mg++, LDH, ALT, AST, total bilirubin (direct and indirect), creatinine, amylase, GGT, lipase, alkaline phosphatase (fractionated if alkaline phosphatase is grade 2 or higher), bicarbonate, phosphorus, uric acid, total cholesterol, HDL, LDL, triglycerides, glucose, urea or BUN, albumin, and total protein are required at baseline and at end of treatment. Subsequent assessments always include K+, Na+, Ca++, ALT, AST, total bilirubin (direct and indirect),
creatinine, alkaline phosphatase, bicarbonate, phosphorus, glucose, urea or BUN, albumin, and total protein BUT, lipase, total cholesterol, HDL, LDL, triglycerides should be obtained on the first day of odd numbered cycles only.  
5Coagulation - PT or INR, PTT. Patient entering the study while receiving anti-coagulation therapy or those who have the initiation of an anti-coagulation therapy should have their coagulation test performed on a weekly basis.  
6Patients must be fasting overnight for at least 8 hours. Additional measurements may be performed as clinically indicated.  
7Urinalysis includes macroscopic (protein, glucose, ketones, blood, and specific gravity). A microscopic (WBC/HPF, RBC/HPF, and any additional findings) exam need only be performed if the urinalysis result is abnormal.  
8Screening radiological assessments should be performed within 4 weeks of the first dose. Radiological tumor assessment should be performed at baseline within 28 days before start of treatment and subsequently every 8 weeks of combination therapy (first restaging at the end of week 8), until progression of disease or end of treatment. All assessments should be performed within ±7 days of the scheduled day of assessment. The assessment at the end of treatment visit is only to be performed if the prior assessment occurred ≥ 21 days before.  
9Biopsies will be done at Screening, Cycle 1 Day 15, and within 14 days of any radiographic examination documenting disease progression by RECIST from all patients with visible or palpable disease unless the PI determines that a biopsy would pose an unacceptable risk to the patient.  
10 Echo/MUGA will be performed at baseline and every 4 cycles, or more often as clinically indicated. 11 ECG will be performed at baseline and (+/- 2 days) on cycle 1 day 15, on cycle 2, 3, and 4 day 1, and every 3 months thereafter in accordance with the manufacturer"s standard-of-care recommendations for vemurafenib 12 Laboratory assessments including hematology, blood chemistries, and fasting blood glucose do not need to be repeated prior to the first dose of BKM120 if screening laboratories were performed within 72 hours of C1D1.  
13 If toxicity is present at C1D15, C1D22 visit may be done at the discretion of the physician.  
Note: A Brain MRI may be performed at screening and/or at any time during the study as clinically indicated
a phase 1/2 trial of
3.4.2 efficacy assessments

Patients will undergo systemic imaging with a contrast-enhanced CT scan of the chest, abdomen, and pelvis (or a whole body PET/CT scan if this scan includes a CT resolution that is comparable to standard institutional protocols for CT alone) with 28 days prior to the initiation of therapy (baseline imaging) and on the last day of every even-numbered treatment cycle(+/- 3 days). Imaging assessments will be made by a radiologist, and final assessment using Response Evaluation Criteria in Solid Tumors (RECIST, version 1.1) will be made by the PI 37,38. Any documentation of a PR or CR in a target or non-target lesion must be confirmed by a repeat scan at least4 weeksafter the initial scan indicating the PR or CR. The PI bears the final responsibility for determining tumor response and progression.
a phase 1/2 trial of
3.4.3 laboratory evaluations pregnancy test

A serum pregnancy test (β-HCG) is required for all women of child-bearing potential at screening, within 72 hours prior to the first dose of BKM120. Note: Women are considered postmenopausal and not of child bearing potential if they have had 12 months of natural
(spontaneous) amenorrhea with an appropriate clinical profile (e.g. age appropriate, history of vasomotor symptoms) or six months of spontaneous amenorrhea with serum FSH levels > 40 mIU/mL [*for US only*: and estradiol < 20 pg/mL] or have had surgical bilateral oophorectomy (with or without hysterectomy) at least six weeks ago. In the case of oophorectomy alone, only when the reproductive status of the woman has been confirmed by follow up hormone level assessment is she considered not of child bearing potential.
a phase 1/2 trial of
hematology

Hematology includes the following parameters: complete blood count (CBC) consisting of red blood cell (RBCs), a total white blood cell count (WBC) with differential (total neutrophil count including bands, lymphocyte, monocyte, eosinophil, and basophil counts); hemoglobin (Hgb); and platelet count.
a phase 1/2 trial of
coagulation profile

The coagulation profile includes prothrombin time or INR, and activated partial thromboplastin time.
a phase 1/2 trial of
blood chemistry

Biochemistry includes the following parameters: urea or blood urea nitrogen (BUN), creatinine, sodium, potassium, calcium, magnesium, phosphorus, glucose, albumin, total protein, total bilirubin (direct and indirect), amylase and lipase, GGT, alkaline phosphatase (fractionated if alkaline phosphatase is grade 2 or higher), bicarbonate, AST (SGOT), ALT (SGPT), and uric acid, lactic dehydrogenase (LDH), total cholesterol, high density lipoprotein (HDL), low density lipoprotein (LDL) and triglycerides are required at baseline and at end of treatment. Subsequent assessments always include K+, Na+, Ca++, ALT, AST, total bilirubin (direct and indirect), creatinine, alkaline phosphatase, bicarbonate, phosphorus, glucose, urea or BUN, albumin, and total protein BUT, lipase, total cholesterol, HDL, LDL, triglycerides should be obtained on the first day of odd numbered cycles only. C1D-7assessments may be performed up to 72 hours prior to the scheduled visit. Cycle 1 draws may occur within 24 hours prior to the scheduled visit. All other draws should occur within 3 days of the intended visit. Because accurate serum glucose and lipid measurements are required; patients should be fasting at the time of the blood sampling.
a phase 1/2 trial of
glucose monitoring (fpg c-peptide and

Fasting plasma glucose (FPG), C-peptide, and HbA1C will be assessed. Patients must be fasting overnight for at least 8 hours prior to the blood draw. The study personnel will ask the patient whether he or she has been fasting, which will be captured in the eCRF as well.  
HbA1cand C-peptide will be measured at screening and on Day 1 of every third treatment cycle starting with Cycle 2 Day 1 and at EOT.
a phase 1/2 trial of
urinalysis

Urinalysis includes macroscopic (protein, glucose, ketones, blood, and specific gravity) and will be performed at screening visit and EOT visit. A microscopic (WBC/HPF, RBC/HPF, and any additional findings) exam need only be performed if the urinalysis result is abnormal. This must be supplemented with laboratory quantification of any potentially relevant abnormalities.
a phase 1/2 trial of
3.4.4 clinical evaluations 3.4.4.1 vital

Vital sign assessment consists of height (first visit), pulse, blood pressure, respiration rate, temperature and weight. Blood pressure, pulse and respiration rate should be measured on patients after at least 3 minutes in the sitting position
a phase 1/2 trial of
3.4.4.2 physical examination

Physical examination will be performed which must comprise a total body examination (general appearance, skin, neck, including thyroid, eyes, ears, nose, throat, lungs, heart, abdomen, back, lymph nodes, extremities and basic nervous system). Significant findings made after the start of study drug which meet the definition of an Adverse Event must be recorded.
a phase 1/2 trial of
3.4.4.3 neuropsychiatric assessments

Patient self-rating mood questionnaires for anxiety and depression (PHQ-9, GAD-7) will be applied at:
Screening Days 1 and 15 of Cycle 1 Day 1 and 15 of Cycle 2 Day 1 of Cycle 3 and subsequent cycles (only for patients who have not shown mood alterations during the first 2 cycles, patients who did should continue to fill out the questionnaire on a weekly base).
a phase 1/2 trial of
end of study treatment

Additional assessments may be done according to the clinical judgment of the Investigator. Symptomatic patients (≥ CTCAE grade 1) must continue with questionnaires on a weekly basis while active on the treatment portion of the study. Instructions on how to instruct the patient to complete the questionnaires as well as how to determine the scores will be provided together with each instrument.
a phase 1/2 trial of
3.4.4.4 performance status

Performance status will be assessed at screening and per the visit schedule using the Eastern Cooperative Oncology Group (ECOG) performance scale.
a phase 1/2 trial of
3.4.5 additional evaluations 3.4.5.1 ecg/echo

A standard 12 lead ECG is to be performed at screening and significant findings must be recorded. An echocardiogram (ECHO) or MUGA will be performed to assess eligibility.  
ECHO/MUGA will be repeated at Cycle 4 and then every 4th cycle thereafter.
a phase 1/2 trial of
3.4.5.2 brain imaging

An MRI of the brain with gadolinium maybe performed during screening and patient with untreated or symptomatic brain metastases will be excluded from participation in this trial. Patients with asymptomatic, treated brain metastases with documented radiographic stability over at least 4 weeks may participate in this trial. For all patients enrolled on the trial, additional MRI imaging of the brain may be obtained as clinically indicated.
a phase 1/2 trial of
3.4.6 drug levels and pharmacokinetic

Data regarding the preclinical and clinical pharmacology of vemurafenib are presented in section 1.2.1.3 and 1.2.3 respectively. Data regarding the preclinical and clinical pharmacology of BKM120 are presented in section 1.4.1.3 and 1.4.2.1 respectively. All BKM120 pharmacokinetic analysis will be performed by Novartis (refer to Appendix 4 for details) and vemurafenib analysis will be performed at UCSF (refer to Appendix 5 for details).
a phase 1/2 trial of
phase 1 part a

Historical controls for PK of vemurafenib alone are well established and vemurafenib has minimal hepatic metabolism4. Pharmacokinetic measurements of serum levels of BKM120 after single dose will be made during a 7-day lead-in (day -7, t = 0, 1, 2, 6 hrs +/- 15 minutes; day -4 at 72 hrs post-dose +/- 1 hour). Serum levels of BKM120 and vemurafenib will be assessed on cycle 1 treatment day 1 (t = 0, 1, 2, 6 hrs +/- 15 minutes) and day 15 (t = 0, +/- 1 hour) as well as trough levels (t = 0 +/- 1 hour) on day 1 of cycles 2, 3, and 4. Vemurafenib is a weak CYP3A4 inducer and BKM120 is primarily metabolized by CYP3A4. Therefore, the effect of vemurafenib on BKM120 serum levels is of particular interest.
a phase 1/2 trial of
phase 1 part b

Serum levels of BKM120 and vemurafenib will be assessed on cycle 1 treatment days 1 (t = 0, 1, 2, 6 hrs +/- 15 minutes) and day 15 (t = 0, +/- 1 hour) as well as trough levels (t = 0 +/- 1 hour) on day 1 of cycles 2, 3, and 4.
a phase 1/2 trial of
phase 1 parts a &

At each sample time point, two aliquots (2 mL each) of whole blood will be collected in EDTA blood collection tubes and the exact time of the dose and the blood draw will be noted. Detailed sample collection and shipping instructions are given in Appendices 4 and 5. Patients should take the daily doses of BKM120 and the first dose of vemurafenib in the morning. Patients must fast forat least 2 hours after a light breakfast (morning meal) before taking BKM120 and vemurafenib. Vemurafenib and BKM120 should be taken with a glass of water and consumed over as short a time as possible. Patients should swallow the capsules as a whole and not chew or crush them. Patients should continue to fast for 2 hours after the administration of the morning doses. PK measurements will be compared to historical controls for BKM120 and vemurafenib individually with the goal of comparing peak and trough exposure levels.
a phase 1/2 trial of
3.4.7 correlative studies and pharmacodynamic

Biopsies of palpable melanoma lesions and nodal metastases will be taken at baseline, on Cycle 1 Day 15 (+/- 3 days), and within 14days of radiographic progression of disease. In addition, existing paraffin-embedded biopsy specimens will also be obtained for analysis and archival. Biopsies for patients with cutaneous, subcutaneous, and palpable nodal metastatic disease may be waived if the PI believes that such biopsies would pose an excessive risk to the patient. Imaging guided biopsies of other metastatic sites are optional and permitted in patients without visible or palpable disease unless the PI believes that such a biopsy would pose an excessive risk to the patient. For skin lesions, punch or core biopsies are preferred. For other lesions, core biopsies are preferred and an attempt should be made to obtain 3 cores if core biopsies are selected. Fine needle aspiration is permitted with punch or core biopsies are not feasible. At the time of tumor progression, biopsies should be taken from both progressing and non-progressing lesions if feasible. Portions of all new tumor biopsy specimens will be immediately immersed in formalin and subsequently embedded in paraffin and additional tissue will be flash-frozen and stored at
-70 oCuntil the time of analysis. Paraffin embedded biopsies will be stored at room temperature.  
Pre-treatment melanoma tumor specimens will be analyzed by PCR to confirm the presence of a BRAFV600Eor BRAFV600K mutation and to assess for concurrent mutations of NRAS. Specific correlative analyses are outlined below. Any remaining tissue specimens may be archived for future studies that may include but that are not limited to nucleic acid sequencing, microarray analysis, and immunohistochemistry.
a phase 1/2 trial of
6-month pfs as a function

Our hypothesis is that patients with PTEN loss at baseline will be more likely to survive for 6 months without disease progression. PTEN expression will be assessed as present or absent using immunohistochemical staining for PTEN. Pre-treatment tissue for PTEN IHC will be available for all patients (estimate N = 46) since the availability of pre-treatment tissue for BRAF genotyping is required. PTEN staining in tumor specimens will be graded as "present" or "absent" for each patient by a collaborating pathologist. Attainment of 6 month PFS as a function of PTEN status will be assessed using Fisher"s exact test. For PTEN and pS6 IHC, paraffin-embedded sections will be deparaffinized, rehydrated, and subjected to heat-induced antigen retrieval. Sections will be incubated with appropriate primary antibody (PTEN: Cell Signaling D4.3, 1:50 dilution; phospho-S6 Cell Signaling Polyclonal, 1:200 dilution) and incubated for 45 minutes. After overnight incubation with a secondary polyclonal rabbit antibody, slides will be developed using 3-3′-diaminobenzidine chromogen and counterstained with hematoxylin39.
a phase 1/2 trial of
change in phospho-s6 as a

Our hypothesis is that patients surviving for 6 months without disease progression will demonstrate a larger decrease in PI3K pathway activity as assessed by IHC for phopsho-S6 than those patients with disease progression or death prior to 6 months. The change in pS6 will be determined by comparing H-scores to quantify pS6 protein levels by IHC prior to treatment at after 8 weeks of treatment40,39. The H-Score will be calculated for staining of tumor cells using the following formula; H-Score = (% at 0) * 0 + (% at 1+) * 1 + (% at 2+) * 2 + (% at 3+) * 3. Thus, this score produces a continuous variable that ranges from 0 to 300. The change in phospho-S6 staining will be determined as follows: pS6 = (H4w-H0)/H0. Patients will be categorized based on whether or not they survived for 6 months without disease progression.  
pS6 over the first 8 weeks of treatment will be compared between the two groups using the Wilcoxon rank-sum test.
a phase 1/2 trial of
gene expression profiles of pi3k

Our hypotheses are: 1. Treatment response by RECIST v1.1 criteria after 8 weeks of treatment will be associated with an absence of PI3K and MAPK signaling as assessed by gene expression profiling and 2. Disease progression is associated with activation of either pathway. Gene expression profiling has emerged as in important tool for elucidating mechanisms of resistance to BRAF inhibitors in melanoma by identifying gene signatures of oncogenic pathway activation in an unbiased manner41. cDNA will be derived from RNA extracted from flash-frozen tissue specimens. Gene expression will be determined using GeneChip Human Gene 1.0 ST Arrays (Affymetrix) on cycle 3 day 1 (+/- 3 days) and within 7 days of determination of tumor progression. These profiles will be referenced to the profile of tumor tissue obtained prior to the initiation of treatment. Expression data will be normalized and background-corrected. Clustering will be performed with MeV 4.4. Differentially expressed genes will be identified using significance analysis of microarrays (SAM) with the R package. To identify and rank pathways enriched among differentially expressed genes, P-values (Fisher"s exact test) will be calculated for gene sets with at least 20% differentially expressed genes. Curated gene sets of canonical pathways including PI3K and MAPK in the Molecular Signatures Database (MSigDB) will be used as the comparator. Gene expression signatures consistent with MAPK, PI3K, or alternate pathways activation will be confirmed by RT-PCR and immunohistochemistry for phospho-protein levels such as pS6 and pERK. Our initial goal is to perform microarray analysis on matched biopsy specimens from a total of 10 patients: 5 who meet the 6 month PFS endpoint, and 5 with early disease progression within 4 months of the initiation of treatment. Until these patients have been identified, all patients with visible or palpable disease will undergo pretreatment biopsies. Additional biopsies and additional analyses may be performed at the discretion of the PI.
a phase 1/2 trial of
3.5 treatment compliance

Records of study medication used, dosages administered, and intervals between visits will be recorded during the study. Drug accountability will be noted and patients will be asked to return all unused study medication.
a phase 1/2 trial of
3.6 safety monitoring plan 3.6.1

Safety assessments will consist of monitoring and recording all adverse events and serious adverse events, the regular monitoring of hematology, blood chemistry and urine values, regular measurement of vital signs and the performance of physical examinations. Dermatologic assessments will be performed at screening, on week 3 day 1, and at every 8 week intervals thereafter. These assessments should be performed within ±1 day (during DLT period) or ±3days (all subsequent cycles) of the scheduled day of assessment except for adverse events that will be evaluated continuously through the study. Safety and tolerability will be assessed according to the NIH/NCI CTC: http://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm
a phase 1/2 trial of
3.6.2 adverse events

Information about all adverse events, whether volunteered by the subject, discovered by investigator questioning, or detected through physical examination, laboratory test or other means, will be collected and recorded and followed as appropriate. An adverse event is the appearance or worsening of any undesirable sign, symptom, or medical condition occurring after starting the study drug even if the event is not considered to be related to study drug. Medical conditions/diseases present before starting study drug are only considered adverse events if they worsen after starting study drug. Abnormal laboratory values or test results constitute adverse events only if they induce clinical signs or symptoms, are considered clinically significant, or require therapy. The occurrence of adverse events should be sought by non-directive questioning of the patient at each visit during the study. Adverse events also may be detected when they are volunteered by the patient during or between visits or through physical examination, laboratory test, or other assessments. As far as possible, each adverse event should be evaluated to determine: 1. the severity grade (mild, moderate, severe) or (grade 1-4) 2. its relationship to the study drug(s) (suspected/not suspected) 3. its duration (start and end dates or if continuing at final exam) 4. action taken (no action taken; study drug dosage adjusted/temporarily interrupted; study drug permanently discontinued due to this adverse event; concomitant medication taken; non-drug therapy given; hospitalization/prolonged hospitalization)
5. whether it constitutes a serious adverse event (SAE) All adverse events should be treated appropriately. Such treatment may include changes in study drug treatment including possible interruption or discontinuation, starting or stopping concomitant treatments, changes in the frequency or nature of assessments, hospitalization, or any other medically required intervention. Once an adverse event is detected, it should be followed until its resolution, and assessment should be made at each visit (or more frequently, if necessary) of any changes in severity, the suspected relationship to the study drug, the interventions required to treat it, and the outcome. Information about common side effects already known about BKM120 can be found in the Investigators" Brochure and additional data regarding vemurafenib can be found in the published literature. This information should be included in the patient informed consent and should be discussed with the patient during the study as needed.  
Adverse Event Monitoring: Adverse events (AEs) will be recorded on the OnCoreeResearch database, all grade 3-5 expected and unexpected AEs will be recorded and updated at each visit.
a phase 1/2 trial of
3.6.3 serious adverse events

A serious adverse event is an undesirable sign, symptom or medical condition which:
is fatal or life-threatening results in persistent or significant disability/incapacity constitutes a congenital anomaly/birth defect requires inpatient hospitalization or prolongation of existing hospitalization, unless hospitalization is for:
routine treatment or monitoring of the studied indication, not associated with any deterioration in condition elective or pre-planned treatment for a pre-existing condition that is unrelated to the indication under study and has not worsened since the start of study drug treatment on an emergency outpatient basis for an event not fulfilling any of the definitions of a SAE given above and not resulting in hospital admission social reasons and respite care in the absence of any deterioration in the patient"s general condition is medically significant, i.e., defined as an event that jeopardizes the patient or may require medical or surgical intervention to prevent one of the outcomes listed above To ensure patient safety, every SAE, **regardless of suspected causality**, occurring after the patient has provided informed consent and until 4 weeks after the patient has stopped study treatment/participation after the patient is randomized and until 4 weeks after the patient has stopped study treatment after the patient begins taking study drug and until 4 weeks after the patient has stopped study treatment after protocol-specified procedures begin (e.g., placebo run-in, washout period, double-blind treatment, etc.) and until 4 weeks after the patient has stopped study treatment after the start of any period in which the study protocol interferes with the standard medical treatment given to a patient (e.g., treatment withdrawal during washout period, change in
treatment to a fixed dose of concomitant medication) and until 4 weeks 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 4-week period should only be reported if the investigator suspects a causal relationship to the study drug. 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.
a phase 1/2 trial of
3.6.4 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 24 business hours of knowledge of the event. The contact may be by phone or e-mail.
a phase 1/2 trial of
reporting to ucsf's committee on

The Investigator must report events meeting the CHR definition of "Unanticipated Problem" (UP) within 10 working days of his/her awareness of the event.  
Guidance on Adverse Event Reporting to the CHR is available online at the *UCSF Human* Research Protection Program website.
a phase 1/2 trial of
expedited reporting to the food

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  
Serious
Unexpected If the adverse event does not meet all three of the definitions, it should not be submitted as an expedited IND safety report.  
The timeframe 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 must 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 must 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)). The investigator (or designee) should prepare *Form FDA 3500A (MedWatch)*detailing the event, and contact the Institutional Trials Unit for assistance in the preparation of the IND Safety Report. For additional information and guidance on IND Safety Reports, please refer to FDA"s Guidance document*Safety Reporting Requirements for INDs*.
a phase 1/2 trial of
reporting to genentech and novartis

Serious AE and AEs of Special Interest (regardless of causality) will be transmitted to Genentech within 24 hours of the Awareness Date.The completed MedWatch/case report should be faxed immediately upon completion to**Genentech Drug Safety** at:
a phase 1/2 trial of
(650) 225-4682or (650) 225-5288

Additional Reporting Requirements to Genentech include the following:
Any reports of pregnancy following the start of administration with the vemurafenib will be transmitted to Genentech within thirty (30) calendar days of the Awareness Date. All Non-serious Adverse Events originating from the Study will be forwarded in a quarterly report Genentech. Relevant follow-up information should be submitted to Genentech Drug Safety as soon as it becomes available.
a phase 1/2 trial of
reconciliation

The Sponsor agrees to conduct reconciliation for the product. Genentech and the Sponsor will agree to the reconciliation periodicity and format, but agree at minimum to exchange monthly line listings of cases received by the other party. If discrepancies are identified, the Sponsor and Genentech will cooperate in resolving the discrepancies. The responsible individuals for each party shall handle the matter on a case-by-case basis until satisfactory resolution.
a phase 1/2 trial of
novartis

All events must be reported by FAX (888-299-4565) to Novartis Pharmaceuticals DS&E Department within 24 hours of learning of its occurrence using an SAE Report form provided by Novartis. This includes serious, related, labeled (expected) and serious, related, unlabeled (unexpected) adverse experiences. All deaths during treatment or within 30 days following completion of active protocol therapy must be reported within 5 working days. The original copy of the SAE Report and the fax confirmation sheet must be kept within the Study File. Relevant follow-up information should be submitted to Novartis Drug Safety as soon as it becomes available. Follow-up information is sent to the same person(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, and whether the patient continued or withdrew from study participation. If the SAE is not previously documented in the BKM120 or vemurafenib Investigators" Brochure or Package Insert (new occurrence) and is thought to be related to the study drugs, a Drug Safety and Epidemiology 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.
a phase 1/2 trial of
3.6.5 oversight and monitoring

The UCSF Helen Diller Family Comprehensive Cancer Center (HDFCCC) Data Safety Monitoring Committee (DSMC) is responsible for monitoring data quality and patient safety for all UCSF-CCC institutional clinical studies. A summary of DSMC activities for this study includes:  
Review of subject data in each cohort Review of all serious adverse events Minimum of a yearly audit
a phase 1/2 trial of
3.6.5.1 monitoring and reporting guidelines

Investigators will conduct continuous review of data and patient safety at monthly study group or site committee meetings where the results of each patient"s treatment are discussed and the discussion is documented in the minutes. The discussion will include the number of patients, significant toxicities as described in the protocol, doses adjustments, and observed responses. All grade 3-5 AEs and SAEs will be entered in the HDFCCC OnCoreClinical Trial Management System (CTMS).  
Review of Adverse Event Rates: If the study has an increase of unexpected or expected Adverse Event grade 3 or 4 above the rate reported in the Investigational Brochure or package insert, the increase rate of AEs will be reported to the DSMC at the time of Identification. The Chair and PI will discuss the finding and proceed with a written course of action. If at any time the Investigator stops enrollment or stops the study due to safety issues the DSMC Chair and Administrator must be notified within 24 business hours via e-mail. The DSMC must receive a formal letter within 10 business days and the CHR must be notified.  
Data Safety Monitoring Committee Contacts: DSMC Chair: Thierry Jahan, MD DSMC Monitors - address Phone: Email: Address:  
| Phone:  Email: Address:   | 415-353-2745 venook@cc.ucsf.edu Box 1705 UCSF Helen Diller Family  Comprehensive Cancer Center   |
|---------------------------|--------------------------------------------------------------------------------------------------|
a phase 1/2 trial of
3.6.6 pregnancies

| Box 1297 UCSF Helen Diller Family  Comprehensive Cancer Center San Francisco, CA 94115   |
|------------------------------------------------------------------------------------------|  
To ensure patient safety, each pregnancy in a patient on study treatment must be reported to Novartis. The pregnancy should be followed up for 3 months after the termination of the pregnancy 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 Study Pregnancy Form and reported by the investigator to the oncology Novartis Drug Safety and Epidemiology (DS&E) department. Pregnancy follow-up should be recorded on the same form and should include an assessment of the possible relationship to the Novartis study treatment of any pregnancy outcome. Any SAE experienced during pregnancy must be reported on the SAE Report Form. Pregnancy outcomes must be collected for the female partners of any males who took study treatment in this study. Consent to report information regarding these pregnancy outcomes should be obtained from the mother. The team needs to prepare information for the female partner of the male patient on required contraception. This information needs to be given to the male patient at the ICF signing for him to share it with his female partner.
a phase 1/2 trial of
information for female partners of

Your male partner is offered to participate in a clinical research study. As a prerequisite to participate in this study your partner must agree to use a condom during intercourse. This is important because test results of the study treatment in pregnant animals indicated that the medicine can harm an unborn baby through the sperm. At the same time it is also important that you do not become pregnant while your partner is taking the medication. Therefore, you should use a highly effective method of birth control (contraception) during the time your male partner receives the study treatment and thereafter for another 3 months. Highly effective methods of contraception are those methods of birth control that have less than 1% of unwanted pregnancy during one year, if used appropriately according to the instructions of the manufacturer.  
Those methods are the following:
1. True abstinence: When this is in line with the preferred and usual lifestyle of the subject.  
Periodic abstinence (e.g., calendar, ovulation, symptothermal, post-ovulation methods) and withdrawal are not acceptable methods of contraception.  
2. Sterilization: have had surgical bilateral oophorectomy (with or without hysterectomy)
or tubal ligation at least six weeks ago. In case of oophorectomy alone, only when the
reproductive status of the woman has been confirmed by follow up hormone level assessment.  
3. Male partner sterilization (with the appropriate post-vasectomy documentation of the absence of sperm in the ejaculate). For female subjects on the study, the vasectomised male partner should be the sole partner for that patient.  
4. Use of a combination of any two of the following (a+b):
a) Placement of an intrauterine device (IUD) or intrauterine system (IUS) b) Barrier methods of contraception: Condom or Occlusive cap (diaphragm or cervical/vault caps) with spermicidal foam/gel/film/cream/vaginal suppository Oral contraception, injected or implanted hormonal methods are not allowed as BKM120 potentially decreases the effectiveness of hormonal contraceptives.  
Fertile males, defined as all males physiologically capable of conceiving offspring must use condom during treatment, for 5 T1/2 (8 days) after stopping treatment and for additional 12 weeks (3 months in total after study drug discontinuation) and should not father a child in this period.
For details on the most appropriate contraception you may talk to your regular doctor, or if check that your male partner agrees with the study doctor. If you get pregnant despite taking the birth control precautions, please ask your partner to inform the study doctor as soon as possible. The study doctor will ask your permission to collect information about you, your pregnancy and your child.
a phase 1/2 trial of
4 protocol amendments or changes

Any change or addition to this protocol requires a written protocol amendment that must be approved by the PRC and the CHR prior to implementation. These requirements for approval should in no way prevent any immediate action from being taken by the investigator in the interests of preserving the safety of all patients included in the trial. If an immediate change to the protocol is implemented for safety reasons the CHR will be informed immediately.
a phase 1/2 trial of
5 statistical methods 5.1 study

This is a phase 1/2 clinical trial designed to determine the recommended phase 2 dose of PI3K inhibitor BKM120 in combination with BRAF inhibitor vemurafenib (phase 1) followed by a determination of 6 month progression-free survival rate (phase 2) in patients with BRAF mutant melanoma.
a phase 1/2 trial of
for phase 1 part a

This is a single-arm, open-label phase 1 clinical trial. The primary endpoint for phase I, part A is the RP2D of vemurafenib twice daily and BKM120 daily in BRAF mutant melanoma patients with no prior exposure to potent BRAF inhibitorsand the primary safety endpoint is DLT. Phase 1 dose levels are described in *Table 5* and details regarding dose escalation and identifying the RP2D are given in section 3.3.2.1.
a phase 1/2 trial of
for phase 1 part b

The primary endpoint for phase 1, part B is the RP2D of vemurafenib twice daily in BRAF mutant melanoma patients with prior progression of disease on potent BRAF inhibitors and BKM120 daily and the primary safety endpoint is DLT.
a phase 1/2 trial of
for the phase 2 portion

The primary endpoint of the Phase 2 portion is the progression-free survival rate at 6 months. Imaging assessments will be made by a radiologist, and final assessment using Response Evaluation Criteria in Solid Tumors (RECIST, version 1.1) will be made by the PI. Any documentation of a PR or CR in a target or non-target lesion must be confirmed by a repeat scan at least 4 weeks after the initial scan indicating the PR or CR. Disease response will be assessed at scheduled visits by diagnostic anatomic imaging, and clinical exam. All patients will be followed for 6 months and proportion of patients that are progression free at 6 months will be calculated.
a phase 1/2 trial of
secondary endpoints

Median PFS and OS defined by the Kaplan-Meier method. Tumor progression will be defined using RECIST version 1.1.Analysis of tolerability will be descriptive with reporting of all events by grade that are thought to be possibly, probably, and definitely attributable to study drug. Correlative assessments for PTEN expression, changes in pS6, and gene expression analysis are described in section 3.4.7 along with statistical analysis plans for these assessments.
a phase 1/2 trial of
5.2. sample size/accrual rate

This study will use the standard 3+3 dose escalation design to determine the RP2D of BKM120 in combination with vemurafenib (phase 1) followed by a single-stage binomial phase 2 design of 37 evaluable patients (any patient receiving at least 75% of prescribed cohort dose during the DLT period) to determine the PFS rate at 6 months.
a phase 1/2 trial of
for the phase 1 portion

A Phase 1 dose escalation design using the standard 3+3 scheme will be followed and the sample size is not predetermined. We estimate the phase 1 portion of this trial will require a minimum of 2 patients from four predefined dose levels (see *Table 5*) to determine the phase 2 dose (MTD).  
The estimated maximum number of patients is 24. The final sample size of the study depends primarily on clinical considerations rather than on statistical considerations.
a phase 1/2 trial of
for the phase 2 portion

The sample size for the phase 2 portion of this study is determined using single-stage binomial design for phase 2 studies. Preliminary data from trials of vemurafenibmonotherapy in advanced melanoma suggest a median PFS of approximately 6 months4,5,17. The proposed design will be used to test the null hypothesis that the 6 month PFS rate of the study combination is 50% or less (which would not be clinically desirable) versus the alternative hypothesis that the true 6 month PFS rate is greater 70%, which would be considered clinically meaningful. The maximum total sample size will be 37 in Phase 2 including patients in the phase 1 portion of the study treated at the RP2D.
a phase 1/2 trial of
5.3 analysis plan

All patients who received at least 75% of prescribed cohort dose during the DLT period will be considered evaluable. Patients not evaluable will be replaced.
a phase 1/2 trial of
phase 1 portion of the

Safety and tolerability will also be assessed by clinical review of all relevant parameters including adverse experiences (AEs), laboratory tests, and physical exam. Adverse experiences will be summarized as counts and frequencies for each dose level. Other safety endpoints will be summarized as appropriate. These data are descriptive in nature and statistical analysis tools will not be required. The recommended phase 2 dose will be determined using safety data including DLTs and post-DLT toxicity, the dose-response relationship, and PK data. Pharmacokinetic data will be acquired as described in section 3.4.6 and average values and standard deviations at each time point will be reported.
a phase 1/2 trial of
phase 2 portion of the

The PFS duration is defined as the time from the date of start of protocol therapy to the date of the first documented progression or death due to any cause. A patient who has not progressed or died by the date of the analysis cut-off or when the patient received any further anticancer therapy would have the PFS censored at the time of the last adequate tumor assessment before the first of the cut-off date or of the anticancer therapy date. All patients will be followed for 6 months and proportion of patients that are progression free at 6 months will be calculated. We assume that combination treatment will have at least 70% PFS rate versus the undesirable PFS of <50% at 6 months. The phase 2portion is designed based single stage binomial design with the type I alpha of 5% and the power of 80%. If ≥ 23 patients ultimately achieve 6 months PFS, then further investigation of the drug is warranted. As secondary efficacy endpoints, the median PFSand OS will be estimated using exact binomial distribution; time to progression will be estimated using Kaplan-Meier methods. The 6-month PFS and 95% confidence intervals will be reported. ORR will be reported as frequencies and proportions with exact 95% confidence intervals from the Binomial distribution. 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. Correlative assessments for PTEN expression, changes in pS6, and gene expression analysis are described in section 3.4.7 along with statistical analysis plans.
a phase 1/2 trial of
6 procedures and instructions 6.1.1

Any formal presentation or publication of data from this trial may be published after review and comment by Novartis and prior to any outside submission. Novartis must receive copies of any intended communication in advance of publication (at least fifteen working days for presentational materials and abstracts and thirty working days for manuscripts). These requirements acknowledge Novartis" responsibility to provide peer input regarding the scientific content and conclusions of such publications or presentations. Principal Investigation/Institution shall have the final authority to determine the scope and content of its publications, provided such authority shall be exercised with reasonable regard for the interests of Novartis and, in accord with the trial contract and shall not permit disclosure of Novartis confidential or proprietary information.
a phase 1/2 trial of
6.1.2 disclosure and confidentiality

The investigator agrees to keep all information provided by Novartis in strict confidence and to request similar confidentiality from his/her staff and the IRB/IEC/REB. Study documents provided by Novartis (investigators' brochures and other material) will be stored appropriately to ensure their confidentiality. The information provided by Novartis to the investigator may not be disclosed to others without direct written authorization from Novartis, except to the extent necessary to obtain informed consent from patients who wish to participate in the trial.
a phase 1/2 trial of
6.1.3 discontinuation of study

Novartis reserves the right to discontinue any study under the conditions specified in the clinical trial agreement.
a phase 1/2 trial of
6.2 ethics and good clinical

This study must be carried out in compliance with the protocol and the principles of Good Clinical Practice and:
ICH Harmonized Tripartite Guidelines for Good Clinical Practice 1996. Directive 91/507/EEC, The Rules Governing Medicinal Products in the European Community US 21 Code of Federal Regulations dealing with clinical studies (including parts 50 and 56 concerning informed consent and IRB regulations) Declaration of Helsinki and amendments, concerning medical research in humans (Recommendations Guiding Physicians in Biomedical Research Involving Human Subjects)
The investigator agrees to adhere to the instructions and procedures described in it and thereby to adhere to the principles of Good Clinical Practice that it conforms to.
a phase 1/2 trial of
6.2.1 institutional review board/independent ethics

Before implementing this study, the protocol, the proposed informed consent form and other information to subjects, will be reviewed by the Committee on Human Research (CHR) (UCSF"s Institutional Review Board [IRB]). A signed and dated statement that the protocol and informed consent have been approved by the CHR will be providedto Novartis before study initiation. Any amendments to the protocol will be approved by the CHR prior to implementation.
a phase 1/2 trial of
6.2.2 informed consent

The investigator must explain to each subject (or legally authorized representative) the nature of the study, its purpose, the procedures involved, the expected duration, the potential risks and benefits involved and any discomfort it may entail. Each subject must be informed that participation in the study is voluntary and that he/she may withdraw from the study at any time and that withdrawal of consent will not affect his/her subsequent medical treatment or relationship with the treating physician.  
This informed consent should be given by means of a standard written statement, written in nontechnical language. The subject should read and consider the statement before signing and dating it, and should be given a copy of the signed document. If the subject cannot read or sign the documents, oral presentation may be made or signature given by the subject"s legally appointed representative, if witnessed by a person not involved in the study, mentioning that the patient could not read or sign the documents. No patient can enter the study before his/her informed consent has been obtained. The informed consent form is considered to be part of the protocol, and willbe submitted by the investigator to the CHR for approval.
a phase 1/2 trial of
6.2.3 multicenter communication

The UCSF Coordinating Center provides administration, data management, and organizational support for the participating sites in the conduct of a multicenter clinical trial. The UCSF Coordinating Center will also coordinate, at minimum, biweekly conference calls with the participating sites for Phase I dose escalation studies prior to each cohort escalation and at the completion of each cohort or more frequently as needed to discuss risk assessment. The following issues will be discussed as appropriate:
Enrollment information  
Cohort updates (i.e. DLTs) Adverse events (i.e. new adverse events and updates on unresolved adverse events and new safety information) Protocol violations Other issues affecting the conduct of the study
a phase 1/2 trial of
6.2.4 record keeping and record

The Principal Investigator is required to maintain adequate records of the disposition of the drug, including dates, quantity, and use by subjects, as well as written records of the disposition of the drug when the study ends. The Principal Investigator is required to prepare and maintain adequate and accurate case histories that record all observations and other data pertinent to the investigation on each individual administered the investigational drug or employed as a control in the investigation. Case histories include the case report forms and supporting data including, for example, signed and dated consent forms and medical records including, for example, progress notes of the physician, the individual's hospital chart(s), and the nurses' notes. The case history for each individual shall document that informed consent was obtained prior to participation in the study. Study documentation includes all CRFs, data correction forms or queries, source documents, Sponsor-Investigator correspondence, monitoring logs/letters, and regulatory documents (e.g., protocol and amendments, CHR correspondence and approval, signed patient consent forms). Source documents include all recordings of observations or notations of clinical activities and all reports and records necessary for the evaluation and reconstruction of the clinical research study. In accordance with FDA regulations, the investigator shall retain records for a period of 2 years following the date a marketing application is approved for the drug for the indication for which it is being investigated; or, if no application is to be filed or if the application is not approved for such indication, until 2 years after the investigation is discontinued and FDA is notified.
a phase 1/2 trial of
6.2.5 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.
a phase 1/2 trial of
6.2.6 regulatory documentation

Prior to implementing this protocol at UCSF HDFCCC, the protocol, informed consent form, HIPAA authorization and any other information pertaining to participants must be approved by the UCSF Committee on Human Research (CHR). Prior to implementing this protocol at the participating sites, approval for the UCSF CHR approved protocol must be obtained from the participating site"s IRB. The following documents must be provided to UCSF HDFCCC before the participating site can be initiated and begin enrolling participants:  
Participating Site IRB approval(s) for the protocol, appendices, informed consent form and HIPAA authorization Participating Site IRB approved consent form Participating Site IRB membership list Participating Site IRB"s Federal Wide Assurance number and OHRP Registration number 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.
a phase 1/2 trial of
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inhibitor, in patients (pts) with advanced solid tumors. *J Clin Oncol (Meeting Abstracts)*28, Abstract 3003 (2010).  
12. Bollag, G. et al. Clinical efficacy of a RAF inhibitor needs broad target blockade in BRAFmutant melanoma. *Nature* (2010).doi:10.1038/nature09454 13. Kaplan, F.M., Shao, Y., Mayberry, M.M. & Aplin, A.E. Hyperactivation of MEK-ERK1/2 signaling and resistance to apoptosis induced by the oncogenic B-RAF inhibitor, PLX4720, in mutant N-RAS melanoma cells. *Oncogene* (2010).doi:10.1038/onc.2010.408 14. Poulikakos, P.I., Zhang, C., Bollag, G., Shokat, K.M. & Rosen, N. RAF inhibitors transactivate RAF dimers and ERK signalling in cells with wild-type BRAF. *Nature*464, 427-430 (2010).  
15. Yang, H. et al. RG7204 (PLX4032), a selective BRAFV600E inhibitor, displays potent antitumor activity in preclinical melanoma models. *Cancer Res*70, 5518-5527 (2010).  
16. Lee, J.T. et al. PLX4032, a potent inhibitor of the B-Raf V600E oncogene, selectively inhibits V600E-positive melanomas. *Pigment Cell Melanoma Res*23, 820-827 (2010).  
17. Plexxikon Plexxikon Announces Preliminary PLX4032 Phase 2 Data Confirming Substantial Response Rate in Metastatic Melanoma Patients. (2011).at <http://www.plexxikon.com/view.cfm/83/Press-Releases>
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(2008).  
19. Katso, R. et al. Cellular function of phosphoinositide 3-kinases: implications for development, homeostasis, and cancer. *Annu. Rev. Cell Dev. Biol*17, 615-675 (2001).  
20. Kim, H.H., Sierke, S.L. & Koland, J.G. Epidermal growth factor-dependent association of phosphatidylinositol 3-kinase with the erbB3 gene product. *J. Biol. Chem*269, 24747-24755
(1994).  
21. Ram, T.G. & Ethier, S.P. Phosphatidylinositol 3-kinase recruitment by p185erbB-2 and erbB-3 is potently induced by neu differentiation factor/heregulin during mitogenesis and is constitutively elevated in growth factor-independent breast carcinoma cells with c-erbB-2 gene amplification. *Cell Growth Differ*7, 551-561 (1996).  
22. Ma, Y.Y. et al. PIK3CA as an oncogene in cervical cancer. *Oncogene*19, 2739-2744 (2000). 23. Fry, M.J. Phosphoinositide 3-kinase signalling in breast cancer: how big a role might it play?  
Breast Cancer Res3, 304-312 (2001).  
24. Roymans, D. & Slegers, H. Phosphatidylinositol 3-kinases in tumor progression. *Eur. J.*
Biochem268, 487-498 (2001).  
25. Bachman, K.E. et al. The PIK3CA gene is mutated with high frequency in human breast cancers. *Cancer Biol. Ther*3, 772-775 (2004).  
26. Broderick, D.K. et al. Mutations of PIK3CA in anaplastic oligodendrogliomas, high-grade astrocytomas, and medulloblastomas. *Cancer Res*64, 5048-5050 (2004).  
27. Samuels, Y. et al. High frequency of mutations of the PIK3CA gene in human cancers.  
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29. Zeng, Z. et al. Simultaneous inhibition of PDK1/AKT and Fms-like tyrosine kinase 3 signaling by a small-molecule KP372-1 induces mitochondrial dysfunction and apoptosis in acute myelogenous leukemia. *Cancer Res*66, 3737-3746 (2006).  
30. Chow, L.M.L. & Baker, S.J. PTEN function in normal and neoplastic growth. Cancer Lett241, 184-196 (2006).  
31. Cully, M., You, H., Levine, A.J. & Mak, T.W. Beyond PTEN mutations: the PI3K pathway as an integrator of multiple inputs during tumorigenesis. *Nat. Rev. Cancer*6, 184-192 (2006).  
32. Kwiatkowski, D.J. Rhebbing up mTOR: new insights on TSC1 and TSC2, and the pathogenesis of tuberous sclerosis. *Cancer Biol. Ther*2, 471-476 (2003).  
33. Bandaru, S.S., Lin, K., Roming, S.L., Vellipuram, R. & Harney, J.P. Effects of PI3K
inhibition and low docosahexaenoic acid on cognition and behavior. *Physiol. Behav*100, 239244 (2010).  
34. Polter, A. et al. Forkhead box, class O transcription factors in brain: regulation and behavioral manifestation. *Biol. Psychiatry*65, 150-159 (2009).  
35. Beaulieu, J., Gainetdinov, R.R. & Caron, M.G. Akt/GSK3 signaling in the action of psychotropic drugs. *Annu. Rev. Pharmacol. Toxicol*49, 327-347 (2009).  
36. Riddle, M.C., Rosenstock, J. & Gerich, J. The treat-to-target trial: randomized addition of glargine or human NPH insulin to oral therapy of type 2 diabetic patients. *Diabetes Care*26, 3080-3086 (2003).  
37. Tsuchida, Y. & Therasse, P. Response evaluation criteria in solid tumors (RECIST): new guidelines. *Med. Pediatr. Oncol*37, 1-3 (2001).  
38. Eisenhauer, E.A. et al. New response evaluation criteria in solid tumours: revised RECIST
guideline (version 1.1). *Eur. J. Cancer*45, 228-247 (2009).  
39. Schultz, L. et al. Expression status and prognostic significance of mammalian target of rapamycin pathway members in urothelial carcinoma of urinary bladder after cystectomy.  
Cancer116, 5517-5526 (2010).  
40. Armstrong, A.J. et al. A pharmacodynamic study of rapamycin in men with intermediate- to high-risk localized prostate cancer. *Clin. Cancer Res*16, 3057-3066 (2010).  
41. Nazarian, R. et al. Melanomas acquire resistance to B-RAF(V600E) inhibition by RTK or NRAS upregulation. *Nature*468, 973-977 (2010).
a phase 1/2 trial of
appendix 1 questionnaires

| PHQ-9   | GAD-7    |               |       |          |               |
|---------|----------|---------------|-------|----------|---------------|
| Score   | Severity | CTCAE grading | Score | Severity | CTCAE grading |
| 0-4     | None     | Normal        | 0-4   | None     | Normal        |
| 5-9     | Mild     | Grade 1       | 5-9   | Mild     | Grade 1       |
| 10-19   | Moderate | Grade 2       | 10-14 | Moderate | Grade 2       |
| 20-27   | Severe   | Grade 3       | ≥ 15  | Severe   | Grade 3       |  
At Screening, a patient as judged by the investigator or who meets the cut-off score of ≥ 10 inthe PHQ-9 or a cut-off of ≥ 15 in the GAD-7 mood scale, respectively, will be excluded fromthe study unless overruled by the psychiatric assessment. During the study, for patients who meet the cut-off score of ≥ 10 (≥ CTCAE grade 2 moodalteration) in either questionnaire, a psychiatrist will be consulted for diagnosis and determination ofmost appropriate medical treatment. For anxiety, this applies only if status has worsened frombaseline. Patients who experience ≥ grade 2 mood alteration will be followed twice weekly bypatient self-rating mood scale and will be seen weekly by the psychiatrist until resolved ≤grade 1 or baseline (for anxiety). Questionnaire responses will be checked by the psychiatristat the weekly visits (until resolution to Grade 1 or baseline (for anxiety).  
Version date: June 24, 2013
a phase 1/2 trial of
table a2. gad-7 anxiety scale

| Over the last 2 weeks, how often have you         | More than   |           |        |    |
|---------------------------------------------------|-------------|-----------|--------|----|
| been bothered by the following problems?          | Not at      | Several   | Nearly |    |
| half the                                          |             |           |        |    |
| all                                               | dys         | every day |        |    |
| dys                                               |             |           |        |    |
| (Use "✔" to indicate your answer"                 |             |           |        |    |
| 1. Feeling nervous, anxious or on edge            | 0           | 1         | 2      | 3  |
| 2. Not being able to stop or control worrying     | 0           | 1         | 2      | 3  |
| 3. Worrying too much about different things       | 0           | 1         | 2      | 3  |
| 4. Trouble relaxing                               | 0           | 1         | 2      | 3  |
| 5. Being so restless that it is hard to sit still | 0           | 1         | 2      | 3  |
| 6. Becoming easily annoyed or irritable           | 0           | 1         | 2      | 3  |
| 7. Feeling afraid as if something awful           | 0           | 2         | 3      |    |
| might happen                                      | 1           |           |        |    |
a phase 1/2 trial of
table a3. phq-9 depression scale

| Over the last 2 weeks, how often have you been                | More          | Nearly   |           |       |
|---------------------------------------------------------------|---------------|----------|-----------|-------|
| bothered by any of the following problems?                    | Not at        | Several  | than half | every |
| all                                                           | dys           | the days | day       |       |
| (Use "✔" to indicate your answer"                             |               |          |           |       |
| 1. Little interest or pleasure in doing things......          | 0             | 1        | 2         | 3     |
| 2. Feeling down, depressed, or hopeless.                      | 0             | 1        | 2         | 3     |
| 3. Trouble falling or staying asleep, or sleeping too         | 0             | 1        | 2         | 3     |
| much .                                                        |               |          |           |       |
| 4. Feeling tired or having little energy..................... | 0             | 1        | 2         | 3     |
| 5. Poor appetite or overeating                                | 2             | 3        |           |       |
| 0                                                             | 1             |          |           |       |
| 6. Feeling bad about yourself - or that you are a             | o             | 1        | 2         | 3     |
| failure or have let yourself or your family down……            |               |          |           |       |
| 7. Trouble concentrating on things, such as reading           | 0             | 1        | 2         | 3     |
| the newspaper or watching television…………….                    |               |          |           |       |
| 8. Moving or speaking so slowly that other people             |               |          |           |       |
| couldhave noticed? Or the opposite - being so                 | 0             | 1        | 2         | 3     |
| fidgety or restless that you have been moving                 |               |          |           |       |
| around a lot more than usual                                  |               |          |           |       |
| 9. Thoughts that you would be better off dead or of           | 0             | 1        | 2         | 3     |
| hurting yourself in some way                                  |               |          |           |       |
| Column totals:                                                | = Total Score |          |           |       |
a phase 1/2 trial of
appendix 2 prohibited medications

| Table A4. List of prohibited CYP3A Inhibitors and Inducers Strong CYP3A4,5,7 inhibitors Moderate CYP3A4,5,7   | CYP3A4 inducers   |                 |
|---------------------------------------------------------------------------------------------------------------|-------------------|-----------------|
| inhibitors                                                                                                    |                   |                 |
| Clarithromycin                                                                                                | aprepitant        | Barbiturates    |
| Conivaptan                                                                                                    | atazanavir        | Carbamazepine   |
| grapefruit juice                                                                                              | cimetidine        | Efavirenz       |
| Indinavir                                                                                                     | ciprofloxacin     | Modafenil       |
| Itraconazole                                                                                                  | darunavir         | Nevirapine      |
| Ketoconazole                                                                                                  | diltiazem         | Oxcarbazepine   |
| Lopinavir                                                                                                     | erythromycin      | Phenobarbital   |
| Mibefradil                                                                                                    | fluconazole       | Phenytoin       |
| Nefazodone                                                                                                    | tofisopam         | pioglitazone    |
| Nelfinavir                                                                                                    | verapamil         | Rifabutin       |
| Posaconazole                                                                                                  | amprenavir        | Rifampin        |
| Ritonavir                                                                                                     | fosamprenavir     | St. John's wort |
| Saquinavir                                                                                                    | Topiramate        |                 |
| Telithromycin                                                                                                 | troglitazone      |                 |
| troleandomycin Voriconazole                                                                                   |                   |                 |  
| Table A5. List of CYP450 Substrates to be used with caution CYP2C8 CYP2C9 CYP2C19                                                                         | CYP3A**       |                  |               |               |
|-----------------------------------------------------------------------------------------------------------------------------------------------------------|---------------|------------------|---------------|---------------|
| amodiaquine                                                                                                                                               | celecoxib     | amitriptyline    | Adinazolam    | felodipine1   |
| cerivastatin                                                                                                                                              | diclofenac    | citalopram       | alfentanil1,2 | fentanyl2     |
| pioglitazone                                                                                                                                              | flurbiprofen  | clobazam         | alphadihydroergocryptine1               | flunitrazepam |
| repaglinide                                                                                                                                               | fluvastatin   | clomipramine     | Alprazolam    | fluticasone1  |
| rosiglitazone                                                                                                                                             | glibenclamide | clopidogrel      | Amlodipine    | lovastatin1   |
| (glyburide)                                                                                                                                               |               |                  |               |               |
| torasemide                                                                                                                                                | gliclazide    | diazepam         | Aripiprazole  | maraviroc1    |
| troglitazone                                                                                                                                              | glimepiride   | fluoxetine       | Atorvastatin  | midazolam1    |
| glipizide                                                                                                                                                 | imipramine    | Brecanavir       | nifedipine    |               |
| indomethacin                                                                                                                                              | lansoprazole  | brotizolam1      | nisoldipine   |               |
| irbesartan                                                                                                                                                | mephobarbital | budesonide1      | nitrendipine  |               |
| ketobemidone                                                                                                                                              | moclobemide   | buspirone1       | perospirone1  |               |
| lornoxicam                                                                                                                                                | omeprazole    | Capravirine      | quinine       |               |
| losartan                                                                                                                                                  | pantoprazole  | Cerivastatin     | sildenafil1   |               |
| meloxicam                                                                                                                                                 | progesterone  | Chlorpheniramine | simvastatin1  |               |
| naproxen                                                                                                                                                  | quazepam      | cyclosporine2    | sirolimus1,2  |               |
| nateglinide                                                                                                                                               | rabeprazole   | darifenacin1     | tolvaptan     |               |
| piroxicam                                                                                                                                                 | sertraline    | Diazepam         | trazodone     |               |
| rosiglitazone                                                                                                                                             | S-mephenytoin | diergotamine2    | triazolam1    |               |
| S-ibuprofen                                                                                                                                               | ebastine1     |                  |               |               |
| sulfamethoxazole                                                                                                                                          | eletriptan1   |                  |               |               |
| tenoxicam                                                                                                                                                 | eplerenone1   |                  |               |               |
| tolbutamide                                                                                                                                               | ergotamine2   |                  |               |               |
| torasemide                                                                                                                                                | Estazolam     |                  |               |               |
| valdecoxib                                                                                                                                                | everolimus1   |                  |               |               |
| * This database of CYP substrates was compiled from the Indiana University School of Medicine"s "Clinically Relevant"  Table, and from (Zhou et al. 2009) |               |                  |               |               |  
valdecoxib everolimus1
* This database of CYP substrates was compiled from the Indiana University School of Medicine"s "Clinically Relevant" Table, and from (Zhou et al. 2009) ** CYP3A substrates were compiled from the Indiana University School of Medicine"s "Clinically Relevant" Table; and supplemented by the FDA"s "Guidance for Industry, Drug Interaction Studies" and the University of Washington"s Drug Interaction Database.  
1 Sensitive substrates: Drugs whose plasma AUC values have been shown to increase 5-fold or higher when co-administered with a potent inhibitor of the respective enzyme.  
2 Substrates with narrow therapeutic index (NTI): Drugs whose exposure-response indicates that increases in their exposure levels by the concomitant use of potent inhibitors may lead to serious safety concerns (e.g., Torsades de Pointes).
a phase 1/2 trial of
appendix 3 qt prolonging drugs

Note: If a patient, **PRIOR** to enrollment, is on a chronic treatment with any medication listed in Table A6, AND the treatment cannot be discontinued or switched to a different medication prior to starting study drug, then the patient cannot enter the trial (see exclusion criteria).  
If a patient, **AFTER** she/he has been enrolled, requires the concomitant use of any medication listed in *Table A6*, then investigators, at their discretion, may co-administer such medications. Patients receiving such medications must however be monitored.  
| Table A6. QT prolonging drugs with risk of Torsades de Pointes to avoid Drug QT risk(*) Comment Amiodarone known risk for TdP Females>Males, TdP risk regarded as low Arsenic trioxide known risk for TdP Astemizole known risk for TdP No longer available in US.  CYP3A4 substrate with narrow therapeutic index. Bepridil known risk for TdP Females>Males Chloroquine known risk for TdP Chlorpromazine known risk for TdP Cisapride known risk for TdP Restricted availability; Females>Males. CYP3A substrate with narrow therapeutic index. Disopyramide known risk for TdP Females>Males Dofetilide known risk for TdP Domperidone known risk for TdP Not available in the US. Droperidol known risk for TdP Halofantrine known risk for TdP Females>Males Haloperidol known risk for TdP When given intravenously or at higher-thanrecommended doses, risk of sudden death, QT  prolongation and torsades increases. Ibutilide known risk for TdP Females>Males Levomethadyl known risk for TdP Sensitive CYP3A substrate Mesoridazine known risk for TdP Methadone known risk for TdP Females>Males Pentamidine known risk for TdP Females>Males Pimozide known risk for TdP Females>Males. Sensitive CYP3A substrate with narrow therapeutic index Probucol known risk for TdP No longer available in U.S. Procainamide known risk for TdP Quetiapine possible risk for TdP Sensitive CYP3A substrate Quinidine known risk for TdP Females>Males. Sensitive CYP3A substrate  Sotalol known risk for TdP Females>Males Sparfloxacin known risk for TdP   |
|---|  
Table A6. QT prolonging drugs with risk of Torsades de Pointes to avoid  
| Drug                                                                                                                                                                                                     | QT risk(*)            | Comment                                                                              |
|----------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|-----------------------|--------------------------------------------------------------------------------------|
| Tacrolimus                                                                                                                                                                                               | possible risk for TdP | Sensitive CYP3A substrate with narrow therapeutic  index                             |
| Terfenadine                                                                                                                                                                                              | known risk for TdP    | No longer available in U.S. Sensitive CYP3A  substrate with narrow therapeutic index |
| Thioridazine                                                                                                                                                                                             | Known risk for TdP    |                                                                                      |
| Vardenafil                                                                                                                                                                                               | possible risk for TdP | Sensitive CYP3A substrate                                                            |
| (*) Classification according to the Qtdrugs.org Advisory Board of the Arizona CERT Sensitive substrates: Drugs whose plasma AUC values have been shown to increase 5-fold or higher when co-administered |                       |                                                                                      |  
| Drug            | QT Risk                                  |
|-----------------|------------------------------------------|
| Alfuzosin       | possible risk for Torsades de Pointes    |
| Amantadine      | possible risk for Torsades de Pointes    |
| Amitriptyline   | conditional risk for Torsades de Pointes |
| Azithromycin    | possible risk for Torsades de Pointes    |
| Chloral hydrate | possible risk for Torsades de Pointes    |
| Citalopram      | conditional risk for Torsades de Pointes |
| Clomipramine    | conditional risk for Torsades de Pointes |
| Clozapine       | possible risk for Torsades de Pointes    |
| Desipramine     | conditional risk for Torsades de Pointes |
| Diphenhydramine | conditional risk for Torsades de Pointes |
| Dolasetron      | possible risk for Torsades de Pointes    |
| Doxepin         | conditional risk for Torsades de Pointes |
| Dronedarone     | possible risk for Torsades de Pointes    |
| Felbamate       | possible risk for Torsades de Pointes    |
| Flecainide      | possible risk for Torsades de Pointes    |
| Fluoxetine      | conditional risk for Torsades de Pointes |
| Foscarnet       | possible risk for Torsades de Pointes    |
| Fosphenytoin    | possible risk for Torsades de Pointes    |
| Galantamine     | conditional risk for Torsades de Pointes |
| Gatifloxacin    | possible risk for Torsades de Pointes    |
| Gemifloxacin    | possible risk for Torsades de Pointes    |
| Granisetron     | possible risk for Torsades de Pointes    |
| Imipramine      | conditional risk for Torsades de Pointes |
| Indapamide      | possible risk for Torsades de Pointes    |
| Isradipine      | possible risk for Torsades de Pointes    |
| Levofloxacin    | possible risk for Torsades de Pointes    |
| Lithium         | possible risk for Torsades de Pointes    |
| Mexiletine      | conditional risk for Torsades de Pointes |
| Moexipril/HCTZ  | possible risk for Torsades de Pointes    |
| Moxifloxacin    | possible risk for Torsades de Pointes    |
| Nicardipine     | possible risk for Torsades de Pointes    |
| Nortriptyline   | conditional risk for Torsades de Pointes |
| Octreotide      | possible risk for Torsades de Pointes    |
| Ofloxacin       | possible risk for Torsades de Pointes    |  
Table A7. List of QT prolonging drugs to be used with caution
(*Classification according to the Qtdrugs.org Advisory Board of the Arizona CERT*)  
| Drug                                 | QT Risk                                  |
|--------------------------------------|------------------------------------------|
| Ondansetron                          | possible risk for Torsades de Pointes    |
| Oxytocin                             | possible risk for Torsades de Pointes    |
| Paliperidone                         | possible risk for Torsades de Pointes    |
| Paroxetine                           | conditional risk for Torsades de Pointes |
| Perflutren lipid                     | possible risk for Torsades de Pointes    |
| microspheres Protriptyline           | conditional risk for Torsades de Pointes |
| Ranolazine                           | possible risk for Torsades de Pointes    |
| Risperidone                          | possible risk for Torsades de Pointes    |
| Roxithromycin*                       | possible risk for Torsades de Pointes    |
| Sertindole                           | possible risk for Torsades de Pointes    |
| Sertraline                           | conditional risk for Torsades de Pointes |
| Solifenacin                          | conditional risk for Torsades de Pointes |
| Tizanidine                           | possible risk for Torsades de Pointes    |
| Trazodone                            | conditional risk for Torsades de Pointes |
| Trimethoprim-Sulfa                   | conditional risk for Torsades de Pointes |
| Trimipramine                         | conditional risk for Torsades de Pointes |
| Venlafaxine                          | possible risk for Torsades de Pointes    |
| Ziprasidone                          | possible risk for Torsades de Pointes    |
| * Not available in the United States |                                          |  
Table A7. List of QT prolonging drugs to be used with caution
(*Classification according to the Qtdrugs.org Advisory Board of the Arizona CERT*)
a phase 1/2 trial of
appendix 4 bkm120 pharmacokinetic analysis

BKM120 sampling and shipping information Draw 2 mL into a 5 mL EDTA (K3) coated tube Invert the tube gently several times to avoid clotting Place the tube into an ice bath at approximately 4°C during the sampling period Within 30 min after collection, centrifuge the tube at 3-5°C for 15 min at 1500 to 2000g Transfer the plasma into uniquely labeled 2ML SMART SCAN TUBES from Thermo
(Reference for rack/48 tubes: Nr. AB1411 or Reference for only 100 tubes: AB-1389) and frozen immediately over solid carbon dioxide (dry ice) or in a freezer at approximately -70°C or below.  
Ship frozen on dry ice to Central Lab
a phase 1/2 trial of
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. Shipping reservations should be made to allow delivery to Novartis before 16:00 (4 pm) local time Monday to Thursday and before 11:00 (11 am) local time on Friday. Shipments should not be sent between Thursday and Sunday, to prevent arrival over the weekend.
a phase 1/2 trial of
instructions for shipment of biological

All pharmacokinetic specimens will be kept at the temperature specified in the PK collection and processing section until shipment. 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: Novartis Pharma AG Gerardo de Pierro for WalidElbast Fabrikstrasse 14 - 3.28.2 CH-4002 Basel,Switzerland Telephone: +41-79-535 96 32 Fax: +41-61-696 85 84 Email: *ts-dmpk.sample-management@novartis.com*
a phase 1/2 trial of
please notify the addressee in

Number of the airbill, The time and date of shipping and approximate time of arrival, Flight Number, 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 at Novartis when a shipment has been scheduled. The samples should be sent at the beginning of a week in order to arrive not later than Thursday.
a phase 1/2 trial of
appendix 5vemurafenib pharmacokinetics and correlative

Under the supervision of Drs. Yong Huang and Leslie Floren, vemurafenib analysis will be performed at UCSF.  
Vemurafenib sampling and shipping information Draw 2 mL into a 5 mL EDTA (K3) coated tube Invert the tube gently several times to avoid clotting Place the tube into an ice bath at approximately 4°C during the sampling period Within 30 min after collection, centrifuge the tube at 3-5°C for 15 min at 1500 to 2000g Transfer the plasma into uniquely labeled 2ML SMART SCAN TUBES from Thermo (Reference for rack/48 tubes: Nr. AB1411 or Reference for only 100 tubes: AB-1389) and frozen immediately over solid carbon dioxide (dry ice) or in a freezer at approximately -70°C or below. Ship frozen on dry ice to:
Yong Huang, Ph. D. 296 Lawrence Street University of California, San Francisco San Francisco, CA. 94143 - 0912 Email: *yong.huang@ucsf.edu* Phone: 415-476-5220
a phase 1/2 trial of
correlative studies assessments

Portions of all new tumor biopsy specimens will be immediately immersed in formalin and subsequently embedded in paraffin and additional tissue will be flash-frozen and stored at
-70ºC until the time of analysis The primary contact for acquisition and processing of these specimens at UCSF is: Kim Chong, MD UCSF Melanoma Fellow Phone: 353-9986 Email: chongk@derm.ucsf.edu
a phase 1/2 trial of
appendix 6 multicenter institutional studies

The UCSF Helen Diller Family Comprehensive Cancer Center (HDFCCC) Data and Safety Monitoring Committee (DSMC) is responsible for monitoring data quality and subject safety for all HDFCCC institutional clinical studies. A summary of DSMC activities for this study includes:
Review of subject data in each cohort Review of suspected adverse reactions considered "serious" Approval of dose escalation by DSMC Chair (or qualified alternate) Monthly monitoring (depending on study accrual)
Minimum of a yearly regulatory audit
a phase 1/2 trial of
monitoring and reporting guidelines

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

The UCSF Coordinating Center provides administration, data management, and organizational support for the participating sites in the conduct of a multicenter clinical trial. The UCSF Coordinating Center will also coordinate, at minimum, monthly conference calls with the participating sites at the completion of each cohort or more frequently as needed to discuss risk assessment. The following issues will be discussed as appropriate:
Enrollment information Cohort updates (i.e. DLTs) Adverse events (i.e. new adverse events and updates on unresolved adverse events and new safety information)  
Protocol violations Other issues affecting the conduct of the study Dose Level Considerations
The PI/Study Chair, participating investigators, and research coordinators from each site will review enrollment for each dose level cohort during the regularly scheduled conference calls. The dose level for ongoing enrollment will be confirmed for each subject scheduled to be enrolled at a site. Dose level assignments for any subject scheduled to begin treatment must be confirmed by the UCSF Coordinating Center via fax or e-mail. If a Dose Limiting Toxicity (DLT) arises in a subject treated at a study site, all sites must be notified immediately by the UCSF Coordinating Center. The Study Chair has 1 business day (after first becoming aware of the event at either the UCSF Coordinating Center or the participating site) in which to report the information to all participating sites. If the DLT occurs at a participating site, the local investigator must report it to the UCSF Coordinating Center within**1 business day**, after which the UCSF Coordinating Center will notify the other participating sites. Adverse events reporting to the DSMC will include reports from both the UCSF Coordinating Center, as well as the participating sites. The DSMC will be responsible for monitoring all data entered in OnCore® at the UCSF Coordinating Center and the participating sites. The data (i.e.  
copies of source documents) from the participating sites will be sent electronically or faxed over to the UCSF Coordinating Center prior to the monitoring visits in order for the DSMC to monitor the participating site"s compliance with the protocol, patient safety, and to verify data entry.
a phase 1/2 trial of
review and oversight requirements adverse

All clinically significant adverse events (AEs), whether or not unexpected, and whether or not considered to be associated with the use of study drug, will be entered into OnCore®, UCSF"s Clinical Trial Management System.  
All clinically significant adverse events entered into OnCore® will be reviewed on a weekly basis at the UCSF Coordinating Center"s Site Committee. All clinically significant adverse events must be reported to the UCSF Coordinating Center by the participating sites within **10 business**
days of becoming aware of the event. The Site Committee will review and discuss the selected toxicity, the toxicity grade, and the attribution of relationship of the adverse event to the administration of the study drug(s).  
In addition, all suspected adverse reactions considered "serious" are entered into OnCore® and will be reviewed and monitored by the Data and Safety Monitoring Committee on an ongoing basis and discussed at the DSMC meetings, which take place every six (6) weeks. All suspected adverse reactions considered "serious" should be reported to the UCSF
Coordinating Center within **1 business day** of becoming aware of the event or during the next scheduled conference call, whichever is sooner. If a death occurs during the treatment phase of the study or within 30 days after the last administration of the study drug(s) and is determined to be related either to the investigational drug or any research related procedure, the Study Chair at the UCSF Coordinating Center or the assigned designee must be notified within **1 business day** from the participating site(s) and the Study Chair must then notify the DSMC Chair or qualified alternate within **1 business day** of this notification. The contact may be by phone or e-mail.
a phase 1/2 trial of
increase in adverse event rates

If an increase in the frequency of Grade 3 or 4 adverse events (above the rate reported in the Investigator Brochure or package insert), the Study Chair at the UCSF Coordinating Center is responsible for notifying the DSMC at the time the increased rate is identified. The report will indicate if the incidence of adverse events observed in the study is above the range stated in the Investigator Brochure or package insert. If at any time the Study Chair stops enrollment or stops the study due to safety issues, the DSMC Chair and DSMC Manager must be notified within **1 business day** via e-mail. The DSMC must receive a formal letter within **10 business days** and the CHR must be notified.  
Data and Safety Monitoring Committee Contacts: DSMC Chair: Alan Venook, MD DSMC Monitors Phone: Email: Address:  
| DSMC Chair:             | Alan Venook, MD                                                       | DSMC Monitors   |
|-------------------------|-----------------------------------------------------------------------|-----------------|
| Phone:  Email: Address: | 415-353-2745 venook@cc.ucsf.edu Box 1705 UCSF San Francisco, CA 94115 |                 |  
| Box 1297 UCSF Helen Diller Family  Comprehensive Cancer Center San Francisco, CA 94115   |
|------------------------------------------------------------------------------------------|  
* DSMP approved by NCI 09/February2012
a phase 1/2 trial of
6.2 ucsf policy/procedure for required

This policy defines the required Regulatory Documents for Single Site and Multicenter Investigator Initiated Oncology Clinical Trials at the Helen Diller Family Comprehensive Cancer Center (HDFCCC) where the Principal Investigator (PI) holds the IND.
a phase 1/2 trial of
background

The International Conference on Harmonization (ICH) Good Clinical Practices (GCP) Guidelines define Essential Regulatory Documents as those documents which individually and collectively permit evaluation of the conduct of a trial and the quality of data produced. These documents serve to demonstrate compliance with standards of GCP and with all applicable regulatory requirements. Filing essential documents in a timely manner can greatly assist in the successful management of a clinical trial.  
The Regulatory Documents will consist of electronic files in both iMedRIS and OnCore®, as well as paper files in the Regulatory Binders for both the Coordinating Site and the Participating Site(s) in the HDFCCC Investigator Initiated Oncology Clinical Trials.
a phase 1/2 trial of
procedures 1. hdfccc essential regulatory

CHR approvals for initial submission of application, all modifications, and continuing annual renewals Current and prior approved protocol versions with signed protocol signature page(s) Committee for Human Research (CHR) approval letters and Informed Consent Form(s) (ICF) Current and prior versions of the Investigator Brochure (IB). Serious Adverse Event Reporting Protocol Violations and Single Patient Exception (SPE) Reports to CHR with supporting fax documentation
a phase 1/2 trial of
documents filed in oncore

Package Insert (if the study drug is commercial) or Investigator Brochure Protocol Review Committee (PRC) approved protocols, protocol amendments and Summary of Changes (SOC) Patient handouts Screening/enrollment log Data and Safety Monitoring Committee (DSMC) monitoring reports DSMC dose escalation approvals with study status summary forms OnCore® Case Report Form (CRF) completion manual
a phase 1/2 trial of
documents filed in regulatory binder

Completed Food and Drug Administration (FDA) 1572 document with Principal Investigator"s signature For all Principal Investigators and Sub-Investigators listed on the FDA 1572, will need Financial Disclosure Forms, CVs, MD Licenses, Drug Enforcement Agency (DEA) Licenses, and Staff Training Documents (i.e. Collaborative Institute Training Initiative (CITI), etc.) Site Initiation Visit (SIV) minutes and correspondence with participating site(s). As applicable, approvals for Biosafety Committee, Radiation Committee, and Infusion Center Serious Adverse Event (SAE) reports to CHR and sponsor. MedWatch reporting to FDA and sponsor Delegation of Authority Form Drug Destruction Standard Operating Procedure (SOP) For all laboratories listed on the FDA 1572, will need CLIA certifications, CAP certifications, lab licenses, CVs of Lab Directors, and laboratory reference ranges 2. Additional Essential Documents for Multicenter Trials for the Coordinating Center (filed in Regulatory Binder or OnCore)
Institutional Review Board (IRB) approval letters, IRB roster, Informed Consent Form (ICF), and Health Insurance Portability and Accountability Act (HIPAA) Consent Form for the Participating Site(s)
For all Principal Investigators and Sub-Investigators listed on the 1572 at the Participating Site(s) - Financial Disclosure Forms, CVs, MD Licenses, and Staff Training documents (i.e. Collaborative Institute Training Initiative (CITI), etc.) (for Investigational New Drug Application Site Initiation Visit (SIV) minutes and correspondence with Participating Site(s). As applicable, approvals for Biosafety Committee, Radiation Committee, and Infusion Center for the Participating Site(s) Protocol Violations and Single Patient Exception (SPE) reports to IRB with supporting fax documentation for Participating Site(s) Drug Destruction Standard Operating Procedure (SOP) for the Participating Site(s) Data and Safety Monitoring Committee (DSMC) monitoring reports for the Participating Site(s) For all laboratories listed on FDA 1572, will need CLIA certifications, CAP certifications, lab licenses, CVs of Lab Directors, and laboratory reference ranges for the Participating Site(s) Copy of the Data and Safety Monitoring Plan (DSMP) Monitoring Plan for all participating site(s) in Multicenter studies or Contract Research Organization (CRO) Monitoring Plan (if an outside CRO is used for the study) Serious Adverse Event (SAE) forms submitted to both the IRB and the sponsor for the Participating Site(s)
27 April 2012
a phase 1/2 trial of
6.3 required regulatory documents for

Directions: 1) Fax the documents listed below to the UCSF Coordinating center at 415-514-6955or 2) Scan the documents and upload to OnCore® and create a Note to File for the on-site Regulatory binder to indicate where these documents may be found 1572 PI and Sub investigators:
CV and Medical license Financial disclosure form NIH or CITI human subject protection training certification Laboratories CLIA and CAP CV of Lab Director and Lab Licenses Laboratory reference ranges
a phase 1/2 trial of
local institutional review board

IRB Approval letter Reviewed/Approved documents Protocol version date: ___________ Informed consent version date: ___________ Investigator Brochure version date: ___________ HIPAA
Current IRB Roster
a phase 1/2 trial of
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