A Phase II Study of the BRAF Inhibitor, Vemurafenib, in Patients With Relapsed or Refractory Hairy Cell Leukemia
Phase: PHASE2
Conditions: Hairy Cell Leukemia
Sponsor: Memorial Sloan Kettering Cancer Center

Memorial Sloan Kettering Cancer Center 
IRB Number: 12-200 A(17) 
Approval date: 15-Jun-2022 
Page 1 of 39 
 
 
MSK PROTOCOL COVER SHEET 
A Phase II Study of the BRAF Inhibitor, Vemurafenib, in Patients with Relapsed or 
Refractory Hairy Cell Leukemia 
 
Principal Investigator/Department: Jae Park, MD/ Medicine 

Memorial Sloan Kettering Cancer Center 
IRB Number: 12-200 A(17) 
Approval date: 15-Jun-2022 
Page 2 of 39 
 
 
 
Table of Contents 
1.0 
PROTOCOL SUMMARY AND/OR SCHEMA ......................................................................... 4 
2.0 
OBJECTIVES AND SCIENTIFIC AIMS .................................................................................. 5 
3.0 
BACKGROUND AND RATIONALE ........................................................................................ 5 
4.0 
OVERVIEW OF STUDY DESIGN/INTERVENTION................................................................. 8 
4.1 
Design ................................................................................................................................. 8 
4.2 
Intervention .......................................................................................................................... 9 
5.0 
THERAPEUTIC/DIAGNOSTIC AGENTS ................................................................................ 9 
6.0 
CRITERIA FOR SUBJECT ELIGIBILITY .............................................................................. 10 
6.1 
Subject Inclusion Criteria ................................................................................................... 10 
6.2 
Subject Exclusion Criteria .................................................................................................. 11 
7.0 
RECRUITMENT PLAN ......................................................................................................... 11 
8.0 
PRETREATMENT EVALUATION ......................................................................................... 12 
9.0 
TREATMENT/INTERVENTION PLAN .................................................................................. 12 
10.0 EVALUATION DURING TREATMENT/INTERVENTION ...................................................... 14 
11.0 TOXICITIES/SIDE EFFECTS ................................................................................................ 19 
11.0 TOXICITIES/SIDE EFFECTS ................................................... Error! Bookmark not defined. 
12.0 CRITERIA FOR THERAPEUTIC RESPONSE/OUTCOME ASSESSMENT .......................... 27 
13.0 CRITERIA FOR REMOVAL FROM STUDY .......................................................................... 27 
14.0 BIOSTATISTICS ................................................................................................................... 28 
15.0 
RESEARCH PARTICIPANT REGISTRATION AND RANDOMIZATION PROCEDURES .... 29 
15.1 Research Participant Registration ...................................................................................... 29 
15.2 Randomization................................................................................................................... 29 
16.0 DATA MANAGEMENT ISSUES ........................................................................................... 29 
16.1 Quality Assurance ............................................................................................................. 29 
16.2 Data and Safety Monitoring ............................................................................................... 29 
17.0 PROTECTION OF HUMAN SUBJECTS ............................................................................... 30 
17.1 Privacy .............................................................................................................................. 30 
17.2 Serious Adverse Event (SAE) Reporting ............................................................................ 30 
17.2.2 SAE Reporting to Genentech (MSKCC STAFF ONLY)................................................... 31 
17.3 Procedures for Eliciting, Recording, and Reporting Adverse Events .... Error! Bookmark not 
defined. 
Eliciting Adverse Events .............................................................. Error! Bookmark not defined. 
Specific Instructions for Recording Adverse Events ..................... Error! Bookmark not defined. 
17.4 
Serious Adverse Event Reporting (For Participating Sites)............ Error! Bookmark not 
defined. 
17.5 Safety Reports (For Participating Sites) ............................................................................. 34 
17.6 Unanticipated Problems (For Participating Sites) .................. Error! Bookmark not defined. 
18.0 INFORMED CONSENT PROCEDURES ............................................................................... 35 
18.1 
Informed Consent Procedures (For Participating Sites) ..... Error! Bookmark not defined. 
19.0 REFERENCES ..................................................................................................................... 36 

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IRB Number: 12-200 A(17) 
Approval date: 15-Jun-2022 
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20.0 APPENDICES ....................................................................................................................... 38 

Memorial Sloan Kettering Cancer Center 
IRB Number: 12-200 A(17) 
Approval date: 15-Jun-2022 
Page 4 of 39 
 
 
 
 
1.0 
PROTOCOL SUMMARY AND/OR SCHEMA 
Title: A phase II trial of the BRAF Inhibitor, Vemurafenib, in patients with relapsed or refractory hairy 
cell leukemia (HCL) 
Objectives: To determine the efficacy of vemurafenib as assessed by overall response rates after 
three months of treatment in patients with relapsed or refractory HCL. 
Patient Population: Patients with HCL who are refractory to or intolerant of purine analogs, who have 
relapsed disease within 2 years of purine analog-based therapy, or who have ≥ 2 relapses will be 
eligible for the trial. 
Study Design: This is a multi-center, open label, single arm, phase II trial of the oral BRAF inhibitor, 
vemurafenib. A Simon mini-max two-stage design will be employed to assess the efficacy of 
vemurafenib. In the first stage of the protocol, 19 patients will be treated. If 3 or fewer responses (CR 
or PR) are seen among the first 19 patients, the study will be closed for lack of efficacy. If at least 4 
patients respond to the treatment, then an additional 17 patients will be accrued to the second stage. 
At the end of the trial, if 11 or more patients have responded out of the 36 patients then the drug will 
be considered worthy of further investigation. 
Treatment Plan: Eligible patients will receive vemurafenib at a dose of 960mg orally twice daily (b.i.d.) 
continuously in cycles of 4 weeks (28 days). A bone marrow aspirate and/or biopsy will be performed 
after the first cycle for research purposes only. After the completion of the third cycle, a repeat bone 
marrow aspirate and/or biopsy will be performed for assessment of response and evaluation of 
minimal residual disease (MRD). Following the third cycle assessments, patients who achieve 
complete response (CR) with detectable MRD or partial response (PR) may continue with vemurafenib 
for up to 3 additional cycles at the treating physician’s discretion (Cycles 4-6). Patients who achieve 
CR without MRD will be observed as part of post-treatment followup, and may be re-treated with 
vemurafenib after relapse (as per below). Patients who achieve no response (NR) after the initial 3 
cycles of vemurafenib will be removed from the study. 
 
After patients discontinue vemurafenib, they will be followed every 3 months as part of post-treatment 
followup for a total of 12 months. Patients who previously experienced CR, PR (either hematologic or 
MRD) or clinical benefit, but who subsequently relapse after ending treatment may be retreated with 
Vemurafenib until disease progression or at the treating physician’s discretion. Patients who are re- 
treated will follow the treatment/evaluation plan as outlined in Table 3 (see Section 10). A bone 
marrow aspirate and/or biopsy may be performed for assessment of response at the end of the third 
re-treatment cycle or during a subsequent re-treatment cycle when clinically indicated. 
 
In case of certain defined toxicities, dose reductions by 50% (480mg b.i.d.) or interruptions of up to 15 
days are permitted. If additional dose reduction is required, vemurafenib may be reduced to 240mg 
oral b.i.d. 
Time to Completion: As of August 17th 2016, this protocol is closed to accrual as target accrual was 
met. 

Memorial Sloan Kettering Cancer Center 
IRB Number: 12-200 A(17) 
Approval date: 15-Jun-2022 
Page 5 of 39 
 
 
 
 
 
2.0 
OBJECTIVES AND SCIENTIFIC AIMS 
Primary Objective 
 
To determine the efficacy of vemurafenib as assessed by overall response rates (complete response 
(CR) and partial response (PR)) after three months of treatment 
Secondary Objectives 
 
1. To assess the safety and tolerability of vemurafenib in patients with HCL 
2. To assess the efficacy of vemurafenib based on time to response, duration of response, and 
kinetics of minimal residual disease (MRD) response assessed by immunohistochemistry 
3. To determine the progression-free and overall survival of HCL patients treated with vemurafenib 
4. To characterize molecular profiling of HCL by high throughput next generation sequencing using 
Raindance multiplex PCR and Ilumina next generation sequencing 
5. To assess the pharmacodynamics of vemurafenib via measurement of BRAF downstream targets 
(MEK, p-MEK, ERK, p-ERK) from the peripheral blood or bone marrow aspirate samples, and by 
examining the MAPK, PI3K and JAK-STAT signaling pathways using Cell Biosciences NanoPro 
1000 technology 
6. To evaluate biomarkers that may be relevant to explain primary or acquired resistance to 
vemurafenib as assessed by additional BRAF mutations, reactivation of MAPK pathways, 
activation of alternative signaling pathways (e.g. PI3K and STAT) 
 
3.0 
BACKGROUND AND RATIONALE 
3.1 
Hairy Cell Leukemia 
Hairy cell leukemia (HCL) is a chronic B-cell lymphoproliferative disorder that is characterized 
by marked splenomegaly, progressive pancytopenia, and infiltration of leukemic B cells in the 
bone marrow, spleen, and liver. Despite the usually indolent course of HCL, most patients 
require therapy when cytopenias become life-threatening or when they develop symptomatic 
splenomegaly. 

Memorial Sloan Kettering Cancer Center 
IRB Number: 12-200 A(17) 
Approval date: 15-Jun-2022 
Page 6 of 39 
 
 
3.2 
Treatment of Newly Diagnosed HCL 
Currently, the standard first-line treatment of HCL is based on purine analogs, either 
pentostatin or cladribine as a single agent, which can induce complete response (CR) and 
partial response (PR) in 80-90% and 10-20% of treated patients, respectively1. However, 
despite the high percentage of patients achieving CR and PR, approximately 30-40% of 
patients (more patients with PR than CR) will relapse after the initial treatment with either 
pentostatin or 2-chlorodeoxyadenosine (2-CdA) with the median time to relapse ranging from 
10.5 to 42 months1-5. The propensity for relapse may be related to the extent of residual 
disease reported to be present in 50-100% of patients in CR following the initial therapy with 
purine analogs6-8, suggesting that most patients, if not all, will relapse if given sufficient time. 
3.3 
Treatment of refractory and relapsed HCL 
For patients who fail to respond to the initial purine analog therapy or who have relapsed 
disease within 1-2 years of purine analogs, there is currently no standard treatment options 
and they do not respond well to a second course of purine analog therapy. In patients who 
have relapsed disease following the initial therapy with purine analogs, CRs can be achieved 
with repeated courses of purine analogs, and the anticipated response to subsequent lines of 
therapy can be judged by the duration and quality of the initial response. If there was an initial 
remission of short duration (e.g. < 2 years), then repeat administration of the original therapy 
is less likely to result in a longer second remission9. Several long-term follow-up studies report 
the CR and PR rates of 52-62% and 26-30%, respectively, in patients treated with another 
cycle of purine analogs at the 1st relapse2,3,10. However, the ability to attain CR and its duration 
decline with each subsequent line of purine analog-based therapy1,4,11. Due to the limited 
number of patients with HCL, the outcome information on patients with ≥ 2 relapses are scarce 
and only reported in a limited number of patients. Three largest studies conducted in patients 
with HCL include only 10 – 34 patients at 2nd relapse and even less patients at 3rd relapse, and 
no information is available on patients with > 3 relapses1,4,11. In these studies, CR rates ranging 
of 50-60% have been reported. However, due to such a small sample size, it is unclear 
whether these high responses rates accurately represent a response rate expected in these 
patients. Furthermore, the relapsed patients included in these previous published reports are 
highly selected patient population with a long duration of response to previous purine analog 
treatments with a median time to 2nd and 3rd relapse ranging from 32 to 70 months. Therefore, 
the response rates in patients with a short duration of response to the previous purine analog 
treatments remains unknown. Lastly, there is no evidence to suggest that repeated courses 
of purine analogs or other alternative therapies offer any survival benefit in these patients, but 
may cause treatment-related bone marrow injury and prolonged immunodeficiency with 
successively shorter remission duration. 
 
3.4 
Limitations of Current Therapeutic Approach in HCL 
Although retreatment with purine analogs is associated with a high response rate, 
approximately 50% of patients will continue to relapse after each line of treatment requiring 
further therapy, subjecting these patients to cumulative side effects of purine analogs including 
prolonged myelosuppression with increased susceptibility to viral and fungal infections12,13 and 
a small trend toward an increased risk of secondary malignancies14-16. While the latter risk is 
controversial, the excess frequency of secondary malignancies was reported to be 1.88 in one 
series10. In a 2014 patient follow-up from the National Cancer Institute (NCI), a small trend 
toward an increased risk for second cancers was also noted (observed/expected ratio of 1.63 
for patients who were treated with 2-CdA). However, other studies fail to show an increased 

Memorial Sloan Kettering Cancer Center 
IRB Number: 12-200 A(17) 
Approval date: 15-Jun-2022 
Page 7 of 39 
 
 
risk for secondary malignancies, although some of them noted an increased risk of lymphoid 
malignancies15-17. 
More importantly, the relapse-free survival (RFS) curves in HCL patients treated with purine 
analogs do not appear to reach a plateau, and as high as 11.5% of patients become refractory 
to this class of agents when treated at 2nd or higher relapses11. In fact, all the long-term studies 
published to date have observed no plateau in the progression-free survival (PFS) curve after 
follow-up close to 14 years, suggesting that late relapse do occur and purine analogues are 
not likely curative3. 
 
Since neither purine analogs can cure the disease as monotherapy and due to associated 
prolonged immune suppression (particularly among older patients) and increased risk of 
secondary malignancies, there is an urgent need for novel targeted and potentially curative 
therapies for patients with HCL who have failed or who have multiply relapsed disease. 
 
3.5 
BRAF as a Therapeutic Target in HCL 
A recent exome sequencing study of HCL has identified BRAF a potential therapeutic target18. 
The BRAF protein is part of the RAS-RAF-MAPK signaling pathway, which plays a major role 
in regulating cell survival, proliferation, and differentiation19. BRAF mutations constitutively 
activate the MEK-ERK pathway, leading to enhanced cell proliferation, survival, and ultimately, 
neoplastic transformation20. Activation of the MAPK pathway in HCL has previously been 
described by several investigators, who reported constitutively activated ERK21, providing a 
survival signal for the leukemic hairy cells22. 
BRAF inhibition is an attractive therapeutic target for HCL for several reasons: 1) BRAF V600E 
mutation is present in 100% of HCL patients, and not found in other B cell lymphoproliferative 
disorders23-26; 2) BRAF mutation is present in the entire tumor-cell clone in virtually all patients; 
3) BRAF mutations become undetectable at remission but re-appears at relapse23-25; and 4) 
treatment of primary HCL cells with the BRAF inhibitor vemurafenib markedly inhibited the 
activation of signaling downstream of BRAF (MEK and ERK) at a very low drug concentrations 
(≤1 µM)18. Previous clinical trials with Vemurafenib in patients with metastatic melanoma 
reported that concentrations of approximately 80 µM can be safely achieved with 960mg twice 
daily oral dosing27. 
These data implicate the BRAF V600E mutation in the pathogenesis of HCL, and provides a 
strong rationale for targeting BRAF in patients with HCL. BRAF inhibition in HCL may not only 
represent the first targeted therapeutic approach, but also an attractive therapy for patients 
with suboptimal response to purine analogs as well as for patients with repeated relapses and 
with unacceptable toxic effects of purine analogs. 
 
3.6 
BRAF Inhibitor, Vemurafenib: Clinical Data in Melanoma 
The BRAF inhibitor, vemurafenib (previously known as PLX4032 and RO5185426), has been 
extensively studied both in preclinical models and in clinical trials. In vitro studies have 
demonstrated that PLX4032 selectively inhibits the growth of tumor cells expressing BRAF 
V600E mutation by inhibiting ERK signaling only in mutant BRAF tumor cells, thus achieving 
a broader therapeutic index without causing toxicity resulting from the inhibition of ERK 
signaling in normal cells28. This is in contrast to MAPK/ERK (MEK) inhibitors that inhibit ERK 
phosphorylation in both normal and tumor cells29,30. The anti-tumor efficacy of PLX4032 was 
also demonstrated in several in vivo studies using tumor xenograft models of BRAF V600E 
mutant melanoma with partial or complete tumor regressions and improved animal survival 
with no significant toxicity31. 

Memorial Sloan Kettering Cancer Center 
IRB Number: 12-200 A(17) 
Approval date: 15-Jun-2022 
Page 8 of 39 
 
 
Based on these preclinical data, several clinical trials have been conducted in patients with 
metastatic melanoma where approximately 50% of patients carry the BRAF V600E mutation. 
In a phase I trial, the maximum tolerated dose of 960mg twice daily was established, and 
frequent tumor regressions were observed27. Notably, the analysis of paired tumor biopsies 
(at baseline and at day 15 of PLX4032 treatment) revealed a strong correlation between a 
decrease in phosphorylated ERK and a clinical response, suggesting that PLX4032 inhibited 
the MAP kinase pathway (at 960mg twice daily dosing level) and the need to obtain effective 
ERK signaling inhibition for significant tumor response27,31. In a phase II trial involving patients 
with previously treated metastatic melanoma harboring the BRAF V600E mutation, a response 
rate of 53% was observed with a median duration of response of 6.7 months32. More recently, 
the results from a randomized, multicenter phase III trial was published, demonstrating a 
remarkable activity in patients with BRAF-mutated metastatic melanoma with a response rate 
of 48% (compared to 5% in patients treated with standard chemotherapy dacarbazine) and a 
relative reduction of 63% in the risk of death33. Common adverse events noted in these trials 
with vemurafenib in melanoma patients included arthralgia, rash, fatigue, alopecia, 
keratoacanthoma, photosensitivity, nausea, diarrhea and squamous-cell carcinoma, but with 
very little hematologic toxicity27,33. 
 
3.7 
BRAF Inhibitor, Vemurafenib: Clinical Data in HCL 
A group of investigators at Heidelberg University Hospital in Germany have recently reported 
the striking therapeutic activity of vemurafenib in one patient with refractory HCL34. According 
to the authors, a patient with HCL and massive splenomegaly and pancytopenia, who was 
refractory to three lines of purine analogue-based treatment, received vemurafenib for 2 
months. Within 2 days of treatment, the patient’s spleen decreased in size and his leukocytes 
and platelet counts began to rise. By day 43 of therapy, a CR was achieved as assessed by 
bone marrow biopsy showing an absence of disease with complete resolution of 
splenomegaly. While very preliminary, this report suggests the BRAF V600E allele as a driver 
mutation in HCL and validates mutant BRAF as a therapeutic target in HCL. 
 
3.8 
Rationale for Dose Selection 
Selection of the dose of vemurafenib is based on the clinical efficacy and safety observed at 
the MTD of 960mg twice daily in the phase I, II and III studies in melanoma patients. At this 
clinical dose, it is associated with suppression of pERK in biopsy specimens and consistent 
with exposures in preclinical models that were associated with anti-tumor activity. The same 
dose and administration schedule was used in a patient with refractory HCL mentioned above. 
Although the patient was started at a lower dose initially, the dose was quickly titrated up to 
960mg twice daily with no reported toxicity34. 
 
4.0 
OVERVIEW OF STUDY DESIGN/INTERVENTION 
4.1 
Design 
We propose a single arm, multi-center, open-label, phase II study of vemurafenib in patients 
with HCL who are resistant to or intolerant of purine analogs, who have relapsed disease within 
2 years of purine analog-based therapy, or who have ≥ 2 relapses. A Simon mini-max two- 
stage design will be employed to assess the efficacy of Vemurafenib after three months of 
treatment. In the first stage of the protocol, 19 patients will be treated. If 3 or fewer responses 
(CR or PR) are seen among the first 19 patients, the study will be closed for lack of efficacy. 
If at least 4 patients respond to the treatment, then an additional 17 patients will be accrued to 

Memorial Sloan Kettering Cancer Center 
IRB Number: 12-200 A(17) 
Approval date: 15-Jun-2022 
Page 9 of 39 
 
 
the second stage. At the end of the trial, if 11 or more patients have responded out of the 36 
patients then the drug will be considered worthy of further investigation. 
 
 
4.2 
Intervention 
Eligible patients will receive vemurafenib at a dose of 960mg orally b.i.d. continuously in cycles 
of 4 weeks (28 days). A bone marrow aspirate and/or biopsy will be performed after the first 
cycle for research purposes only. After the completion of the third cycle, a repeat bone marrow 
aspirate and/or biopsy will be performed for assessment of response and evaluation of minimal 
residual disease (MRD). Following the third cycle assessments, patients who achieve 
complete response (CR) with detectable MRD or partial response (PR) may continue with 
vemurafenib for up to 3 additional cycles at the treating physician’s discretion (Cycles 4-6). 
Patients who achieve CR without MRD will be observed as part of post-treatment followup, 
and may be re-treated with vemurafenib after relapse (as per below). Patients who achieve no 
response (NR) after the initial 3 cycles of vemurafenib will be removed from the study. 
After patients discontinue vemurafenib, they will be followed every 3 months as part of post- 
treatment followup for a total of 12 months. Patients who previously experienced CR, PR 
(either hematologic or MRD) or clinical benefit, but who subsequently relapse after ending 
treatment may be retreated with Vemurafenib until disease progression or at the treating 
physician’s discretion. Patients who are re-treated will follow the treatment/evaluation plan as 
outlined in Table 3 (see Section 10). A bone marrow aspirate and/or biopsy may be performed 
for assessment of response at the end of the third re-treatment cycle or during a subsequent 
re-treatment cycle when clinically indicated. 
 
In case of certain defined toxicities, dose reductions by 50% (480mg b.i.d.) or interruptions of 
up to 15 days are permitted. If additional dose reduction is required, vemurafenib may be 
reduced to 240mg oral b.i.d. 
 
BRAF inhibition is an attractive therapeutic target for HCL for several reasons: 1) BRAF V600E 
mutation is present in 100% of HCL patients, and not found in other B cell lymphoproliferative 
disorders23-26; 2) BRAF mutation is present in the entire tumor-cell clone in virtually all patients; 
3) BRAF mutations become undetectable at remission but re-appears at relapse23-25; and 4) 
treatment of primary HCL cells with the BRAF inhibitor vemurafenib markedly inhibited the 
activation of signaling downstream of BRAF (MEK and ERK) at a very low drug concentrations 
(≤1 µM)18. Therefore, BRAF inhibition in HCL may not only represent the first targeted 
therapeutic approach, but also an attractive therapy for patients with suboptimal response to 
purine analogs as well as for patients with repeated relapses and with unacceptable toxic 
effects of purine analogs. Furthermore, there are several limitations with the current standard 
of care therapies (i.e. purine analogs) for patients with relapsed HCL, including 1) neither 2- 
CdA nor pentostatin is curative; 2) the use of purine analogs is associated with prolonged 
immune suppression and potentially increased risk of secondary malignancies; and 3) the 
ability to attain CR, which is critical to achieve longer PFS and DFS, decline with each 
subsequent line of purine analog-based therapy1,3,5,35,36. 
 
5.0 
THERAPEUTIC/DIAGNOSTIC AGENTS 
Description: Vemurafenib, also known as PLX4032 and RO5185426, will be labeled in compliance 
with Good Manufacturing Procedures (GMP).  The drug label will include: the contents, protocol 

Memorial Sloan Kettering Cancer Center 
IRB Number: 12-200 A(17) 
Approval date: 15-Jun-2022 
Page 10 of 39 
 
 
number, batch number, and storage conditions, as well as any required statements that the drug is: 
“For Investigational Use Only.” The drug will be labeled as “RO5185426.” 
 
 
 
Drug Supply and Distribution: Vemurafenib is manufactured and distributed by Genentech. 
 
How Supplied: Each bottle of oral study treatment of vemurafenib contains a total of 120 tablets that 
are 240 mg each. Patients should be instructed to administer 4 tablets in morning and 4 tablets in 
evening (total daily dose of 1920mg [960mg b.i.d.]). If a dose is missed, it can be taken up to 4 hours 
prior to the next dose to maintain the twice daily regimen. Both doses should not be taken at the same 
time. All missed doses should be recorded in the patient diary. 
 
Storage: Vemurafenib will be stored at the clinical site under recommended storage conditions: “Do 
Not Store above 25 C” as indicated on the study drug label. Patients will be requested to store the 
drug at the recommended storage conditions noted on the label out of reach of children or other 
cohabitants. 
 
Assessment of Compliance: Accountability and patient compliance will be assessed by maintaining 
adequate “drug dispensing” and return records. A dosing diary will be given to patients to record the 
time, date, and number of tablets administered on days vemurafenib is dosed outside of clinic and will 
assist study centers in measuring patient compliance with vemurafenib treatment administration. 
 
Approximately, a 4-week supply of Vemurafenib will be given to the patients on day 1 of each dosing 
cycle. The drugs may be shipped to patients, one month supply at a time. Patients should be 
instructed not to open a new bottle until the previous bottle has been finished. Patients are asked to 
return all used and unused drug supply of vemurafenib for reconciliation (whether bottles are emptied 
or unused) at their scheduled clinic visits. Study drug should not be crushed, chewed or dissolved. 
 
6.0 
CRITERIA FOR SUBJECT ELIGIBILITY 
6.1 
Subject Inclusion Criteria 
1. ≥ 18 years of age 
2. Histologically confirmed classical HCL with one of the following: 
• 
Intolerance to purine analogs or considered to be poor candidates for purine analog- 
based therapy 
• 
Failure to achieve any response (CR or PR) to the initial purine analog-based therapy 
• 
Relapse ≤ 2 years of purine analog-based therapy 
• 
≥ 2 relapses 
Histologic confirmation of diagnosis will be performed at MSKCC or a participating site. 
3. Patients who meet the standard treatment initiation criteria, as defined by ANC ≤1.0, Hgb 
≤ 10.0 or PLT ≤100K 
4. ECOG performance status of 0-2 
5. Acceptable pre-study organ function during screening as defined as: Total bilirubin ≤ 1.5 
times the upper limit of normal (ULN), aspartate aminotransferase (AST) and alanine 
aminotransferase (ALT) ≤ 2.5x ULN, and serum creatinine ≤ 1.5x ULN 
6. Electrocardiogram (ECG) without evidence of clinically significant ventricular arrhythmias 
or ischemia as determined by the investigator and a rate-corrected QT interval (QTc, 
Bazett’s formula) of < 480 msec. 

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7. For women of childbearing potential, agreement to the use of two acceptable methods of 
contraception, including one barrier method, during the study and for 6 months after 
discontinuation of vemurafenib 
8. For men with female partners of childbearing potential, agreement to use a latex condom 
and to advise their female partner to use an additional method of contraception during the 
study and for 6 months after discontinuation of vemurafenib 
9. Negative serum pregnancy test within 7 days of commencement of treatment in 
premenopausal women. 
10. Agreement not to donate blood or blood products during the study and for at least 6 months 
after discontinuation of vemurafenib; for male partners, agreement not to donate sperm 
during the study and for at least 6 months after discontinuation of vemurafenib 
11. Ability to understand and willingness to sign a written informed consent document. 
Willingness and ability to comply with scheduled visits, treatment plans, laboratory tests, 
and other study procedures. 
 
6.2 
Subject Exclusion Criteria 
1. Pregnant or breast-feeding 
2. Have had chemotherapy (including purine analogs, rituximab, and other investigational 
agents) within six weeks prior to entering the study 
3. Major surgery within 4 weeks prior to entering the study 
4. Invasive malignancy within the past 2 years prior to first study drug administration, except 
for adequately treated (with curative intent) basal or squamous cell carcinoma, 
melanoma, in situ carcinoma of the cervix, in situ ductal adenocarcinoma of the breast, in 
situ prostate cancer, or limited stage bladder cancer or other cancers from which the 
patient has been disease-free for at least 2 years 
5. Refractory nausea or vomiting, malabsorption, external biliary shunt, or history of any 
type of gastrointestinal surgery that would preclude adequate absorption of study drug 
6. Prior treatment with MEK or BRAF inhibitors 
7. Active HIV, hepatitis B and hepatitis C 
8. Patients with HCL variant (as defined by absence of expression of CD25 or absence of 
BRAF V600E mutation) 
 
7.0 
RECRUITMENT PLAN 
Potential research subjects will be identified by a member of the patient’s treatment team, the protocol 
investigator, or research team at Memorial Sloan-Kettering Cancer Center (MSKCC). Patient 
recruitment will occur in medical oncology clinics or the inpatient service of the Leukemia Service at 
MSKCC. Investigators will screen the patient’s medical records of suitable research study participants 
and discuss the study and their potential for enrolling in the research study. Similar recruitment 
procedures will be followed at collaborating institutions. It is expected that each of the participating 
sites will enroll 5-7 patients each over a 2-year period. 
 
Participating site recruitment will be conducted as outlined within the protocol. Any participating sites 
that require a limited waiver must obtain it from their site IRB/PB via a separate protocol addendum or 
request. It is the responsibility of the MSK staff to confirm participating data collection sites have a 
limited waiver approved by their local IRB(s)/PBs. 

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IRB Number: 12-200 A(17) 
Approval date: 15-Jun-2022 
Page 12 of 39 
 
 
8.0 
PRETREATMENT EVALUATION 
The following assessments must be performed prior to treatment start: 
Within 4 Weeks of Study Start: 
• 
A complete history and physical exam including general ophthalmologic examination 
for any signs of conjunctiva inflammation and regular constrictions of pupils 
• 
Head and neck examination: visual inspection of the oral mucosa and lymph node 
palpation 
• 
ECG 
• 
Laboratory studies: CBC with differential and platelets, smear review, Comprehensive 
Metabolic Panel (albumin, alkaline phosphatase, total bilirubin, bicarbonate, BUN, 
calcium, chloride, creatinine, glucose, potassium, total protein, SGOT [AST], SGPT 
[ALT], and sodium), phosphorus, uric acid, LDH, PT/PTT, HIV, Hepatitis B and C testing 
• 
CT chest 
• 
CT abdomen in patients with intact spleen 
• 
Bone marrow aspirate for histology, cytogenetics, immunophenotyping by flow 
cytometry, and a bone marrow biopsy. If bone marrow aspirate cannot be obtained, 
peripheral blood samples will be tested for cytogenetics and immunophenotyping by 
flow cytometry. 
• 
Full skin assessment by a dermatologist or equivalent trained skin cancer expert 
• 
Research blood or bone marrow aspirate (if obtained) analysis (please see Section 
10.3 for details of the study) 
Within 7 Days of Study Start: 
• 
Serum pregnancy test for women of child-bearing potential 
 
9.0 
TREATMENT/INTERVENTION PLAN 
9.1 
Administration of Vemurafenib 
Patients will receive vemurafenib at a dose of 960mg orally b.i.d. continuously in cycles of 4 
weeks (28 days) as outpatient. A bone marrow aspirate and/or biopsy will be performed after 
the first cycle for research purposes only. After the completion of the third cycle, a repeat bone 
marrow aspirate and/or biopsy will be performed for assessment of response and evaluation 
of MRD. Following the third cycle assessments, patients who achieve complete response (CR) 
with detectable MRD or partial response (PR) may continue with vemurafenib for up to 3 
additional cycles at the treating physician’s discretion (Cycles 4-6). Patients who achieve CR 
without MRD will be observed as part of post-treatment followup, and may be re-treated with 
vemurafenib after relapse (as per below). Patients who achieve no response (NR) after the 
initial 3 cycles of vemurafenib will be removed from the study. 
 
After patients discontinue vemurafenib, they will be followed every 3 months as part of post- 
treatment followup for a total of 12 months. Patients who previously experienced CR, PR 
(either hematologic or MRD) or clinical benefit, but who subsequently relapse after ending 
treatment may be retreated with Vemurafenib until disease progression or at the treating 
physician’s discretion. Patients who are re-treated will follow the treatment/evaluation plan as 
outlined in Table 3 (see Section 10). A bone marrow aspirate and/or biopsy may be performed 
for assessment of response at the end of the third re-treatment cycle or during a subsequent 
re-treatment cycle when clinically indicated. 

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IRB Number: 12-200 A(17) 
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Page 13 of 39 
 
 
Patients who achieve no response after the initial 3 cycles of vemurafenib will be removed from 
the study. In case of certain defined toxicities, dose reductions by 50% (480mg b.i.d.) or 
interruptions of up to 15 days are permitted. If additional dose reductions are required, 
vemurafenib may be reduced to 240mg oral b.i.d. 
 
9.2 
Dose Modifications 
Management of Symptomatic Drug Reactions: Symptomatic drug reactions (e.g. arthralgia, 
fatigue, rash) may require temporary interruptions and/or dose reduction of vemurafenib 
treatment. Arthralgia is one of the common side effects of the drug, and can be first managed 
with prednisone 5-10mg daily before dose reduction is attempted. When dose reduction is 
needed, initial dose reduction to 480mg b.i.d. is recommended based on individual safety and 
tolerability data from the trials in melanoma patients. If additional dose reduction is required 
or the drug is interrupted for up to 15 days, vemurafenib may be reduced to 240mg b.i.d. Dose 
escalation after dose reduction is generally not recommended unless under special 
circumstances (i.e. increased likelihood of clinical benefit for the dose increase and no safety 
concern). This should be done after discussion with the the principal investigator of the study 
(Dr. Jae Park). Dose increase above 960mg b.i.d. will NOT be allowed. 
 
Management of QTc Prolongation: Special consideration must be taken with any patient on 
study with an increase in QTC >500ms or change from baseline >60ms. If QTC exceeds 500 
ms or the change from baseline is > 60ms on ECG (measured in triplicate), vemurafenib 
treatment should be temporarily interrupted. When QTC decreases to < 500ms, re-initiation of 
vemurafenib treatment may occur and patients should be dose reduced by one dose level. 
Permanent discontinuation of vemurafenib treatment is recommended if QTC increase meets 
both criteria of >500ms and >60ms change from pre-treatment values of if QTC >500ms or 
change from baseline >60ms is observed on 2 prior independent occurrences. 
 
Management of Grade 1-4 Non-Hematologic Toxicities: For any grade 1 and tolerable 
grade 2-3 toxicities, patients may continue full dose. For any intolerable grade 2-3 toxicities, 
dosing will be interrupted until resolution to grade 1 or less and dose reductions to 480mg b.i.d. 
are required, except for arthralgia in which case prednisone 5-10mg daily can be attempted 
first before the study drug dose reduction. If additional dose reduction is required, investigators 
can further reduce the dose to 240mg b.i.d. On the third appearance of any grade 2 or grade 
3 adverse events despite two dose reductions, it is recommended that patients discontinue 
vemurafenib. For any grade 4 toxicities, patients should discontinue study treatment or, based 
on investigator judgment, interrupt until resolution to grade 1 or less with dose reduction to 
240mg b.i.d. upon restarting study drug. Dose escalation after dose reduction is generally not 
recommended unless under special circumstances (i.e. increased likelihood of clinical benefit 
for the dose increase and no safety concern). It is recommended that patients permanently 
discontinue vemurafenib for a second occurrence of any grade 4 toxicities. 
 
Prolonged Drug Interruptions: If a patient’s study dose has been interrupted for >15 days, 
the patient will be considered to have discontinued from the study. If the patient is still 
benefiting from treatment and an interruption greater than 15 days deemed necessary by the 
investigator, the length of the requested interruption should be discussed with the principal 
investigator of the study (Dr. Jae Park). Restarting vemurafenib treatment after discontinuation 
of drug is permitted during the re-treatment phase if the investigator deems there is a clinical 
benefit for re-starting drug and there are no safety concerns. 

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IRB Number: 12-200 A(17) 
Approval date: 15-Jun-2022 
Page 14 of 39 
 
 
10.0 EVALUATION DURING TREATMENT/INTERVENTION 
10.1 
Clinic Visits 
 
Outpatient clinic visits will occur weekly during the Cycle 1 (Days 1, 8, 15, 22), and on Day 1 
of subsequent 28-day cycle (i.e. monthly, days 29, 57, 85, etc.). A +/- 4 day window will be 
allowed for completion of scheduled clinic visits. Please refer to the Table 1 below for details 
of routine tests to be performed during the clinic visits. As specified in Table 1, some of the 
blood tests and assessments can be obtained locally if the patient has an established local 
oncologist. 
10.2 
Disease Response Assessment 
 
Disease response assessment will be performed after the completion of Cycle 3, and will 
involve CBC with diff and platelets, a bone marrow aspirate and/or biopsy (flow cytometry, 
cytogenetics, IHC), and CT Abdomen (CT Abdomen is applicable only if splenomegaly was 
present on screening the CT abdomen). MRD analysis will be performed on bone marrow 
biopsy specimens as assessed by IHC for anti-CD20, DBA 44 and anti-CD45RO6,37,38. If 
patients receive additional cycles of therapy (i.e. Cycles 4, 5 and 6), the above disease 
response assessment will occur within 2 weeks of the last therapy. 
10.3 
Research Tests 
 
The following research tests will be performed at the time points indicated in Table 1. Bone 
marrow aspirate samples will be collected in an EDTA-containing syringe (3-5ml) and 
peripheral blood samples will be collected in either green top or purple top tubes (10ml). At 
each specified time point (Table 1), 3 green or purple top tubes of peripheral blood samples 
will be collected. These samples can be collected locally if the patient has an established local 
oncologist and only after discussing with the study PI. The collected samples will be delivered 
to the Abdel-Wahab’s laboratory in Zuckerman 519 at Memorial Sloan-Kettering Cancer 
Center. 
 
BRAF Mutation Analysis: Peripheral blood and/or bone marrow aspirate samples from pre- 
treatment and post-treatment at specified time points will be assessed for BRAF V600E 
mutation by allele-specific PCR of genomic DNA followed by conventional agarose-gel 
electrophoresis24 and/or by quantitative real-time allele-specific PCR in complimentary DNA 
(cDNA)26. 
Pharmacodynamic (PD) Studies: Peripheral blood and/or bone marrow aspirate samples 
from pre-treatment and post-treatment at specified time points will be assessed by Western 
Blot or by phospho-flow for the downstream targets of BRAF (MEK, pMEK, ERK, pERK) to 
assess the on-target effect of the Vemurafenib. In addition, signaling studies using Cell 
Biosciences NanoPro 1000 technology will be performed on the same samples, which will 
allow us to obtain accurate, quantitative signaling on the entire MAPK, PI3K, and JAK-STAT 
pathways before and after treatment on sorted circulating hairy cells. 
 
*For MSKCC Patients ONLY: Additional research blood samples for the above mentioned 
pharmacodynamic studies will be collected in patients who receive their treatment at MSKCC. 
These additional time points include 2-4 hours and 24 hours after the first dose of vemurafenib. 
24-hour blood sample can be collected locally if the patient has an established local oncologist 
and only after discussing with the MSKCC PI. 

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Approval date: 15-Jun-2022 
Page 15 of 39 
 
 
Molecular Characterization of HCL: Peripheral blood and/or bone marrow aspirate samples 
from pre-treatment and post-treatment at specified time points will be analyzed by high 
throughput next generation sequencing using the Raindance multiplex PCR platform and 
Illumina next generation sequencing to perform comprehensive mutation profiling for BRAF 
and for 29 additional genes known to be mutated in HCL patient and/or in other chronic B-cell 
lymphoid malignancies. 
 
Biomarkers for Resistance: The following tests will be performed in all patients at baseline, 
and in patients who do not achieve CR or PR after completing 3 cycles of therapy, or who 
progresses after achieving CR or PR. 
• 
Reactivation of MAPK pathways: Increased expression of the other RAF isoforms 
CRAF and ARAF), and MAPK (MAPK8 or COT) will be analyzed by Western Blot 
and/or real-time PCR39,40. 
• 
Secondary BRAF mutations (all 18 BRAF exons) and RAS mutations40 will be analyzed 
by bi-directional Sanger sequencing and by Raindance multiplex PCR and Illumina next 
generation sequencing, respectively. 
• 
Activation of RTKs (i.e. PDGFRβ and IGF-IR) will be assessed by Western Blot. 
• 
Cell Biosciences NanoPro 1000 technology will be used to examine quantitative 
signaling on the entire MAPK, PI3K and JAK-STAT pathways41. 

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IRB Number: 12-200 A(17) 
Approval date: 15-Jun-2022 
Page 16 of 39 
 
 
Table 1: Evaluation on Study 
 
Phase 
Screening 
Study Visits 
Cycle 
1 
2 
3 
4 
5 
6 
Day1 
-28 to -1 
Day 1 
Day 8 
Day 15 
Day 22 
Day 1 
Day 15 
Day 1 
Day 28+/-4 
Day 113 
Day 1 
Day 1 
Day 28+/-4 
Informed Consent 
X 
History and Physical Exam 
X 
X 
X 
X 
X 
X 
X 
Head and Neck Exam2 
X 
X 
X 
X 
ECG 
X 
X 
X12 
X 
X 
X 
Serum Pregnancy Test3 
X 
Dermatology Exam4,12 
X 
X 
X 
CBC w/ diff, Platelets 
X 
X 
X12 
X12 
X12 
X 
X12 
X 
X 
X 
X 
X 
X 
Smear Review 
X 
X 
X12 
X12 
X12 
X 
X 
X 
X 
X 
COMP, LDH 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Phosphorus, Uric Acid 
X 
X 
X12 
X12 
X12 
PT/PTT 
X 
HIV, Hepatitis B and C 
X 
Adverse Events 
X 
X 
X 
X 
X 
X 
Review of Concomitant Medications 
X 
X 
X 
X 
X 
X 
X 
CT Chest 
X 
X5 
CT Abdomen 
X6 
X7 
Bone Marrow Aspirate and/or Biopsy 
X 
X 
X8 
Research Tests 
Bone Marrow Aspirate and/or Biopsy 
X9 
X9 
X9 
X8,9 
Peripheral Blood10 
X 
X11 
X12 
X12 
X12 
X 
X 
X 
X8 
1A +/- 4 day window will be allowed for completion of scheduled clinic visits (i.e. holidays, travel delays, site closures, other reasons, etc.) A +/- 7day window is allowed for Cycle 4 Day 1 to allow the adequate time 
for bone marrow response evaluation from Cycle 3 Day 28. 
2Head and neck examination can be performed as part of general physical exam, and consist of visual inspection of the oral mucosa and lymph node palpation.21 
3In women of child-bearing potential, serum pregnancy test should be obtained within 7 days prior to start of treatment. 
4A window of +/- 21 days of scheduled visit (with exception of screening) is allowed for completion of these assessments. 
5CT chest at Cycle 3, Day 28 will be performed if considered clinically indicated at the discretion of treating physicians (e.g. monitoring infection or pulmonary nodules). 
6CT abdomen at screening will be performed if patient has intact spleen. 
7CT abdomen at Cycle 3, Day 28 will be performed if splenomegaly present on screening CT abdomen. 
8Only for those who continue vemurafenib for > 3 cycles. 
93-5ml of bone marrow aspirate will be collected in an EDTA-containing syringe. 
103 green or purple top tubes (10cc tubes) will be collected for all patients at the specified time-points. 
11For MSKCC patients only, 3 green/purple top tubes will be collected at 2-4 hours and 24 hours after the first dose of vemurafenib. For patients treated at other centers, only the pre-treatment blood samples will be 
drawn (3 green top tubes). 
12 This test may be done locally 
13Cycle 3 Day 28 visit may serve as Cycle 4 Day 1 visit for patients who will continue beyond 3 cycles for high suspicion of residual disease before waiting for BMB result at the treating phsyicain’s discretion. 

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IRB Number: 12-200 A(17) 
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Page 17 of 39 
 
 
 
Table 2: Procedures for End of Treatment and Post Treatment Follow Up Visits 
Phase 
End of Treatment 
Post Treatment Follow-Up1,2 
Time Frame 
4 weeks from last treatment dose 
Every 3 months post last dose 
History and Physical Exam 
X 
X 
Head and Neck Examination 
X 
Dermatology Evaluation3, 5 
X 
X 
CBC w/ diff & Platelets, COMP, LDH 
X 
X 
Survival assessments4 
X 
X 
1These evaluations will continue up to 12 months after study drug discontinuation. 
2A +/- 14 day window is allowed for this assessment. 
3This evaluation may be perforned locally 
4Survival assessment will be collected on an ongoing basis and at least every 3 months. 
5If clinically indicated 
 
Table 3: Re-Treatment Evaluation on Study 
Phase 
Study Visits 
Cycle 
1 
2 
3 
“X” 
Day1 
Day 1 
Day 8 
Day 15 
Day 22 
Day 1 
Day 15 
Day 1 
Day 28+/-4 
Day 1 
As clinically 
indicated 
History and Physical Exam 
X 
X 
X 
X 
Head and Neck Exam2 
X 
X 
ECG 
X 
X8 
X 
X 
X10 
Dermatology Exam3, 8 
X 
X 
CBC w/ diff, Platelets 
X 
X8 
X8 
X8 
X 
X8 
X 
X 
X 
Smear Review 
X 
X8 
X8 
X8 
X 
X 
X 
COMP, LDH 
X 
X 
X 
X 
X 
Phosphorus, Uric Acid 
X 
X8 
X8 
X8 
PT/PTT 
HIV, Hepatitis B and C Testing 
Adverse Events 
X 
X 
X 
X 
Review of Concomitant Medications 
X 
X 
X 
X 
CT Chest 
X4 
CT Abdomen 
X5 
Bone Marrow Aspirate and/or Biopsy 
X9 
X9 
Research Tests 
Bone Marrow Aspirate and/or Biopsy6 
X9 
X9 
Peripheral Blood7 
X 
X 
X 
X9 
X9 
1A +/- 4 day window will be allowed for completion of scheduled clinic visits (i.e. holidays, travel delays, site closures, other reasons, etc.) 
2Head and neck examination can be performed as part of general physical exam, and consist of visual inspection of the oral mucosa and lymph node palpation. 
3A window of +/- 21 days of scheduled visit is allowed for completion of these assessments. 
4CT chest at Cycle 3, Day 28 will be performed if considered clinically indicated at the discretion of treating physicians (e.g. monitoring infection or pulmonary nodules). 
5CT abdomen at Cycle 3, Day 28 will be performed if splenomegaly present on screening CT abdomen. 
63-5ml of bone marrow aspirate will be collected in an EDTA-containing syringe. 

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IRB Number: 12-200 A(17) 
Approval date: 15-Jun-2022 
Page 18 of 39 
 
 
73 green or purple top tubes (10cc tubes) will be collected for all patients at the specified time-points. 
8This test may be done locally 
9The bone marrow aspirate and/or biopsy may be performed for assessment of response at the end of the third retreatment cycle OR during a subsequent re-treatment cycle when clinically indicated. The timing also 
applies for research samples. 
10ECGs are to be performed every 3 months after Cycle 3 of Re-Treatment 

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IRB Number: 12-200 A(17) 
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Page 19 of 39 
 
 
11.0 TOXICITIES/SIDE EFFECTS 
 
 
11.1 
Expected Side Effects of Vemurafenib 
Although vemurafenib has been extensively studied in patients with melanoma in phase I, II and III trials, 
the side effects in patients with HCL are unknown. Based on clinical experience in patients with 
melanoma, following adverse events can be expected at the dose of 960mg b.i.d. Guidelines for 
management of the toxicity are given in Section 9.2. 
• 
Common: rash, photosensitivity, pruritus, palmar-plantar erythrodysesthesia (PPE), cutaneous SCC, 
fatigue, arthralgia, dry skin, mild hair loss and acute kidney injury 
• 
Uncommon: increased AST, ALT, alkaline phosphatase and bilirubin, fever, nausea, vomiting, 
diarrhea, anorexia, weight loss, headache, neuropathy, altered taste 
• 
Rare: pancytopenia, pancreatitis, conjunctivitis, pericarditis, renal impairment, dysphagia, arthritis, 
gastrointestinal polyps, allergic reactions, Stevens-Johnson syndrome, drug reaction with 
eosinophilia and systemic symptoms (DRESS), retinal vein occlusion, Dupuytren’s contracture and 
plantar fibromatosis, Peripheral Edema. 
11.2 
Assessments of Adverse Events 
11.2.1 Adverse Events 
An adverse event (AE) is any unfavorable and unintended sign, symptom, or disease temporarily 
associated with the use of an investigational medicinal product or other protocol-imposed 
intervention, regardless of attribution. 
 
This includes the following: 
• 
AEs not previously observed in the subject that emerge during the protocol-specified AE 
reporting period, including signs or symptoms associated with HCL that were not present prior 
to the AE reporting period. 
• 
Complications that occur as a result of protocol-mandated interventions 
• 
If applicable, AEs that occur prior to assignment of study treatment associated with 
medication washout, no treatment run-in, or other protocol-mandated intervention. 
• 
Preexisting medical conditions (other than the condition being studied) judged by the 
investigator to have worsened in severity or frequency or changed in character during the 
protocol-specified AE reporting period. 
 
To ensure consistency of AE and SAE (see below in Section 11.2.2) causality assignments, the 
following general guidelines should be applied: 
 
• 
Yes: There is a plausible temporal relationship between the onset of the AE and 
administration of vemurafenib and the AE cannot be readily explained by the subject’s clinical 
state, intercurrent illness, or concomitant therapies; and/or the AE follows a known pattern of 
response to vemurafenib; and/or the AE abates or resolves upon discontinuation of 
vemurafenib or dose reduction and, if applicable, reappears upon re-challenge. 
• 
No: Evidence exists that the AE has an etiology other than vemurafenib (e.g., preexisting 
medical condition, underlying disease, intercurrent illness, or concomitant medication); and/or 
the AE has no plausible temporal relationship to vemurafenib administration (e.g., cancer 
diagnosed 2 days after first dose of study drug). 

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IRB Number: 12-200 A(17) 
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Expected AEs are those adverse events that are listed or characterized in the Package Insert (P.I.) 
or current Investigator Brochure (I.B.). Unexpected AEs are those not listed in the P.I. or current I.B. 
or not identified. This includes AEs for which the specificity of severity is not consistent with the 
description in the P.I. or I.B. For example, under this definition, hepatic necrosis would be unexpected 
if the P.I. or I.B. only referred to elevated hepatic enzymes or hepatitis. 
Toxicity will be graded and recorded using the NCI Common Toxicology Criteria version 4.0. Clinically 
significant adverse events will be noted and compared to the baseline condition. Adverse events 
that will be noted will include expected side effects, and any other clinically significant symptom or 
laboratory value. An assessment will be made concerning the severity of the event, and if the event 
appears to be related to the study drug. Adverse events, toxicity grading, and attributions will be 
recorded in the electronic database by the Clinical Research Associate (CRA) after review of the 
data by the Principal Investigator. 
11.2.2 Serious Adverse Events (SAEs) Reporting 
 
An adverse event is considered serious if it results in ANY of the following outcomes: 
• 
Death 
• 
A life-threatening adverse event 
• 
An adverse event that results in inpatient hospitalization or prolongation of existing 
hospitalization 
• 
A persistent or significant incapacity or substantial disruption of the ability to conduct normal life 
functions 
• 
A congenital anomaly/birth defect 
• 
Important Medical Events (IME) that may not result in death, be life threatening, or require 
hospitalization may be considered serious when, based upon medical judgment, they may 
jeopardize the patient or subject and may require medical or surgical intervention to prevent 
one of the outcomes listed in this definition 
 
Note: Hospital admission for a planned procedure/disease treatment is not considered an SAE. 
SAE reporting is required as soon as the participant starts investigational treatment/intervention. 
SAE reporting is required for 30-days after the participant’s last investigational treatment/intervention. 
Any event that occur after the 30-day period that is unexpected and at least possibly related to 
protocol treatment must be reported. 
 
Please note: Any SAE that occurs prior to the start of investigational treatment/intervention and is 
related to a screening test or procedure (i.e., a screening biopsy) must be reported. 
All SAEs must be submitted in PIMS. If an SAE requires submission to the HRPP office per IRB SOP 
RR-408 ‘Reporting of Serious Adverse Events’, the SAE report must be submitted within 5 calendar 
days of the event. All other SAEs must be submitted within 30 calendar days of the event. 
 
The report should contain the following information: 
• 
The date the adverse event occurred 
• 
The adverse event 
• 
The grade of the event 
• 
Relationship of the adverse event to the treatment(s) 
• 
If the AE was expected 
• 
Detailed text that includes the following 

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o An explanation of how the AE was handled 
o A description of the participant’s condition 
o Indication if the participant remains on the study 
• 
If an amendment will need to be made to the protocol and/or consent form 
• 
If the SAE is an Unanticipated Problem 
For IND/IDE protocols: 
The SAE report should be completed as per above instructions. If appropriate, the report will be 
forwarded to the FDA by the IND Office 
 
11.2.3 Adverse Event Reporting Period 
 
The study period during which all AEs and SAEs must be reported begins after informed consent is 
obtained and initiation of study treatment and ends 28 days following the last administration of study 
treatment or study discontinuation/termination, whichever is earlier. After this period, investigators 
should only report SAEs that are attributed to prior study treatment. 
11.2.4 PROCEDURES FOR ELICITING, RECORDING, AND REPORTING ADVERSE EVENTS 
 
Eliciting Adverse Events 
 
A consistent methodology for eliciting AEs at all subject evaluation time points should be adopted. 
Examples of non-directive questions include: 
“How have you felt since your last clinical visit?” 
“Have you had any new or changed health problems since you were last here?” 
Specific Instructions for Recording Adverse Events 
 
Investigators should use correct medical terminology/concepts when reporting AEs or SAEs. Avoid 
colloquialisms and abbreviations. 
a. Diagnosis vs. Signs and Symptoms 
If known at the time of reporting, a diagnosis should be reported rather than individual signs 
and symptoms (e.g., record only liver failure or hepatitis rather than jaundice, asterixis, and 
elevated transaminases). However, if a constellation of signs and/or symptoms cannot be 
medically characterized as a single diagnosis or syndrome at the time of reporting, it is 
acceptable to report the information that is currently available. If a diagnosis is subsequently 
established, it should be reported as follow-up information. 
b. Deaths 
All deaths that occur during the protocol-specified AE reporting period (see Section I), 
regardless of attribution, will be reported to the appropriate parties. When recording a death, 
the event or condition that caused or contributed to the fatal outcome should be reported as 
the single medical concept. If the cause of death is unknown and cannot be ascertained at the 
time of reporting, report “Unexplained Death”. 
c. Preexisting Medical Conditions 
A preexisting medical condition is one that is present at the start of the study. Such conditions 
should be reported as medical and surgical history. A preexisting medical condition should be 
re-assessed throughout the trial and reported as an AE or SAE only if the frequency, severity, 
or character of the condition worsens during the study. When reporting such events, it is 

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Page 22 of 39 
 
 
important to convey the concept that the preexisting condition has changed by including 
applicable descriptors (e.g., “more frequent headaches”). 
d. Hospitalizations for Medical or Surgical Procedures 
Any AE that results in hospitalization or prolonged hospitalization should be documented and 
reported as an SAE. If a subject is hospitalized to undergo a medical or surgical procedure as 
a result of an AE, the event responsible for the procedure, not the procedure itself, should be 
reported as the SAE. For example, if a subject is hospitalized to undergo coronary bypass 
surgery, record the heart condition that necessitated the bypass as the SAE. 
Hospitalizations for the following reasons do not require reporting: 
Hospitalization or prolonged hospitalization for diagnostic or elective surgical procedures for 
preexisting conditions 
Hospitalization or prolonged hospitalization required to allow efficacy measurement for the 
study or 
Hospitalization or prolonged hospitalization for scheduled therapy of the target disease of the 
study 
e. Assessment of Severity of Adverse Events 
 
The adverse event severity grading scale for the NCI CTCAE (v 5 .0) will be used for assessing 
adverse event severity. Below Table should be used for assessing severity for adverse events 
that are not specifically listed in the NCI CTCAE. 
Adverse Event Severity Grading Scale for Events Not Specifically Listed in NCI CTCAE 
 
Grade 
Severity 
1 
Mild; asymptomatic or mild symptoms; clinical or diagnostic observations only; 
or intervention not indicated 
2 
Moderate; minimal, local, or non-invasive intervention indicated; or limiting 
age-appropriate instrumental activities of daily living a 
3 
Severe or medically significant, but not immediately life-threatening; 
hospitalization or prolongation of hospitalization indicated; disabling; or 
limiting self-care activities of daily living b,c 
4 
Life-threatening consequences or urgent intervention indicated d 
5 
Death related to adverse event d 
NCI CTCAE = National Cancer Institute Common Terminology Criteria for Adverse Events. 
Note: 
Based 
on 
the 
most 
recent 
version 
of 
NCI 
CTCAE 
5, 
which 
can 
be 
found 
at: 
http://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm 
a. 
Instrumental activities of daily living refer to preparing meals, shopping for groceries or clothes, using the 
telephone, managing money, etc. 
b. 
Examples of self-care activities of daily living include bathing, dressing and undressing, feeding oneself, using 
the toilet, and taking medications, as performed by patients who are not bedridden. 
c. 
If an event is assessed as a "significant medical event," it must be reported as a serious adverse event 
d. 
Grade 4 and 5 events must be reported as serious adverse events 
 
f. Pregnancy 

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If a female subject becomes pregnant while receiving the Vemurafenib or within 6 months after 
the last dose of Vemurafenib, or if the female partner of a male study subject becomes 
pregnant while the study subject is receiving Vemurafenib or within 6 months after the last 
dose, a report should be completed and expeditiously submitted to Genentech, Inc. Follow-up 
to obtain the outcome of the pregnancy should also occur. Abortion, whether accidental, 
therapeutic, or spontaneous, should always be classified as serious, and expeditiously 
reported as an SAE. Similarly, any congenital anomaly/birth defect in a child born to a female 
subject exposed to the study drug should be reported as an SAE. 
g. 
AEs of Special Interest (AESIs) 
 
AESIs are a subset of Events to Monitor (EtMs) of scientific and medical concern specific to 
the product, for which ongoing monitoring and rapid communication by the Investigator to the 
Sponsor is required. Such an event might require further investigation in order to characterize 
and understand it. Depending on the nature of the event, rapid communication by the trial 
Sponsor to other parties (e.g., Regulatory Authorities) may also be warranted. 
 
Adverse events of special interest for this study include the following: 
 
• 
Cases of potential drug-induced liver injury that include an elevated ALT or AST in 
combination with either an elevated bilirubin or clinical jaundice, as defined by Hy’s law: 
Treatment-emergent ALT or AST > 3 × ULN in combination with total bilirubin 
> 2 × ULN 
Treatment-emergent ALT or AST > 3 × ULN in combination with clinical jaundice 
• 
Data related to a suspected transmission of an infectious agent by the study drug 
(STIAMP), as defined below: 
Any organism, virus, or infectious particle (e.g., prion protein transmitting transmissible 
spongiform encephalopathy), pathogenic or non-pathogenic, is considered an 
infectious agent. A transmission of an infectious agent may be suspected from clinical 
symptoms or laboratory findings that indicate an infection in a patient exposed to a 
medicinal product. This term applies only when a contamination of the study drug is 
suspected 
• 
Acute Kidney Injury 
• 
Bone Marrow Toxicity 
• 
Cutaneous Squamous Cell Carcinomas 
• 
Gastrointestinal Polyps 
• 
Hypersensitivity and Severe Cutaneous Reactions 
• 
Liver Injury 
• 
New/Second Primary Melanomas 
• 
Non cutaneous Squamous Cell Carcinomas 
• 
Pancreatitis 
• 
Photosensitivity 
• 
Potentiation of Radiation Toxicity 
• 
Progression of RAS Mutant Malignancies 
• 
QT Prolongation 
• 
Retinal Vein Occlusion 
• 
Uveitis 
• 
VII Nerve Paralysis 
h. Other Special Situations Reports 

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The following other Special Situations Reports should be collected even in the absence of an 
Adverse Event and transmitted to Genentech: 
Data related to the Product usage during breastfeeding 
Data related to overdose, abuse, misuse or medication error (including potentially 
exposed or intercepted medication errors) 
 
In addition, reasonable attempts should be made to obtain and submit the age or age 
group of the patient, in order to be able to identify potential safety signals specific to a particular 
population 
i. Product complaints 
 
A Product Complaint is defined as any written or oral information received from a complainant 
that alleges deficiencies related to identity, quality, safety, strength, purity, reliability, durability, 
effectiveness, or performance of a product after it has been released and distributed to the 
commercial market or clinical trial. 
f. Post-Study Adverse Events 
The investigator should expeditiously report any SAE occurring after a subject has 
completed or discontinued study participation if attributed to prior vemurafenib exposure. If the 
investigator should become aware of the development of cancer or a congenital anomaly in a 
subsequently conceived offspring of a female subject who participated in the study, this should 
be reported as an SAE. 
 
11.3 
Photosensitivity 
Photosensitivity has been reported in approximately 50% of vemurafenib-treated patients in 
the phase 2 study of metastatic melanoma patients42. The majority of cases were mild or 
moderate in severity. All patients should therefore be advised to avoid sun exposure and/or 
use sun block and lip balm (minimum of SPF 30, re-applied every 2 to 3 hours) during 
vemurafenib treatment and for at least 5 to 10 days after study drug discontinuation. 
 
11.4 
Ophthalmologic Reactions 
In the phase 3 study of 675 metastatic melanoma patients33, five cases of uveitis have been 
reported in patients treated with vemurafenib. Treatment with steroid and mydriatic ophthalmic 
drops may be required to manage uveitis. Patients should be routinely monitored for signs and 
symptoms of uveitis. Additionally, there were five patients with blurry vision, five patients with 
iritis and six patients with photophobia. There was one case of retinal vein occlusion in the 
phase 2 study of 132 metastatic melanoma patients42. 
 
11.5 
Hypersensitivity Reactions 
Serious hypersensitivity reactions, including anaphylaxis, have been reported in association 
with vemurafenib and upon re-initiation of treatment. Severe hypersensitivity reactions included 
generalized rash and erythema or hypotension. In patients who experience a severe 
hypersensitivity reaction, vemurafenib treatment should be permanently discontinued. 
 
11.6 
Dermatologic Reactions 
Severe dermatologic reactions have been reported in patients receiving vemurafenib, including 
one case of Stevens-Johnson syndrome and one case of toxic epidermal necrolysis in the 
phase 3 study33. In patients who experience a severe dermatologic reaction, vemurafenib 

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treatment should be permanently discontinued. 
 
11.7 
Liver Laboratory Abnormalities 
Liver laboratory abnormalities have occurred with vemurafenib. Liver enzymes (transaminases 
and alkaline phosphatase) and bilirubin should be monitored before initiation of treatment and 
monthly during treatment, or as clinically indicated. Laboratory abnormalities should be 
managed with dose reduction, treatment interruption, or treatment discontinuation (see Section 
9.2 for dose modification instructions). 
11.8 
Cutaneous Squamous Cell Carcinoma 
Cutaneous squamous cell carcinoma (cuSCC) is defined as an AE of special interest. 
Investigator and patient should perform routine skin examination at least once per cycle (28 
days). Suspicious lesions or rashes should be referred to a dermatologist. A dermatologist 
should perform a full skin exam during screening/baseline, after 4 weeks of treatment, and 
every 12 weeks thereafter until discontinuation of the drug. Patients who withdrew from the 
study for any reason will be followed for SCC evaluation for 6 months after study drug 
discontinuation, start of new antineoplastic therapy, or until death, withdrawal of consent, or 
lost to follow up, whichever occurs first. Additionally, at baseline, the dermatologist will perform 
a complete dermatological history of prior medications, non-melanoma skin cancers, including 
SCC and actinic keratosis and their associated treatments, and risk factors for development of 
cutaneous malignancies (e.g. radiation therapy, sun exposure, phototherapy, use of tanning 
beds, genetic conditions, and immunosuppression). 
 
Any lesion at baseline or during treatment that is clinically suspected of representing a cuSCC, 
basal cell carcinoma, actinic keratosis, primary melanoma, or other skin condition identified by 
the dermatologist should be completely resected by a dermatologist and submitted for 
pathologic review. A dose reduction is not indicated for this adverse event. 
 
11.9 Non-Cutaneous Squamous Cell Carcinoma 
• 
Head and neck examination: A thorough head and neck examination to monitor for non- 
cutaneous SCC, consisting of at least visual inspection of the oral mucosa and lymph node 
palpation, will be performed by the treating physician during screening/baseline, after 4 weeks 
of treatment, and every 12 weeks thereafter until a maximum of 6 months after discontinuation 
of study drug or at the start of new antineoplastic therapy, death, withdrawal of consent, or lost 
to follow up whichever occurs first. 
 
• 
Chest CT scans: A chest CT scan will be performed during screening/baseline (up to 28 days 
prior to start of treatment) and, if considered clinically indicated at the discretion of treating 
physicians, at Cycle 3 Day 28. 
 
 
11.10 Cardiac Toxicity 
Data from the phase II trial indicate that some patients treated with vemurafenib 960mg twice 
a day developed mild QTc prolongation. The largest mean QTc change from baseline was 
15.1 milliseconds (msec). One patient on study had a QTc change of >60 msec. Two patients 
(1.5%) developed QTc prolongation >500 msec. No ventricular arrhythmias have been 
reported to date. 

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The following recommendations have been developed to minimize the risk of arrhythmias on 
study: 
o Avoid combination with other agents with known potential to lead to QTc prolongation. 
o ECG should be monitored on day 1 prior to the first dose of vemurafenib, pre-dose on day 15 
after study drug initiation, every 4 weeks for the next 3 cycles, and every 12 weeks thereafter. 
o If QTc interval exceeds 500 msec or the change from baseline is >60 msec, on three separate 
ECGs, vemurafenib treatment should be temporarily interrupted. The investigator should 
check electrolytes (K, Mg, and Ca), correct any electrolyte abnormalities prior ot reinstitution 
of therapy, recheck concomitant medications to insure that non has been implicated in QTc 
prolongation, and rule out or control other cardiac risk factors (i.e. ischemia). Monitor ECG 
weekly until QTc decreases to < 500 msec and reinitiate treatment at once reduced level from 
960 mg b.i.d. to 480 mg b.i.d. 
o Vemurafenib should be permanently discontinued if a QTc increase meets both criteria of > 
500 msec and > 60 msec change from pre-treatment values or if QTc > 500 msec or change 
from baseline > 60 msec is observed on two separate occasions. 
 
11.11 
Renal and Urinary Toxicity 
A review of the Roche safety database (with an estimated exposure to vemurafenib of 28,809 
patients) in May 2015 concluded that acute kidney injury is an adverse drug reaction (ADR) in 
patients treated with vemurafenib. This was based on 145 AKI cases with some evidence of 
vemurafenib causality, of which 102 cases were assessed to have strong evidence. The cases 
ranged within a broad spectrum, majority were mild (> 1-1.5 x ULN) to moderate (> 1.5 – 3 x 
ULN) creatinine elevations, that appear to be reversible in nature. There were 3 cases of biopsy- 
proven interstitial nephritis, 4 cases of biopsy-proven tubular injury/acute tubular necrosis (ATN), 
and 20 cases presented with DRESS or DRESS-like symptoms. 
 
11.12 
Reproductive Risk 
The teratogenic potential of vemurafenib has not been investigated. However, women who are 
pregnant or nursing will be excluded from this study. Women of childbearing potential, including 
those who have had a tubal ligation, are required to have a negative serum pregnancy test within 
7 days prior to start of treatment. Women of childbearing potential are required to use two effective 
methods of contraception (including one barrier method) during the study and for 6 months after 
discontinuation of vemurafenib. Male patients (including those who have undergone vasectomy) 
with female partners of childbearing potential should use a latex condom during any sexual contact 
and should advise their partners to use an additional method of contraception during the study and 
for at least 6 months after discontinuation of vemurafenib. 
 
11.13 
Acute Kidney Injury 
Incidence rate on the Phase III Study (NO25026) was 10% among patients who received 
vemurafenib versus 1.4% who received dacarbazine. Approximately 40% patients receiving 
vemurafenib developed creatinine elevations at some point in the study compared to patients 
receiving dacarbazine (6%). 
 
11.14 
Potential for Drug-Drug Interaction 
11.14.1 Effects of Vemurafenib on Drug Metabolizing Enzymes 
 
Vemurafenib is a moderate CYP1A2 inhibitor, a weak CYP2D6 inhibitor, and a CYP3A4 
inducer. Co-administration of vemurafenib increased the AUC of caffeine (CYP1A2 substrate) 

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2.6-fold and increased the AUC of dextromethorphan (CYP2D6 substrate) by 47%, while it 
decreased the AUC of midazolam (CYP3A4 substrate) by 39%. Concomitant use of 
vemurafenib with agents with narrow therapeutic windows that are metabolized by CYP1A2, 
CYP2D6 and CYP3A4 is not recommended as vemurafenib may alter their concentrations. If 
coadministration cannot be avoided, exercise caution and consider a dose reduction of the 
concomitant CYP1A2 and CYP2D6 substrate drug. Co-administration of vemurafenib resulted 
in an 18% increase in AUC of S-warfarin (CYP2C9 substrate). Exercise caution and consider 
additional INR monitoring when vemurafenib is used concomitantly with warfarin. 
 
11.14.2 Drugs that Inhibit or Induce CYP3A4 
 
Vemurafenib is a substrate of CYP3A4, and therefore, concomitant administration of strong 
CYP3A4 inhibitors or inducers may alter vemurafenib concentrations. Strong CYP3A4 
inhibitors (e.g. ketoconazole, itraconazole, clarithromycin, atazanavir, nefazodone, saquinavir, 
telithromycin, ritonavir, indinavir, nelfinavir, voriconazole) and inducers (e.g. phenytoin, 
carbamazepine, rifampin, rifabutin, rifapentine, phenobarbital) should be used with caution 
when co-administered with vemurafenib. 
 
Appendix A includes a non-exhaustive list of typical examples of CYP1A2 and CYP2C9 
substrates and CYP3A4 inducers and inhibitors. 
 
 
12.0 CRITERIA FOR THERAPEUTIC RESPONSE/OUTCOME ASSESSMENT 
Response will be determined by the Consensus Resolution response criteria43. 
Complete Response (CR) 
• 
A morphological absence of hairy cells in the blood and bone marrow 
• 
A normalization of any organomegaly and cytopenias 
Partial response (PR) 
• 
A normalization of cytopenias 
• 
Circulating hairy cells ≤5% of lymphocytes 
• 
≥50% reduction in organomegaly and bone marrow hairy cells. 
 
All other responses are considered as no response (NR) 
Relapse after CR 
• 
Reappearance of hairy cells in the blood or bone marrow 
• 
Development of cytopenias and/or organomegaly on physical examination 
Relapse after PR 
• 
>50% increase of residual disease 
13.0 
CRITERIA FOR REMOVAL FROM STUDY 
 
Ineligibility (at the pretreatment evaluation) of the patient as defined in the 
inclusion/exclusion criteria 
 
Unacceptable toxicity (as defined in Section 11.0) 
 
Disease progression requiring alternate therapy (will still be followed for survival) 
 
Significant protocol violation 

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 
Non-compliance of the patient 
 
Refusal of the patient to continue treatment and/or observation 
 
Unrelated medical illness or complication that increase the risk of protocol therapy to 
unacceptable levels 
 
Decision by the Investigator that termination is in the patient’s best medical interest 
 
Lost to follow-up 
 
Death of the patient 
 
14.0 
BIOSTATISTICS 
The primary objective of this phase II trial is to determine the overall response rate after therapy 
with the BRAF inhibitor, Vemurafenib, in patients with relapsed and refractory HCL. The 
outcome is determined as the overall response by three months. Currently, there is no 
standard treatment for these patients. 
 
We propose a single arm, multi-center, open-label, phase II study of Vemurafenib in patients 
with HCL who are resistant to or intolerant of purine analogs, who have relapsed disease within 
2 years of purine analog-based therapy, or who have ≥ 2 relapses. A Simon’s mini-max two- 
stage design will be employed to assess the efficacy of Vemurafenib. Without a standard of 
care for these relapsed or refractory patients, there is no well-estimated historical benchmark 
to base the response rates for this trial. However, an observed response rate of at least 20% 
would provide sufficient evidence that vemurafenib should be further investigated in this patient 
population. Therefore, this study is designed such that a 20% overall response rate (PR or 
better) by three months would not be considered promising, while a 40% response rate would 
be considered promising.. 
 
In the first stage of the study, 19 patients will be treated. If 3 or fewer responses are seen 
among the first 19 patients, the study will be closed for lack of efficacy. If at least 4 patients 
respond to the treatment, then an additional 17 patients will be accrued to the second stage. 
At the end of the trial, if 11 or more patients have responded out of the 36 patients then the 
drug will be considered worthy of further investigation. The Type I and Type II errors are both 
0.10. Safety and tolerability data of the intervention will be tabulated across all study subjects. 
 
In addition to the primary outcome, there are a number of secondary objectives for this trial. 
Kaplan-Meier methodology will be used to estimate the time to response, duration of response, 
and progression-free and overall survival. Throughout the study, MRD will be evaluated to 
determine whether individuals who achieved CR have residual disease by IHC. 
High throughput next generation sequencing will explore the mutation profile for BRAF and 
29 additional genes at baseline and after three treatment cycles. These binary data will be 
descriptively reviewed by treatment response. 
Pre- and post-treatment peripheral blood or bone marrow samples will be assessed by 
Western Blot and/or phospho-flow cytometry for downstream targets of BRAF (MEK, pMEK, 
ERK, pERK). These binary pre/post data will be tabulated across the sample to describe the 
pharmacodynamics of the intervention. The data will also be compared to a new assay 
developed by the Abdel-Wahab lab. 
 
The final secondary objective will explore various biomarkers at baseline to investigate whether 
any are more frequently observed in individuals who are refractory or resistant to vemurafenib. 
These biomarkers will additionally be obtained in patients who are refractory to vemurafenib 

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after three cycles of treatment or in patients who relapse after vemurafenib. The biomarkers 
are described in Section 10.3. 
 
15.0 
RESEARCH PARTICIPANT REGISTRATION AND RANDOMIZATION PROCEDURES 
15.1 
Research Participant Registration 
Confirm eligibility as defined in the section entitled Inclusion/Exclusion Criteria. Obtain 
informed consent, by following procedures defined in section entitled Informed Consent 
Procedures. During the registration process registering individuals will be required to 
complete a protocol specific Eligibility Checklist. The individual signing the Eligibility Checklist 
is confirming whether the participant is eligible to enroll in the study. Study staff are 
responsible for ensuring that all institutional requirements necessary to enroll a participant to 
the study have been completed. See related Clinical Research Policy and Procedure #401 
(Protocol Participant Registration). 
 
All participants must be registered through CTMS. 
 
 
15.2 
Randomization 
There is no randomization in this trial. 
16.0 
DATA MANAGEMENT ISSUES 
This is a multicenter trial that will be coordinated by the Multicenter Core group at MSKCC. A 
Clinical Research Associate (CRA) will be assigned to the study. The responsibilities of the 
CRA include project compliance, data collection, abstraction and entry, data reporting, 
regulatory monitoring, problem resolution and prioritization, and coordinate the activities of the 
protocol study team. The data collected for this study will be entered into a secure database. 
Source documentation will be available to support the computerized patient record. 
 
16.1 
Quality Assurance 
Weekly registration reports will be generated to monitor patient accruals and completeness of 
registration data. Routine data quality reports will be generated to assess missing data and 
inconsistencies. Accrual rates and extent and accuracy of evaluation and follow-up will be 
monitored periodically throughout the study period and potential problems will be brought to 
the attention of the study team for discussion and action. Random-sample data quality and 
protocol compliance audits will be conducted by the study team, at a minimum of two times per 
year, more frequently if indicated. Additionally, monthly teleconferences including principal 
investigators and/or their designees from all sites will be held to expedite the review of toxicity 
and efficacy data. 
 
16.2 
Data and Safety Monitoring 
The Data and Safety Monitoring (DSM) Plans at Memorial Sloan-Kettering Cancer Center were 
approved by the National Cancer Institute in August 2018. The plans address the new policies 
set forth by the NCI in the document entitled ““Policy of the National Cancer Institute for Data 
and Safety Monitoring of Clinical Trials.” 

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There are several different mechanisms by which clinical trials are monitored for data, safety 
and quality. At a departmental/PI level there exists procedures for quality control by the 
research team(s). Institutional processes in place for quality assurance include protocol 
monitoring, compliance and data verification audits, staff education on clinical research QA 
and two institutional committees that are responsible for monitoring the activities of our clinical 
trials programs. The committees: Data and Safety Monitoring Committee (DSMC) for Phase I 
and II clinical trials, and the Data and Safety Monitoring Board (DSMB) for Phase III clinical 
trials, report to the Deputy Physician-in-Chief, Clinical Research. 
The degree of monitoring required will be determined based on level of risk and documented. 
 
The MSK DSMB monitors phase III trials and the DSMC monitors non-phase III trials. The 
DSMB/C have oversight over the following trials: 
 
- 
MSK Investigator Initiated Trials (IITs; MSK as sponsor) 
- 
External studies where MSK is the data coordinating center 
- 
Low risk studies identified as requiring DSMB/C review 
 
The DSMC will initiate review following the enrollment of the first participant/or by the end of 
the year one if no accruals and will continue for the study lifecycle until there are no 
participants under active therapy and the protocol has closed to accrual. The DSMB will 
initiate review once the protocol is open to accrual. 
. 
17.0 
PROTECTION OF HUMAN SUBJECTS 
17.1 
Privacy 
MSKCC’s Privacy Office may allow the use and disclosure of protected health information 
pursuant to a completed and signed Research Authorization form. The use and disclosure of 
protected health information will be limited to the individuals described in the Research 
Authorization form. A Research Authorization form must be completed by the Principal 
Investigator and approved by the IRB and Privacy Board (IRB/PB). 
The consent indicates that individualized de identified information collected for the purposes 
of this study may be shared with other qualified researchers. Only researchers who have 
received approval from MSK will be allowed to access this information which will not include 
protected health information, such as the participant’s name, except for dates. It is also stated 
in the Research Authorization that their research data may be shared with others at the time 
of study publication. 
17.2 
Serious Adverse Event (SAE) Reporting 
SAE reporting is required as soon as the participant starts investigational 
treatment/intervention. SAE reporting is required for 30-days after the participant’s last 
investigational treatment/intervention. Any event that occur after the 30-day period that is 
unexpected and at least possibly related to protocol treatment must be reported. Please refer 
to section 11.2.2 for more detail information. 

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17.2.2 SAE Reporting to Genentech (MSKCC STAFF ONLY) 
MSK will be responsible for collecting all protocol-defined Adverse Events (AEs)/Serious 
Adverse Events (SAEs), pregnancy reports (including pregnancy occurring in the partner of a 
male study subject), other Special Situation reports, AESIs and Product Complaints with an 
AE where the patient has been exposed to Vemurafenib. The completed MedWatch form 
should be sent to the Genentech contact specified below. 
 
 
Fax: 650-238-6067 
 
Email: usds_aereporting-d@gene.com 
 
All Product Complaints without an AE should call via: 
PC Hotline Number: (800) 334-0290 (M-F: 5 am to 5 pm PST) 
 
 
Transmission of these reports (initial and follow-up) will be either electronically via email or by 
fax and within the timelines specified below: 
• 
Serious Adverse Drug Reactions (SADRs) 
Serious AE reports that are related to the Product or where the causality is assessed 
as unknown or not provided shall be transmitted to Roche within fifteen (15) calendar 
days of the awareness date. 
• 
Other SAEs 
Serious AE reports that are unrelated to the Product shall be transmitted to Roche 
within thirty (30) calendar days of the awareness date. 
 
• 
Special Situation Reports 
 
• 
Pregnancy reports 
While such reports are not serious AEs or Adverse Drug Reactions (ADRs) per se, as 
defined herein, any reports of pregnancy (including pregnancy occurring in the 
partner of a male study subject), where the fetus may have been exposed to the 
Product, shall be transmitted to Roche within thirty (30) calendar days of the 
awareness date. Pregnancies will be followed-up until the outcome of the pregnancy 
is known, whenever possible, based upon due diligence taken to obtain the follow-up 
information. 
Pregnancies in Female Partners of Male Patients 
Male patients will be instructed through the Informed Consent Form to immediately 
inform the investigator if their partner becomes pregnant during the study or within 6 
moths after the last dose of study drug. A Clinical Trial Pregnancy Reporting Form 
should be completed and submitted to Genentech within thirty (30) calendar days of 
the awareness date. 
 
Other Special Situation Reports, as defined above, shall be transmitted to Roche 
within thirty (30) calendar days of the awareness date. 

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• 
Product Complaints 
All Product Complaints (with or without an AE) shall be forwarded to Genentech 
within fifteen (15) calendar days of the awareness date. 
 
• 
AESIs 
AESIs requiring expedited reporting (related or possibly related to Roche product or 
where the causality is assessed as unknown or not provided) shall be forwarded to 
Roche within fifteen (15) calendar days of the awareness date. Others (non-related to 
Roche product) shall be sent within thirty (30) calendar days. 
 
 
Case Transmission Verification of Single Case Reports 
 
MSK agrees to conduct the Case Transmission verification to ensure that all single 
case reports have been adequately received by Genentech via MSK emailing 
Genentech a Quarterly line-listing documenting single case reports sent by MSK to 
Genentech in the preceding quarter. 
The periodic line-listing will be exchanged within seven (7) calendar days of the end of 
the agreed time period. Confirmation of receipt should be received within the time 
period mutually agreed upon. 
 
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. The sponsor shall receive 
reconciliation guidance documents within the ‘Activation Package’. 
 
Following Case Transmission Verification, single case reports which have not been 
received by Genentech shall be forwarded by MSK to Genentech within five (5) 
calendar days from request by Genentech. 
 
At the end of the study, a final cumulative Case Transmission Verification report will be 
sent to Genentech 
For questions related to safety reporting, please contact Genentech Drug Safety: 
Tel: (888) 835-2555 
Fax: (650) 225-4682 or (650) 225-4630 
IND ANNUAL REPORTS 
 
 
All IND annual reports submitted to the FDA by the Sponsor-Investigator should be copied to 
Genentech 
Copies of such reports should be emailed to Genentech at: Genentech Drug Safety CTV mail 
box: ctvist_drugsafety@gene.com 
Final study report: 
 
MSK will forward a copy of the Final Study Report to Genentech upon completion of the Study. 

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STUDY CLOSE-OUT 
 
Any study report submitted to the FDA by the Sponsor-Investigator should be copied to 
Genentech. This includes all IND annual reports and the Clinical Study Report (final study 
report). Additionally, any literature articles that are a result of the study should be sent to 
Genentech. Copies of such reports should be mailed to the assigned Clinical Operations 
contact for the study: 
 
[Bina Machchhar - machchhb@gene.com] 
 
And to Genentech Drug Safety CTV oversight mail box at: ctvist_drugsafety@gene.com 
 
QUERIES 
 
Queries related to the Study will be answered byMSK. However, responses to all safety 
queries from regulatory authorities or for publications will be discussed and coordinated 
between the Parties. The Parties agree that Genentech shall have the final say and control 
over safety queries relating to the Product. MSK agrees that it shall not answer such queries 
from regulatory authorities and other sources relating to the Product independently but shall 
redirect such queries to Genentech. 
 
Both Parties will use all reasonable effort to ensure that deadlines for responses to urgent 
requests for information or review of data are met. The Parties will clearly indicate on the 
request the reason for urgency and the date by which a response is required. 
 
SAFETY CRISIS MANAGEMENT 
 
In case of a safety crisis, e.g., where safety issues have a potential impact on the indication(s), 
on the conduct of the Study, may lead to labeling changes or regulatory actions that limit or 
restrict the way in which the Product is used, or where there is media involvement, the Party 
where the crisis originates will contact the other Party as soon as possible. 
 
The Parties agree that Genentech shall have the final say and control over safety crisis 
management issues relating to the Product. MSK agrees that it shall not answer such queries 
from media and other sources relating to the Product but shall redirect such queries to 
Genentech. 
 
 
COMPLIANCE WITH PHARMACOVIGILANCE AGREEMENT / AUDIT 
 
The Parties shall follow their own procedures for adherence to AE reporting timelines. 
Each Party shall monitor and, as applicable, request feedback from the other Party regarding 
AE report timeliness in accordance with its own procedures. The Parties agree to provide 
written responses in a timely manner to inquiries from the other Party regarding AE reports 
received outside the agreed upon Agreement timelines. If there is any detection of trends of 
increasing or persistent non-compliance to transmission timelines stipulated in this Agreement, 
both Parties agree to conduct ad hoc or institute a regular joint meeting to address the issue. 
 
In case of concerns related to non-compliance of processes, other than exchange timelines, 
with this Agreement, the Parties will jointly discuss and collaborate on clarifying and resolving 
the issues causing non-compliance. Every effort will be made by the non-compliant Party to 

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solve the non-compliance issues and inform the other Party of the corrective and preventative 
actions taken. 
 
Upon justified request, given sufficient notice of no less than sixty (60) calendar days, an audit 
under the provisions of this Agreement can be requested by either Party. The Parties will then 
discuss and agree in good faith upon the audit scope, agenda and execution of the audit. The 
requesting Party will bear the cost of the audit. 
 
 
17.3 Reporting to Regulatory Authorities, Ethics Committees and Investigators 
MSK, as the Sponsor of the Study, will be responsible for the expedited reporting of safety 
reports originating from the Study to the Regulatory Authorities (FDA) where it has filed a 
clinical trial approval, in compliance with local regulations. 
 
MSK, as the Sponsor of the Study, will be responsible for the expedited reporting of safety 
reports originating from the study to the EMA through Eudravigilance Clinical Trial Module 
(EVCTM), where applicable. 
 
17.3.2 Reporting Requirements for IND Holders 
 
For Investigator-Initiated IND Studies, some additional reporting requirements for the FDA 
apply in accordance with the guidance set forth in 21 CFR § 
600.80. 
Events meeting the following criteria need to be submitted to the Food and Drug Administration 
(FDA) as expedited IND Safety Reports according to the following guidance and timelines: 
 
7 Calendar Day Telephone or Fax Report: 
The Investigator is required to notify the FDA of any fatal or life-threatening adverse event that 
is unexpected and assessed by the Investigator to be possibly related to the use of 
Vemurafenib. An unexpected adverse event is one that is not already described in the 
Vemurafenib Investigator Brochure. Such reports are to be telephoned or faxed to the FDA 
and Genentech within 7 calendar days of first learning of the event. 
 
15 Calendar Day Written Report 
 
The Investigator is also required to notify the FDA and all participating investigators, in a written 
IND Safety Report, of any serious, unexpected AE that is considered reasonably or possibly 
related to the use of Vemurafenib. An unexpected adverse event is one that is not already 
described in the [study drug] investigator brochure. 
 
Written IND Safety reports should include an Analysis of Similar Events in accordance with 
regulation 21 CFR 
§ 312.32. All safety reports previously filed by the investigator with the IND concerning similar 
events should be analyzed and the significance of the new report in light of the previous, similar 
reports commented on. 

Memorial Sloan Kettering Cancer Center 
IRB Number: 12-200 A(17) 
Approval date: 15-Jun-2022 
Page 35 of 39 
 
 
Written IND safety reports with Analysis of Similar Events are to be submitted to the FDA, 
Genentech, and all participating investigators within 15 calendar days of first learning of the 
event. The FDA prefers these reports on a MedWatch 3500 form, but alternative formats are 
acceptable (e.g., summary letter). 
FDA fax number for IND Safety Reports: 
 
Fax: 1 (800) FDA 0178 
 
 
All written IND Safety Reports submitted to the FDA by the Investigator must also be faxed to 
Genentech Drug Safety: 
 
Fax: 650-238-6067 
Email: usds_aereporting-d@gene.com 
 
And MSK will be responsible for the distribution of safety information to Site IRB: 
All Product Complaints without an AE should call via: 
PC Hotline Number: (800) 334-0290 (M-F: 5 am to 5 pm PST) 
 
18.0 
INFORMED CONSENT PROCEDURES 
Before protocol-specified procedures are carried out, consenting professionals will explain 
full details of the protocol and study procedures as well as the risks involved to participants 
prior to their inclusion in the study. Participants will also be informed that they are free to 
withdraw from the study at any time. All participants must sign an IRB/PB-approved consent 
form indicating their consent to participate. This consent form meets the requirements of the 
Code of Federal Regulations and the Institutional Review Board/Privacy Board of this Center. 
 
 
The consent form will include the following: 
1. The nature and objectives, potential risks and benefits of the intended study. 
2. The length of study and the likely follow-up required. 
3. Alternatives to the proposed study. (This will include available standard and 
investigational therapies. In addition, patients will be offered an option of supportive 
care for therapeutic studies.) 
4. The name of the investigator(s) responsible for the protocol. 
5. The right of the participant to accept or refuse study interventions/interactions and to 
withdraw from participation at any time. 
Before any protocol-specific procedures can be carried out, the consenting professional will 
fully explain the aspects of patient privacy concerning research specific information. In 
addition to signing the IRB Informed Consent, all patients must agree to the Research 
Authorization component of the informed consent form. 
Each participant and consenting professional will sign the consent form. The participant must 
receive a copy of the signed informed consent form. 

Memorial Sloan Kettering Cancer Center 
IRB Number: 12-200 A(17) 
Approval date: 15-Jun-2022 
Page 36 of 39 
 
 
 
19.0 
REFERENCES 
 
 
19.0 
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Tiacci E, Trifonov V, Schiavoni G, et al. BRAF Mutations in Hairy-Cell Leukemia. N Engl J 
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Solit DB, Garraway LA, Pratilas CA, et al. BRAF mutation predicts sensitivity to MEK 
inhibition. Nature. Jan 19 2006;439(7074):358-362. 
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Wan PT, Garnett MJ, Roe SM, et al. Mechanism of activation of the RAF-ERK signaling 
pathway by oncogenic mutations of B-RAF. Cell. Mar 19 2004;116(6):855-867. 
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Slupsky JR, Kamiguti AS, Harris RJ, Cawley JC, Zuzel M. Central role of protein kinase 
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Boyd EM, Bench AJ, van 't Veer MB, et al. High resolution melting analysis for detection of 
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Haematol. Dec 2011;155(5):609-612. 
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sensitive detection of the BRAF-V600E mutation. Blood. Oct 25 2011. 
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Dietrich S, Glimm H, Andrulis M, von Kalle C, Ho AD, Zenz T. BRAF Inhibition in Refractory 
Hairy-Cell Leukemia. New England Journal of Medicine. 2012;366(21):2038-2040. 
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Else M, Ruchlemer R, Osuji N, et al. Long remissions in hairy cell leukemia with purine 
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Maloisel F, Benboubker L, Gardembas M, et al. Long-term outcome with pentostatin 
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eradicate leukemic cells in hairy cell leukemia patients in complete remission. Leukemia. Jul 
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IRB Number: 12-200 A(17) 
Approval date: 15-Jun-2022 
Page 38 of 39 
 
 
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Wheaton S, Tallman MS, Hakimian D, Peterson L. Minimal residual disease may predict 
bone marrow relapse in patients with hairy cell leukemia treated with 2- 
chlorodeoxyadenosine. Blood. Feb 15 1996;87(4):1556-1560. 
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Johannessen CM, Boehm JS, Kim SY, et al. COT drives resistance to RAF inhibition through 
MAP kinase pathway reactivation. Nature. Dec 16 2010;468(7326):968-972. 
40. 
Nazarian R, Shi H, Wang Q, et al. Melanomas acquire resistance to B-RAF(V600E) inhibition 
by RTK or N-RAS upregulation. Nature. Dec 16 2010;468(7326):973-977. 
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Villanueva J, Vultur A, Lee JT, et al. Acquired resistance to BRAF inhibitors mediated by a 
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20.0 
APPENDICES 
Appendix A: Impact of Vemurafenib on Concomitant Medications 
Appendix B: ECOG Performance Status 
 
Appendix C: Medication Diary for Vemurafenib 
 
Appendix D: Multicenter Addendum for Participating Sites 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Appendix E: Genentech Safety reporting Fax cover sheet 

Memorial Sloan Kettering Cancer Center 
IRB Number: 12-200 A(17) 
Approval date: 15-Jun-2022 
Page 39 of 39 
 
 
 
 
 
 
SAFETY REPORTING FAX COVER SHEET 
Genentech Supported Research 
 
AE / SAE FAX No: (650) 238-6067 
 
Genentech Study Number 
Principal Investigator 
Site Name 
Reporter name 
Reporter Telephone # 
Reporter Fax # 
 
 
Initial Report Date 
[DD] / [MON] / [YY] 
Follow-up Report Date 
[DD] / [MON] / [YY] 
 
 
Subject Initials 
(Enter a dash if patient has no 
middle name) 
[ ] - [ ] - [ ] 
 
SAE or Safety Reporting questions, contact Genentech Drug Safety: (888) 835-2555 
 
 
PLEASE PLACE MEDWATCH REPORT or SAFETY REPORT BEHIND THIS COVER SHEET