Conditions: Waldenstrom Macroglobulinemia
Keywords: Waldenstrom Macroglobulinemia WM
Allocation: NA | Intervention model: SINGLE_GROUP
Enrollment: 33
Healthy volunteers: no

Brief summary:
This research study is studying a targeted therapy as a possible treatment for relapsed or refractory Waldenstrom's Macroglobulinemia (WM). This study is using the study intervention ABT-199.

Detailed description:
This research study is a Phase II clinical trial. ABT-199 is a pill that blocks BCL-2, a protein that is important for the survival of WM cells.

The purpose of this research study is to evaluate how well the study drug works and the safety of ABT-199 as a single agent in participants with WM that has come back or has shown no response to previous treatment.

The FDA (the U.S. Food and Drug Administration) has not approved ABT-199 as a treatment for any disease.

Arms:
arm 1: ABT199 will be administered daily, with 28 consecutive days defined as a treatment cycle for a maximum for 26 cycles

Interventions: intervention 1: ABT199
Intervention descriptions: intervention 1: Oral BCL-2 antagonist

Protocol document:
Prot_SAP_000.pdf: 
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TITLE:  Phase II Study of ABT-199 (GDC-199) in patients with relapsed or refractory 
Waldenström Macroglobulinemia 
 
 
 
Coordinating Center: 
 
 
Dana-Farber Cancer Institute 
 
 
 
 
 
 
 
 
 
450 Brookline Avenue  
 
 
 
 
 
 
 
 
 
Boston, MA 02215 USA 
 
*Principal Investigator (PI): 
Jorge J. Castillo, MD 
 
Dana-Farber Cancer Institute 
 
Jorgej_castillo@dfci.harvard.edu 
 
 
Other Investigators: 
Steven P. Treon, MD, PhD 
 
Dana-Farber Cancer Institute 
 
Steven_treon@dfci.harvard.edu 
 
 
Study Coordinator:  
Kirsten Meid 
Dana-Farber Cancer Institute 
450 Brookline Ave 
Boston, MA 02215 USA 
Kirsten_Meid@dfci.harvard.edu  
 
 
 
 
 
 
Agent: BCL2 inhibitor ABT-199 (GDC-199) 
 
 
IND #:  127663 
IND Sponsor:  Jorge J. Castillo, MD  
 
Protocol Type / Version # / Version Date: 
Original/ Version #10 1.18.18 
 


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SCHEMA 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Screening 
Registration 
ABT-199 Administration 
Lead-in phase followed by 
26 four-week cycles (2 
years)  
Response Evaluation 
Stop ABT-199 
Event Monitoring for 2 
years 
Event Monitoring 
Progressive Disease 
(PD), Unacceptable 
Toxicity, No Response 
Stable Disease or Response 


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TABLE OF CONTENTS 
 
SCHEMA ........................................................................................................................................ ii 
1. 
OBJECTIVES ......................................................................................................................1 
1.1 
Study Design ............................................................................................................1 
1.2 
Primary Objectives ...................................................................................................2 
1.3 
Secondary Objectives ...............................................................................................2 
2. 
BACKGROUND .................................................................................................................2 
2.1 
Study Disease(s).......................................................................................................2 
2.2 
IND Agent ABT-199 ...............................................................................................4 
2.3 
Rationale ..................................................................................................................7 
2.4 
Correlative Studies Background ............................................................................10 
3. 
PARTICIPANT SELECTION ...........................................................................................11 
3.1 
Eligibility Criteria ..................................................................................................11 
3.2 
Exclusion Criteria ................................................................................................12 
3.3 
Inclusion of Women and Minorities ......................................................................12 
4. 
REGISTRATION PROCEDURES ...................................................................................12 
4.1 
General Guidelines for DF/HCC Institutions ........................................................13 
4.2 
Registration Process for DF/HCC Institutions .......................................................13 
4.3 
General Guidelines for Other Investigative Sites ..................................................13 
4.4 
Registration Process for Other Investigative Sites .................................................13 
5. 
TREATMENT PLAN ........................................................................................................14 
5.1 
Treatment Regimen ................................................................................................14 
5.2 
Pre-Treatment Criteria ...........................................................................................14 
5.3 
Agent Administration .............................................................................................14 
5.4 
General Concomitant Medication and Supportive Care Guidelines ......................17 
5.5 
Criteria for Taking a Participant Off Protocol Therapy .........................................20 
5.6 
Duration of Follow Up ...........................................................................................21 
5.7 
Criteria for Taking a Participant Off Study ...........................................................21 
6. 
DOSING DELAYS/DOSE MODIFICATIONS................................................................21 
7. 
ADVERSE EVENTS:  LIST AND REPORTING REQUIREMENTS ............................23 
7.1 
Expected Toxicities ................................................................................................23 
Tumor Lysis Syndrome......................................................................................................26 
7.2 
Adverse Event Characteristics ...............................................................................31 
7.3 
Expedited Adverse Event Reporting ......................................................................32 
7.4 
Expedited Reporting to the Food and Drug Administration (FDA) ......................33 
7.5 
Expedited Reporting to Hospital Risk Management .............................................33 
7.6 
Expedited Reporting to Abbvie Drug Safety Department .....................................33 
7.7 
Routine Adverse Event Reporting .........................................................................34 


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8. 
PHARMACEUTICAL INFORMATION ..........................................................................34 
8.1 
ABT-199 ................................................................................................................34 
9. 
BIOMARKER, CORRELATIVE, AND SPECIAL STUDIES ........................................36 
9.1 
Biomarker Studies ..................................................................................................36 
10. 
STUDY CALENDAR .......................................................................................................37 
STUDY CALENDAR ...................................................................................................................37 
11. 
MEASUREMENT OF EFFECT........................................................................................39 
11.1 
Antitumor Effect – Hematologic Tumors ..............................................................39 
12. 
DATA REPORTING / REGULATORY REQUIREMENTS ...........................................40 
12.1 
Data Reporting .......................................................................................................41 
12.2 
Data Safety Monitoring ..........................................................................................41 
12.3 
Multicenter Guidelines ...........................................................................................41 
12.4 
Collaborative Agreements Language .....................................................................42 
13. 
STATISTICAL CONSIDERATIONS...............................................................................42 
13.1 
Study Design/Endpoints.........................................................................................42 
13.2 
Sample Size, Accrual Rate and Study Duration ....................................................42 
13.3 
Stratification Factors ..............................................................................................43 
13.4 
Interim Monitoring Plan ........................................................................................43 
13.5 
Analysis of Primary Endpoints ..............................................................................43 
13.6 
Analysis of Secondary Endpoints ..........................................................................43 
13.7 
Reporting and Exclusions ......................................................................................44 
14. 
PUBLICATION PLAN .....................................................................................................44 
REFERENCES ..............................................................................................................................45 
APPENDIX A 
PERFORMANCE STATUS CRITERIA ..................................................47 
APPENDIX C.  dEFINITIONS OF LABORATORY AND CLINICAL TUMOR LYSIS 
SYNDROME .....................................................................................................................52 
APPENDIX d 
MULTICENTER GUIDELINES...............................................................53 
15. 
INTRODUCTION .............................................................................................................55 
15.1 
Purpose ...................................................................................................................55 
15.2 
Multi-Center Data and Safety Monitoring Plan Definitions ..................................55 
16. 
GENERAL ROLES AND RESPONSIBILITIES .............................................................56 
16.1 
DF/HCC Sponsor ...................................................................................................56 
16.2 
Coordinating Center ...............................................................................................57 
16.3 
Participating Institution ..........................................................................................57 


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17. 
DF/HCC REQUIREMENTS FOR MULTI-CENTER PROTOCOLS..............................58 
17.1 
Protocol Distribution ..............................................................................................58 
17.2 
Protocol Revisions and Closures ...........................................................................58 
17.3 
Informed Consent Requirements ...........................................................................59 
17.4 
IRB Documentation ...............................................................................................59 
17.5 
IRB Re-Approval ...................................................................................................59 
17.6 
Participant Confidentiality and Authorization Statement ......................................60 
17.7 
DF/HCC Multi-Center Protocol Registration Policy .............................................60 
17.8 
DF/HCC Protocol Case Number ............................................................................61 
17.9 
Safety Assessments and Toxicity Monitoring .......................................................63 
17.10  Data Management ..................................................................................................63 
18. 
REQUISITIONING INVESTIGATIONAL DRUG..........................................................64 
19. 
MONITORING: QUALITY CONTROL ..........................................................................64 
19.1 
Ongoing Monitoring of Protocol Compliance .......................................................64 
19.2 
Monitoring Reports ................................................................................................65 
19.3 
Accrual Monitoring ................................................................................................66 
20. 
AUDITING: QUALITY ASSURANCE ...........................................................................66 
20.1 
Audit Plan: DF/HCC Sponsored Trials..................................................................66 
20.2 
Audit Notification ..................................................................................................66 
20.3 
Audit Reports .........................................................................................................66 
20.4 
Participating Institution Performance ....................................................................66 
20.5 
Corrective Actions .................................................................................................67 


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1. OBJECTIVES 
 
1.1 
Study Design 
 
This is a Phase II study designed to evaluate the safety and efficacy of ABT-199 (GDC-199) in 
previously treated, relapsed/refractory WM patients. Treatment will be administered daily to 
participants with WM, and participants will receive treatment for a duration of completion of the 
lead-in phase to the target dose level, followed by a maximum of 2 years at this dose or until 
progression of disease or unacceptable toxicity. Treatment will be comprised of a lead-in phase 
of ABT-199 at 200 mg PO daily for 1 week, 400 mg PO daily for 1 week, and 800 mg PO daily 
for 2 weeks, for the first six patients enrolled (Cohort 1), followed by ABT-199 at 800 mg PO 
daily for 2 years following the completion of the lead-in phase. If no evidence of tumor lysis 
syndrome is seen, then starting with the seventh patient (Cohort 2), the lead-in phase would 
consist on ABT-199 at a dose of 400 mg PO daily for 1 week, and 800 mg PO daily for 3 weeks, 
followed by ABT-199 at 800 mg PO daily for 2 years following the completion of the lead-in 
phase. Therapy will continue for 2 years at the target dose provided the patients continue to 
tolerate the drug, have no evidence of disease progression, and do not meet any of the criteria for 
subject discontinuation, with permitted dose modification for toxicity as per Table 6-1. 
 
A Screening visit will be conducted within 30 days of Cycle 1, Day 1 of study drug 
administration. At the Screening visit, a medical history will be obtained and a complete physical 
examination will be performed including vital signs and an ECOG performance status.  A bone 
marrow aspirate and biopsy, and CT scanning of the chest, abdomen and pelvis will be done. 
Bone marrow and CT scans will not be required if collected within 90 days prior to Cycle 1 Day 
1 visit. Clinical laboratory tests including a complete blood count plus differential, 
comprehensive chemistry panel (electrolytes, BUN, creatinine, albumin, total protein, total 
bilirubin, SGOT (AST), SGPT (ALT), alkaline phosphatase), magnesium, beta-2-microglobulin, 
serum and protein electrophoresis with quantification of immunoglobulins (IgM, IgG, IgA) and 
immunofixation studies, Von Willebrands factor, HIV, HBsAg, HBsAb, HBcAb and HCV 
antibody. Serum pregnancy tests for women of childbearing potential will also be performed at 
the Screening visit. Cryoglobulins and cold agglutinins will be obtained if clinically indicated. 
Coagulation studies (PT, PTT, PT-INR) and tumor lysis laboratories (calcium, phosphorus, 
LDH, and uric acid) will also be performed at baseline. 
 
Participants who meet the eligibility requirements as assessed at the Screening visit will be 
enrolled in the study and initiated on study drug. Participants will be evaluated for development 
of tumor lysis syndrome (TLS) on Days 1 and 2 of dose escalation days during the lead-in phase. 
TLS, however, is an extremely rare occurrence in patients with WM. To err in the side of safety, 
all patients will receive allopurinol 300 mg PO once daily starting 72 hours prior to first dose of 
ABT-199 and continuing at least throughout the lead-in (Cycle 1) period. All patients will be 
encouraged to drink 2 L of fluid the day before starting ABT-199. Patients in whom oral intake is 
inadequate, 1 L of 0.9% normal saline will be administered IV prior to first dose of ABT-199 
and prior to each dose escalation of ABT-199. All patients will be monitored for TLS at 8 hours 
and 24 hours after starting ABT-199, and at each dose escalation at least until week 2, as needed 
to reach the maximum dose of 800 mg PO daily. Patients with laboratory or clinical evidence of 


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TLS will be hospitalized for further management. The inpatient management of TLS, frequency 
of monitoring and duration of hospitalization will be decided by the investigator, aided by the 
guidelines in Appendix B (Recommendations for Initial Management of Electrolyte 
Abnormalities and Prevention of Tumor Lysis Syndrome [TLS]). In patients who developed 
TLS, hospitalization for at least 24 hours will be needed for subsequent dose escalations. Patients 
will be evaluated for response on the first day of each cycle (4 weeks ± 1 week) at cycle 2, and 3 
and thereafter every 3 cycles (12 weeks ± 2 weeks) for the duration of therapy. Participants will 
be eligible to continue therapy for 2 years at the target dose following the completion of the lead-
in phase, provided the patients continue to tolerate the drug, have no evidence of disease 
progression, and do not meet any of the criteria for subject discontinuation.  
 
Response criteria updated at the Sixth International Workshop on Waldenström 
macroglobulinemia (Owen 2013) will be used to assess response, stable disease, and progressive 
disease. Response outcomes to be determined will include: Best overall response rate (including 
minor, partial, very good partial and complete response rate) and major response rate (including 
partial, very good partial and complete response rate), landmark analysis for 2 and 4-year overall 
survival (OS), progression-free survival (PFS) and median duration of response (DOR). The 
duration of therapy will depend on individual response, evidence of disease progression and 
tolerance of the drug. If at the end of study therapy, it is deemed that WM patients derive benefit 
from ABT-199, AbbVie will work with the investigator to evaluate options for continuation of 
ABT-199. If ABT-199 were to become commercially available, then patients still enrolled in the 
study will have the option of receiving ABT-199 via prescription coverage. Follow-up will 
continue for 2 years or until new therapy after patients had stopped taking ABT-199 for any 
reason, except death. 
 
1.2 
Primary Objectives 
 
 To assess the best overall response rate (ORR) of ABT-199 in symptomatic WM patients 
with relapsed/refractory disease. 
 
1.3 
Secondary Objectives 
 To assess the safety and tolerability of ABT-199 in symptomatic WM patients with 
relapsed/refractory disease. 
 To evaluate the rate of CR, very good partial response (VGPR), partial response (PR), 
minimal response (MR), stable disease (SD) and progressive disease (PD). 
 To evaluate the 2-year and 4-years median OS, median PFS and median duration of response 
(DOR). 
 To evaluate the toxicity profile of ABT-199 in patients with relapsed/refractory WM 
 To evaluate the association between presence of MYD88 and CXCR4 mutations and 
response to ABT-199 
 
2. BACKGROUND 
 
2.1 
Study Disease(s) 
 


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WM is a rare B-cell lymphoproliferative disorder characterized by the uncontrolled accumulation 
of IgM-producing lymphoplasmacytic cells. Such malignant cells accumulate in the bone 
marrow, liver, spleen and lymph nodes. WM is diagnosed by the presence of lymphoplasmacytic 
cells in the bone marrow and an IgM monoclonal spike (M-spike) identified in a serum protein 
electrophoresis (SPEP) (Swerdlow 2002). The incidence of WM in the United States (US) is 
approximately 0.3 per 100,000 persons per year accounting for approximately 1000 new cases 
per year (Sekhar 2012), although this is likely to be an underestimation. The clinical course of 
WM is variable and although patients might experience an overall survival (OS) measured in 
decades (Castillo 2014), WM remains incurable with current therapeutic regimens (Treon 2009). 
Hence, the disease course is characterized by continual relapses, each harder to treat than the 
previous one. Additionally, many of the disabling symptoms associated with the disease, such as 
hyperviscosity, fatigue, anemia or neuropathy, can be exacerbated by therapy. Rituximab can 
induce disabling IgM flare (Treon 2002), alkylating agents and nucleoside analogs can be 
associated with the development of secondary MDS/AML (Leleu 2009), bortezomib can cause 
high rates of peripheral neuropathy (Treon 2009), and carfilzomib can induce severe 
hypogammaglobulinemia (Treon 2014). Hence, the careful evaluation of agents with novel 
mechanisms of action is needed to improve the quality of life (QOL), and response and survival 
rates in patients with WM. 
 
Recently, our group identified a recurrent mutation in the MYD88 gene (MYD88 L265P), which 
is seen in over 90% of cases with WM (Treon 2012). The occurrence of this mutation in WM has 
since been validated in several independent cohorts. In contrast, the MYD88 L265P gene 
mutation was not detected in patients with IgM myeloma, and was detected in less than 10% of 
patients with marginal zone lymphoma. The high specificity and sensitivity of the MYD88 
L265P gene mutation has obvious diagnostic implications in patients in whom a diagnosis of 
WM is suspected but uncertain. The MYD88 L265P gene mutation has shown to support growth 
and survival of WM cells in several studies. A knockdown model of MYD88 showed decreased 
survival of MYD88 L265P expressing WM cells, whereas survival was more enhanced by 
knock-in of mutant versus wild-type MYD88. MYD88 acts as an adaptor molecule in toll-like 
receptor (TLR) and interleukin-1 receptor (IL-1R) signaling. Following stimulation of TLR or 
IL-1R, MYD88 is recruited to the activated receptor complex as a homodimer which complexes 
with IL-1R-associated kinase 4 (IRAK4) and subsequently activates IRAK1 and IRAK2. IRAK1 
activation then leads to NF-κB activation via IκBα phosphorylation. Recently, a study has shown 
that MYD88 L265P also activates the Bruton’s Tyrosine Kinase (BTK) pathway (Yang 2013). In 
this pre-clinical study, the activation of BTK by MYD88 could be abrogated by the use of BTK 
kinase inhibitors. Clinically, the use of the oral BTK inhibitor ibrutinib has shown to be effective 
in patients with WM (Treon 2013). A phase II study on 63 patients with relapsed/refractory WM 
was performed evaluating ibrutinib at a dose of 420 mg PO once daily. The ORR was 
approximately 80% with relatively well-tolerated AE profile. The median time to response (IgM 
level decrease by at least 25% of baseline) was 4 weeks. At a median follow-up of 18 months, 
80% of patients continue on ibrutinib. 
 
Another study from our group reported the occurrence of recurrent somatic CXCR4 gene 
mutations in approximately 30% of WM patients (Hunter 2013). The somatic mutations occur in 
the C-terminal domain, and are similar to those observed in patients with WHIM (Warts, 
Hypogammaglobulinemia, Infections, and Myelokathexis) syndrome. These mutations regulate 


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signaling of CXCR4 by its ligand SDF-1a. In WM patients, two classes of CXCR4 mutations 
occur: non-sense (CXCR4WHIM/NS) and frameshift (CXCR4WHIM/FS) mutations. Non-sense and 
frameshift mutations are almost equally divided among WM patients, and over 30 different types 
of CXCR4 mutations have been identified. Preclinical studies with the most common CXCR4 
S338X mutation in WM have shown sustained signaling of AKT, ERK and BTK following SDF-
1a binding in comparison with wild-type CXCR4, as well increased cell growth and survival of 
WM cells. CXCR4 mutations have been associated with resistance to ibrutinib (Cao 2014). In the 
phase II study of ibrutinib in relapsed/refractory WM patients, patients carrying CXCR4 
mutations had lower rates of response and lower depth of response to ibrutinib (Treon 2014). 
Hence, there is an unmet need for more effective, better-tolerated drugs for patients with WM. 
 
2.2 
IND Agent ABT-199 
 
ABT-199 (GDC-0199) is a novel, orally bioavailable, small-molecule B-cell lymphoma-2 (Bcl-
2) family inhibitor in the biarylacylsulfonamide chemical class. ABT-199 binds with high 
affinity (inhibition constant [Ki] < 0.010 nM) to antiapoptotic protein Bcl-2 and with lower 
affinity to other antiapoptotic Bcl-2 family proteins, like Bcl-XL and Bcl-w (> 4,000-fold and > 
2,000- to > 20,000-fold lower affinity than to Bcl-2, respectively). 
 
Antiapoptotic Bcl-2 family members are associated with tumor initiation, disease progression, 
and chemotherapy resistance, as well as autoimmunity. Overexpression of Bcl-2 is a major 
contributor to the pathogenesis of some lymphoid malignancies; antagonism of the action of 
these proteins may enhance response to therapy and overcome resistance, and thus, these 
proteins are compelling targets for anti-tumor therapy (Fesik 2005). Currently, AbbVie, Inc. and 
Genentech/Roche are investigating ABT-199 in both oncology and immunology studies. 
 
Pre-clinical studies 
 
In vitro, ABT-199 demonstrated cell killing activity against patient-derived chronic lymphocytic 
leukemia (CLL) and acute myeloid leukemia (AML) cells and a variety of lymphoma and 
leukemia cell lines, including B-cell follicular lymphomas (FLs), mantle cell lymphomas 
(MCLs), diffuse large B –cell lymphomas (DLBCLs), AMLs, and multiple myeloma (MM). 
ABT-199 was especially potent against non-Hodgkin lymphoma (NHL) cell lines expressing 
high levels of Bcl-2. 
 
ABT-199 inhibits subcutaneous xenograft growth of human tumor cell lines derived from acute 
lymphoblastic leukemia (ALL), NHL, and AML, and is highly efficacious using various doses 
and combined with other regimens. The drug is also active in a model of disseminated ALL and 
AML. ABT-199 enhanced the activity of a broad variety of chemotherapeutic agents in other 
human hematological models. Specifically, ABT-199 enhances the efficacy of bendamustine and 
rituximab (BR) in models of MCL and DLBCL. Furthermore, ABT-199 demonstrated potential 
to enhance the efficacy of bortezomib in multiple models of MM. 
 
Pre-clinical safety 
 
ABT-199 was tested in a battery of safety pharmacology assays and produced no effects in 


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central nervous system (CNS)/neurobehavioral, or respiratory studies in mice at oral doses up to 
600 mg/kg. In dogs, mild reductions in cardiac contractility and cardiac output were observed at 
plasma concentrations of ≥ 16 μg/mL; concentrations greater than the concentration of ABT-199 
in humans (3.39 μg/mL at the 900 mg dose). However, no effects on blood pressure, heart rate, 
or electrocardiogram (ECG) parameters were observed in dogs at a maximum drug concentration 
of 46 μg/mL. 
 
Pre-clinical pharmacokinetics 
 
ABT-199 exhibited moderate permeability in the Caco-2 assay. In rats, ABT-199 was widely 
distributed into liver, kidneys, spleen, heart, lungs, small intestine, and white fat, but was poorly 
distributed in testes, brain, muscle, and bone. ABT-199 showed moderate in vitro metabolic 
stability in hepatic systems across species tested, with the exception of dog hepatocytes, where 
stability was low to moderate. In rat, 14.3% of the dose was recovered as parent drug after 48 
hours post-dose, while 76.9% of the dose was excreted as metabolites in bile. Profiles in bile 
indicated that metabolism was the major clearance mechanism, while biliary excretion of parent 
drug played a secondary role in drug elimination. Biotransformation of [3H]ABT-199 proceeded 
via a combination of oxidation and conjugation. 
 
ABT-199 was not a potent inhibitor of the cytochrome P450 enzymes CYP3A4, CYP1A2, 
CYP2B6, or CYP2D6 (50% inhibition constant [IC50] > 30 μM), but was a weak inhibitor of 
CYP2C19 (IC50 = 23.9 μM), a moderate inhibitor of CYP2C8 (IC50 = 4.4 μM), and a potent 
inhibitor of CYP2C9 (IC50 = 0.37 μM). At concentrations of 1, 3, and 10 μM, ABT-199 did not 
induce CYP3A4 or CYP1A2 expression in vitro. ABT-199 was metabolized by CYP3A4; thus, 
its exposure could be affected when potent inhibitors or inducers of CYP3A4 are coadministered. 
 
Pre-clinical toxicology 
 
The primary toxicities associated with ABT-199 administration included effects on the 
hematologic system (decreased lymphocytes and erythrocytes) in mice and dogs; the male dog 
reproductive system (testicular germ cell depletion); and embryofetal toxicity in mice. In mice 
and dogs, ABT-199 produced robust decreases in lymphocytes in the peripheral blood (up to 
75% in mice and up to 80% in dogs) and in lymphoid tissues. These findings are consistent with 
the expected pharmacologic effects of selective Bcl-2 inhibition. In dogs, the recovery of 
lymphocyte counts (total lymphocytes, CD4+ and CD8+ T cells and mature B cells) was 
prolonged, requiring up to 18 weeks after completion of 2 weeks of dosing. B cells were the 
most sensitive lymphocyte subtype based on the magnitude of decrease and/or the length of time 
required for recovery. ABT-199 effects on red blood cell mass parameters principally consisted 
of dose-related decreases in hematocrit and hemoglobin in mice and dogs; these effects were 
adverse only at the highest dosages in the 4-week mouse and dog studies and were reversible. In 
dogs, ABT-199 produced adverse, non-reversible, non-dose-related microscopic findings of 
testicular germ cell depletion at all doses tested; there were no testicular effects in mice.  
 
Decreases of lymphocytes in lymphoid tissue were reversible in mice and reversible to partially 
reversible in dogs. ABT-199 resulted in increased post-implantation loss, and decreased fetal 
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administered (150 mg/kg/day); the no-observed-adverse-effect level (NOAEL) was defined at 
the mid-dose of 50 mg/kg/day. ABT-199 was not teratogenic, and there were no other effects on 
development or fertility. Other effects of ABT-199 included loss of hair pigmentation in dogs, 
single cell necrosis in various epithelial tissues in dogs (e.g., gallbladder) that was of minimal 
magnitude and produced no loss of mucosal integrity, and increased pigment in Kupffer cells or 
macrophages in the liver and gallbladder of dogs. None of the effects were considered to be 
adverse, and all were reversible with the exception of hair coat discoloration. There was no 
evidence of in vitro or in vivo genetic toxicity of ABT-199. 
 
Clinical experience with ABT-199 
 
Multiple ongoing Phase I/II AbbVie, Inc. and Genentech/Roche clinical studies are evaluating 
safety, tolerability, pharmacokinetics, and efficacy of ABT-199 as monotherapy or in 
combination with other therapies (rituximab, BR, bortezomib plus dexamethasone, or 
obinutuzumab) in subjects with hematologic malignancies. 
 
A drug-drug interaction (DDI) study evaluating the interaction of ABT-199 and ketoconazole is 
ongoing. Additionally, a Phase 3 study of ABT-199 plus rituximab compared with BR in 
subjects with CLL has been initiated. 
 
Summary of Safety Data 
 
A total of 257 subjects were enrolled and had data available in AbbVie, Inc. studies as of 03 
February 2014. Of these 257 subjects, 150 subjects had CLL/SLL, 82 subjects had NHL, 12 
subjects had MM, and 13 had AML. A total of 192 received the drug as monotherapy and 65 
received the drug in combination with other therapies. Among the subjects who received ABT-
199, the median duration of drug administration was 126 days (range: 1 to 837 days), with 100 
subjects having received 180 days or longer of therapy. Additionally, 10 subjects were enrolled 
and had data available in Genentech/Roche oncology studies as of 03 February 2014. Eight 
subjects with CLL received ABT-199 + obinutuzumab in Study GP28331, and were on study for 
a median of 61 days (range: 3 to 195 days). Two subjects received ABT-199 + BR in Study 
GO28440, and have been on study for 3 and 18 days, respectively.  
 
Based on nonclinical and clinical data available with ABT-199 administration the identified and 
potential risks are nausea, diarrhea, TLS, hematological effects (including neutropenia/febrile 
neutropenia, anemia, thrombocytopenia, and lymphopenia), serious and/or opportunistic 
infections, and decreased spermatogenesis. In addition, as ABT-199 is being evaluated in 
subjects with relapsed/refractory disease and has potential immunomodulatory properties, the 
risks of RS and secondary primary malignancies are closely monitored. 
 
Clinical Pharmacokinetic and Pharmacodynamic Data  
 
Preliminary pharmacokinetic data with ABT-199 are available from ongoing oncology Studies 
M12-175, M12-630, M13-365, and M13-367, and GP28331 in subjects with hematologic 
malignancies, and the ongoing immunology study in subjects with SLE (Study M13-093). 
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of 10, 50, and 100 mg. The tablet formulation was orally administered after a low-fat meal. Food 
increased the bioavailability of ABT-199 by 3- to 4-fold. Preliminary pharmacokinetic results 
indicated that the absorption of ABT-199 after the oral dosing was relatively slow. ABT-199 
plasma concentrations peaked at approximately 6 hours after dosing. The mean harmonic 
terminal phase elimination half-life of ABT-199 was approximately 17 hours and the mean oral 
clearance was approximately 13 L/hr after a single dose. Preliminary data did not suggest 
apparent pharmacokinetics differences among subjects with CLL/small lymphocytic leukemia 
(SLL), NHL, multiple myeloma (MM), or SLE. The combined data from subjects with CLL/SLL 
and NHL suggested that ABT-199 exposure was approximately dose proportional across the 150 
to 1200 mg dose levels at steady state. Coadministration of bendamustine and rituximab did not 
show apparent impact on ABT-199 pharmacokinetics. On the basis of limited preliminary data 
from Cohort 1 of Study GP28331 (ABT-199 administered alone and in combination with 
obinutuzumab), obinutuzumab did not appear to affect ABT-199 exposure. 
 
Clinical Efficacy as monotherapy 
 
Data from a phase I study in patients with relapsed/refractory CLL has been recently presented at 
the 2014 ASCO Annual Meeting (Seymour 2014). The data cut-off date was December 4, 2014. 
From the 84 patients in the study, 23 (27%) had del(17p) and 48 (57%) were refractory to 
fludarabine. The ORR was 79% with a CR/CRi rate of 22% with a median DOR of 21 months. 
At 12 months, 91% of patients in CR and 65% in PR remained progression free. The ORR was 
78% in del(17p) patients and 79% in fludarabine-refractory. The most common AEs were 
diarrhea (37%), nausea (36%), neutropenia (35%) and anemia (8%). TLS was seen in 8%, 
including one grade 5 AE. Febrile neutropenia, thrombocytopenia, hyperglycemia and 
hypokalemia were seen in 6% of patients each. 
 
Also, results from a phase I study in patients with relapsed/refractory NHL were presented 
(Davids 2014). So far, 44 patient have been enrolled, 15 (35%) with MCL, 11 (26%) with FL, 10 
(23%) with DLBCL, 4 (9%) with WM, 2 (5%) with MZL, 1 (2%) with PMBCL, and 1 (2%) with 
MM. The ORR was 48%, 9/12 MCL (1 CR), 3/11 FL, 3/9 DLBCL (1 CR), 3/4 WM (1 CR), 1/2 
MZL, 0/1 PMBCL, and 0/1 MM. All the responses in DLBCL and FL patients were seen at 
doses >600 mg. The most common AEs were nausea (34%), URI (27%), diarrhea (25%) and 
fatigue (21%). Also, Grade 3 or 4 seen were anemia (14%), neutropenia (11%) and 
thrombocytopenia (9%). Laboratory TLS was seen in 1 patients with MCL and 1 patients with 
DLBCL. 
 
2.3 
Rationale 
 
Overexpression of Bcl-2 in WM. The B-cell lymphoma-2 (BCL-2) family of proteins is central 
to the regulation of apoptosis. Altered responses to normal apoptotic signals are one of the 
hallmarks of cancer and they are connected to defects in the apoptotic machinery in cancer cells. 
Apoptosis occurs via activation of two different pathways, the extrinsic pathway, triggered by 
the activation of the cell surface death receptors, and the intrinsic pathway, followed by the 
perturbation of mitochondrial membrane integrity. Studies have shown that the intrinsic pathway 
is tightly controlled by the interactions between the pro- and anti-apoptotic BCL-2 family 
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grouped functionally according to their pro- and anti-apoptotic effects, as well as structurally 
according to the BCL-2 homology (BH) regions they contain. The six known anti-apoptotic 
family members, BCL-2, Bcl-xL, Mcl-1, Bcl-w, Bcl-b and A1, contain four BH domains (BH1-4) 
and a transmembrane domain (TM). Pro-apoptotic proteins are subdivided into two classes: 
multi-domain members, such as Bax, Bak and Bok, which contain and share homology in the 
BH1, BH2, BH3 and BH4 domains and BH3-only proteins, including Bad, Bim, Puma, Bid, Bik, 
Noxa, Hrk and Bmf, which show homology only in the BH3 domain. 
 
By gene expression analysis, we investigated differences in transcriptional regulation of CD19 
and CD138 selected cells representing the B-cell and plasma cell compartments, respectively, 
versus similar healthy donor derived bone marrow cells. Samples from 30 untreated WM patients 
were compared to those of 10 healthy donors (Hatjiharissi 2007). These studies demonstrated 
that Bcl-2 was overexpressed in both B-cell and plasma cell compartments in WM patients in 
comparison to healthy donors. By flow cytometric analysis, the overexpression of Bcl-2 protein 
has also been confirmed in a Spanish study on 60 cases meeting pathologic criteria for WM (San 
Miguel 2003). Enhanced Bcl-2 expression has also been linked to familial predisposition to WM 
in an Icelandic study (Ogmundsdottir 2009), while use of Bcl-2 inhibitors have shown preclinical 
(oblimersen, AT-101) as well as clinical activity (oblimersen) in WM (Gertz 2005; Paulus 2014).  
Previous BCL-2 inhibitors (ABT-263), although active in CLL and NHL, caused dose-dependent 
thrombocytopenia that limited further clinical development. To circumvent this challenge, a 
unique BCL-2–small molecule cocrystal structure was used to design ABT-199, a first-in-class 
BCL-2–selective inhibitor that causes substantially less platelet killing ex vivo and in vivo as 
compared to ABT-263. In addition to showing preclinical efficacy in BCL-2–dependent cell 
lines and tumor xenograft models, ABT-199 demonstrated immediate activity in patients with 
refractory lymphoid malignancies while causing only minor changes in platelet counts (Souers 
2013).  
 
Preclinical evidence of ABT-199 activity in WM cell lines. In our laboratory, we evaluated the 
pro-apoptotic effects of ABT-199 using Annexin V BCWM.1 and MWCL-1 (unpublished data). 
The treatment effects were evaluated following 18 hours of culture with ABT-199 or the BTK 
inhibitor ibrutinib at 5 uM. As a reference, ibrutinib has been shown to be highly effective in 
patients with relapsed/refractory WM, showing an ORR of over 80%. We observed that ABT-
199 was able to induce a higher level of apoptosis than ibrutinib in both cells lines (see figures). 
Interestingly, ABT-199 not only induced higher apoptosis in CXCR4-mutated cell lines but the 
level of apoptosis appeared similar in wild-type as well as cells engineered to express the 
CXCR4 S338X non-sense mutation. Finally, the combination of ABT-199 and ibrutinib showed 
greatly enhanced cytotoxicity in both BCWM.1 and MWCL-1 wild-type and CXCR4 S338X 
expressing cells, an important finding given that CXCR4 S338X mutations confer resistance 
against ibrutinib. 
 
Preclinical evidence of ABT-199 activity in primary WM cells. We have conducted similar 
apoptotic essays using ABT-199, ibrutinib and the phosphatidylinositol 3-kinase inhibitor 
idelalisib in primary cells from WM patients (unpublished data). We observed that ABT-199 at 
concentrations of 0.2 uM and 1 uM induced significantly higher levels of apoptosis than ibrutinib 
and idelalisib at concentrations of 1 uM. 


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In a separate experiment, we evaluated the apoptotic effect of ABT-199, ibrutinib and idelalisib 
at concentrations of 0.5 uM and 1 uM. 


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Clinical evidence of ABT-199 activity in WM patients. Davids and colleagues presented 
updated results from a phase I study using ABT-199 in patients with relapsed/refractory NHL 
[25]. From the 4 patients with WM enrolled, 3 responded for an ORR of 75%, including 1 
VGPR. 
 
Hypothesis 
 
Single agent ABT-199 (GDC-199) is safe and is associated with a high overall response rate in 
patients with relapsed/refractory WM. 
 
2.4 
Correlative Studies Background 
 
MYD88 L265P is a recently identified somatic mutation present in >90% of WM patients but in <5% 
of patients with other related processes such as CLL or MZL with plasmacytic differentiation or IgM 
myeloma (Treon 2012). Many groups have now validated the presence of this somatic mutation in 
WM patients. MYD88 L265P supports growth and survival of WM cells through both IRAK1 and 
IRAK4 (Treon 2012) as well as by activation of Bruton tyrosine kinase (BTK) (Yang 2013). Based 
on these findings, we conducted a clinical trial using the BTK inhibitor ibrutinib in 63 patients with 
relapsed/refractory WM (Treon 2013). In this study, ibrutinib showed to be safe and effective. 
Median hemoglobin improved from 10.5 g/dl to 12.6 g/dl and IgM decreased from 3610 mg/dl to 
1340 mg/dl. Bone marrow involvement decreased from 70% to 45% with a best ORR of 81% and a 
major response rate of 57%. The major response rate was 77% for patients with wild-type CXCR4 
vs. 30% in those with WHIM-like CXCR4 mutations. Decreases in serum IgM as well as 
improvements in hemoglobin were greater in patients with wild-type CXCR4. 
In recent studies, the MYD88 and CXCR4 mutational status are predictive of clinical status, 
response to therapy and survival outcomes (Cao 2013, Treon 2013, Treon 2014). Activating 


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MYD88 as well as nonsense and frameshift WHIM-like CXCR4 somatic mutations are common 
in Waldenström macroglobulinemia. CXCR4 nonsense mutations are present in aggressive cases 
including hyperviscosity syndrome, and MYD88 status is a determinant of survival. The MYD88 
L265P mutational analysis by allele-specific PCR and CXCR4 mutational analysis by Sanger 
sequencing will be performed by the Bing Center for Waldenström Macroglobulinemia in 
Boston, MA. 
3. PARTICIPANT SELECTION 
 
3.1 
Eligibility Criteria 
 
Participants must meet the following criteria on screening examination to be eligible to 
participate in the study: 
 
3.1.1 
Clinicopathological diagnosis of Waldenstrom’s Macroglobulinemia and meeting criteria for treatment 
using consensus panel criteria from the Second International Workshop on Waldenstrom’s 
macroglobulinemia (Owen 2003; Kyle 2003).  
   
3.1.2 
Measurable disease, defined as presence of serum immunoglobulin M (IgM) with a minimum IgM level of 
> 2 times the upper limit of normal of each institution is required. 
 
3.1.3 
Have received at least one prior therapy for WM.  
  
3.1.4 
 Age ≥ 18 years. 
 
3.1.5 
ECOG performance status <2 (see Appendix A). 
  
3.1.6 
Participants must have normal organ and marrow function as defined below: 
 Absolute neutrophil count > 1,000/mm3 
 Platelets > 50,000/mm3 
 Hemoglobin > 8 g/dL 
 Total bilirubin ≤ 1.5 X ULN  
 AST (SGOT) and ALT (SGPT) < 2.5X the institutional upper limit of normal 
 Creatinine clearance ≥50 ml/min 
 
3.1.7 
Not on any active therapy for other malignancies with the exception of topical therapies for basal cell or 
squamous cell cancers of the skin.  
 
3.1.8 
Females of childbearing potential (FCBP) must agree to use two reliable forms of contraception 
simultaneously or have or will have  complete abstinence from heterosexual intercourse during the 
following time periods related to this study:  1) while participating in the study; and 2) for at least 28 days 
after discontinuation from the study. Men must agree to use a latex condom during sexual contact with a 
FCBP even if they have had a successful vasectomy. FCBP must be referred to a qualified provider of 
contraceptive methods if needed. 
 
 
 
3.1.9 
Able to adhere to the study visit schedule and other protocol requirements. 
 
3.1.10 Ability to understand and the willingness to sign a written informed consent document. 


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3.2 
Exclusion Criteria 
 
Participants who exhibit any of the following conditions at screening will not be eligible for 
admission into the study: 
3.2.1 
Any serious medical condition, laboratory abnormality, uncontrolled intercurrent illness, or psychiatric 
illness/social condition that would prevent the participant from signing the informed consent form. 
 
3.2.2 
Concurrent use of any other anti-cancer agents or treatments or any other study agents. 
 
3.2.3 
Concurrent administration of medications or foods that are moderate or strong inhibitors or inducers of 
CYP3A within 7 days prior to first dose of study drug. 
 
3.2.4 
Prior exposure to ABT-199 or BCL2 inhibitors. 
 
3.2.5 
Prior or ongoing clinically significant illness, medical condition, surgical history, physical finding, ECG 
finding, or laboratory abnormality that, in the investigator's opinion, could affect the safety of the patient, 
including symptomatic hyperviscosity; alter the absorption, distribution, metabolism or excretion of ABT-
199; or impair the assessment of study results. 
 
3.2.6 
Grade > 2 toxicity (other than alopecia) continuing from prior anti-cancer therapy. 
 
3.2.7 
Known CNS lymphoma. 
 
3.2.8 
Significant cardiovascular disease such as uncontrolled or symptomatic arrhythmias, congestive heart 
failure, or myocardial infarction within 6 months of screening. 
 
3.2.9 
New York Heart Association classification III or IV heart failure. 
 
3.2.10 Malabsorption syndrome, disease significantly affecting gastrointestinal function, or resection of the 
stomach or small bowel, ulcerative colitis, symptomatic inflammatory bowel disease, or partial or 
complete bowel obstruction. 
 
3.2.11 Known history of Human Immunodeficiency Virus (HIV), chronic hepatitis B virus (HBV), or hepatitis 
C (HCV) requiring treatment.  Note:  Subjects with serologic evidence of prior vaccination to HBV (i.e., 
HBs Ag-, anti-HBs+ and anti-HBc-) and positive anti-HBc from IVIG may participate 
 
3.2.12 Lactating or pregnant women. 
 
3.2.13 Inability to swallow tablets. 
 
3.2.14 History of non-compliance to medical regimens. 
 
3.2.15 Unwilling or unable to comply with the protocol. 
 
3.3 
Inclusion of Women and Minorities 
 
Both men and women of all races and ethnic groups are eligible for this trial. 
4. REGISTRATION PROCEDURES 
 


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4.1 
General Guidelines for DF/HCC Institutions 
 
Institutions will register eligible participants in the Clinical Trials Management System (CTMS) 
OnCore. Registrations must occur prior to the initiation of protocol therapy. Any participant not 
registered to the protocol before protocol therapy begins will be considered ineligible and 
registration will be denied. 
 
An investigator will confirm eligibility criteria and a member of the study team will complete the 
protocol-specific eligibility checklist. 
 
Following registration, participants may begin protocol therapy. Issues that would cause 
treatment delays should be discussed with the Overall Principal Investigator (PI). If a participant 
does not receive protocol therapy following registration, the participant’s registration on the 
study must be canceled. Registration cancellations must be made in OnCore as soon as possible.  
 
4.2 
Registration Process for DF/HCC Institutions 
 
DF/HCC Standard Operating Procedure for Human Subject Research Titled Subject Protocol 
Registration (SOP #: REGIST-101) must be followed.   
 
4.3 
General Guidelines for Other Investigative Sites 
 
Eligible participants will be entered on study centrally at the Dana-Farber Cancer Institute by the 
Study Coordinator.  All sites should call the Project Manager Kirsten Meid at 617-632-5598 to 
verify dose level availabilities.   
 
Following registration, participants should begin protocol therapy within 5 days. Issues that 
would cause treatment delays should be discussed with the Overall PI.  If a participant does not 
receive protocol therapy following registration, the participant’s registration on the study must be 
canceled.  The Project Manager should be notified of cancellations as soon as possible. 
 
4.4 
Registration Process for Other Investigative Sites 
To register a participant, the following documents should be completed by the research nurse or 
data manager and faxed [617-632-6752] or e-mailed [kirsten_meid@dfci.harvard.edu] to the 
Project Manager: 
 Copy of serum protein electropheresis, CBC, COMP, CT C/A/P, bone marrow biopsy 
 Screening visit note 
 Signed participant consent form 
 HIPAA authorization form 
 Eligibility Checklist 
 
The Eligibility Checklist should be filled out by a clinical study staff member and the 
“Screening Staff” section must be signed by them.  Study staff at the Coordinating Center 
will review the eligibility documentation and sign as the “Enrollment Monitor.” 
The research nurse or data manager at the participating site will then call [617-632-5598 or e-
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registration process, the Coordinator will follow DF/HCC Standard Operating Procedure for 
Human Subject Research Titled Subject Protocol Registration (SOP #: REGIST-101B) and 
register the participant on the protocol.  The coordinator will fax or e-mail the participant study 
number, and if applicable the dose treatment level, to the participating site.  The coordinator will 
also call the research nurse or data manager at the participating site and verbally confirm 
registration 
 
5. TREATMENT PLAN 
 
Treatment will be administered on an outpatient basis. No investigational or commercial agents 
or therapies other than those described below may be administered with the intent to treat the 
participant’s malignancy.   
 
5.1 
Treatment Regimen 
 
ABT199 will be administered daily, with 28 consecutive days defined as a treatment cycle for 
cycles 2-26 for a maximum for 25 cycles once the target dose is reached. Treatment will be 
administered on an outpatient basis, except as specified below.  Reported adverse events and 
potential risks are described in Section 7.  Appropriate dose modifications are described in 
Section 6.  No investigational or commercial agents or therapies other than those described 
below may be administered with the intent to treat the participant's malignancy. 
 
5.2 
Pre-Treatment Criteria 
C1D1 results do not need to meet eligibility parameters.  Day 1 chemistry and hematology 
laboratories must be reviewed prior to treatment. 
Participants must meet the following criteria on Day 1 of cycles with clinic visits (i.e. 1, 2, 3, 6, 
9, etc.): 
 No grade 3 or 4 nausea, vomiting, or diarrhea (if persistent despite optimal antiemetic 
and/or antidiarrheal thearpy) 
 No grade 4 or unmanageable nonhematologic grade 3 toxicities 
 Neutrophil count >/=500/ mm3 (growth factor permitted) 
 In subjects without baseline thrombocytopenia:  
o Platelet count >/= 50,000/ mm3 in the presence of bleeding 
o Platelet count >/= 25,000 mm3 without bleeding 
 In subjects with baseline thrombocytopenia: 
o Platelet count decrease <75% or >/= 20,000/ mm3, whichever is higher without 
bleeding 
o Platelet count decrease <50% in the presence of bleeding 
 
5.3 
Agent Administration 
 
Cycle 1 of treatment will consist of the lead-in phase of drug escalation for all patients.  Cycle 1 
will last for a minimum of 4 weeks (+ 2 days) and may continue until patients reach the 
maximum target dose level for 2 consecutive weeks for those needing dose adjustments during 
escalation.  For the first six patients (Cohort 1), the lead-in phase will consist of ABT-199 (GDC-
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mg (4 tablets) PO once daily for 7 (+2) days, followed by 800 mg (8 tablets) PO once daily until 
disease progression, unacceptable toxicity, or for total drug study duration of 26 cycles (2 years), 
whichever comes first. If no evidence of TLS is seen in the first six patients, for the remaining 
patients (Cohort 2) the lead-in phase will consist of ABT-199 (GDC-199) administered at a dose 
of 400 mg (4 tablets) PO once daily for 7 (+2) days followed by 800 mg (8 tablets) PO once 
daily until disease progression or unacceptable toxicity for total drug study duration of 26 cycles 
(2 years), whichever comes first. Dose reductions due to toxicity will be permitted on 
information seen in Table 6-1. 
 
The study drug ABT-199 will be administered at the DFCI, or participating site, infusion room 
on day 1 of study and at first dose of each dose escalation (C1D1, C1D8, and C1D15 for the first 
6 patients, C1D1 and C1D8 for all other patients if no TLS is seen in the first 6) until a dose of 
800 mg PO daily is reached. Otherwise, ABT-199 will be self-administered, and participants will 
be instructed to write in a diary daily, documenting that the drug was taken. Participants will be 
instructed to take the study drug at approximately the same time each day. Participants will also 
be instructed on how to complete the diary. If a dose is missed, it can be taken up to 6 hours after 
the scheduled time with a return to the normal schedule the following day.  If it has been greater 
than 6 hours, the dose should not be taken and the patient should take the next dose at the 
scheduled time the next day.  The missed dose will not be made up and must be returned to the 
site at the next scheduled visit; this must be documented in the study diary.  Furthermore, they 
will be instructed to call the PI or research nurse if vomiting occurs. If the pills are vomited, this 
should be noted on the patient diary, but a replacement dose should not be taken that day. All 
dosages prescribed and dispensed to the participant, and all dose changes during the study must 
be recorded. 
 
One cycle of ABT-199 is once daily, oral administration for 4 weeks ± 1 week. Prescriptions for 
ABT-199 will be written for daily administration for 1 cycle for participants in cycles 1 and 2, 
and will be written for daily administration for 12 weeks ± 2 weeks for participants being seen 
every 12 weeks starting on Cycle 3 Day 1. For patients who have Cycle 1 extended due to 
difficulties reaching the maximum target dose during dose escalation, a new script may be 
written mid-cycle.  Drug accountability will be done at each study visit; unused drug and diaries 
will be collected from the participant, unused drug will be counted and returned to the pharmacy 
to be destroyed. A new prescription for either one cycle or three cycles, as detailed above, will be 
filled by the participant, and they will be given a new diary.   
 
Medication labels will comply with US legal requirements and be printed in English. The storage 
conditions for study drug will be described on the medication label. 
 
Tumor Lysis Syndrome Prophylaxis (Refer to Appendix B for Recommendations for Initial 
Management of Electrolyte Abnormalities and Prevention of Tumor Lysis Syndrome (TLS & 
refer to Appendix C for Definition of Laboratory and Clinical TLS)) 
First Dose of ABT-199  
 
Tumor lysis syndrome prophylaxis must be initiated in all subjects irrespective of their TLS risk 
category prior to the first dose of ABT-199. TLS prophylaxis includes: 
 


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 An oral agent to reduce the uric acid level (e.g., allopurinol) to be initiated at least 72 
hours prior to dosing. Treatment should be continued for at least the lead-in period (Cycle 
1) based on the ongoing risk of TLS development. Subjects allergic to allopurinol must 
use another uric acid reducer. 
 Oral hydration consisting of fluid intake of 2 L per day starting at least 24 hours prior to 
the start of treatment for all subjects prior to first dose and continued for at least 24 hours 
after dosing and all of the chemistries laboratory values remain within ULN. Oral 
hydration is recommended beyond 24 hours post-dose for subjects who demonstrate any 
laboratory changes. 
 Patients who are unable to maintain such oral hydration will receive IV hydration of 1 L 
in the outpatient setting on Day 1 in addition to oral hydration. In subjects for whom 
volume overload is considered a significant risk, hospitalization should be considered. 
 Chemistry and hematology laboratory tests are to be collected and sent to local laboratory 
within 72 hours prior to the first dose of ABT-199. These laboratory values must be 
reviewed by the investigator. The investigator's decision to proceed with ABT-199 
treatment initiation may be based on these laboratory values. 
 Chemistry laboratory tests must be performed by local laboratory STAT at 0 hour (pre-
dose, within 4 hours before ABT-199 administration), 8 hours post-dose (+/-30 minutes), 
and 24 hours after the first dose of ABT-199 at 400 mg. Pre-dose laboratory values will 
be collected and used as baseline to assess potential electrolyte abnormalities occurring 
post ABT-199 administration. Results from pre-dose laboratory values are not required to 
be available prior to initiating ABT-199 treatment. Subjects must remain at the hospital, 
or clinic, until the 8-hour laboratory values have been reviewed by the investigator. 
 Day 2 dose should not be administered until the 24 hours post-dose chemistry laboratory 
values are reviewed by the investigator. 
 If no significant findings suggestive of clinical or lab TLS occur within 24 hours, the 
same dose will be continued until Day 7 in the outpatient setting. 
 If any significant laboratory changes are observed within the first 24 hours after initiation 
of dosing, see Appendix B, (Recommendations for Initial Management of Electrolyte 
Abnormalities and Prevention of Tumor Lysis Syndrome [TLS]) for procedures to 
follow. Additional laboratory assessments may be performed per investigator discretion. 
 All 24-hour post-dose laboratory assessments (Chemistry and Hematology) may be taken 
within a +/- 1 hour window, if necessary. 
 
First Dose of ABT-199 at Dose Escalation to 400 mg and 800 mg 
 
All subjects, irrespective of their risk category, must receive the following TLS prophylaxis 
measures prior to subsequent dose increases of ABT-199: 
 
 Continue administration of an oral uric acid reducer as indicated above.  
 Oral hydration consisting of fluid intake of approximately 2 L/day starting at least 24 hours 
prior to each dose escalation and continued for at least 24 hours after the dose. In subjects 
who are unable to maintain such oral hydration, IV hydration with 1 L of 0.9% normal saline 
will be given in the outpatient setting on the day of dose escalation. In subjects for whom 
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 For subjects who receive their subsequent dose escalations in the outpatient in clinic setting, 
Chemistry laboratory tests will be performed by the investigative site laboratory at 0 hour 
(pre-dose, within 4 hours before ABT-199 administration), 8 hours post-dose (+/-30 minutes) 
and 24 hours post dose administration. Hematology laboratory tests should be performed at 0 
hour (pre-dose, within 4 hours before ABT-199 administration.  These laboratory values 
must be reviewed in real time by the investigator. Pre-dose laboratory values will be 
collected and used as baseline to assess potential electrolyte abnormalities occurring post 
ABT-199 administration. 
 Subjects must remain at the hospital, or clinic, until the 8-hour laboratory values have been 
reviewed by the investigator. 
 Day 2 dose should not be administered until the 24 hours post-dose chemistry laboratory 
values are reviewed by the investigator. 
 If no significant findings suggestive of clinical or lab TLS occur within 24 hours, the same 
dose will be continued until Day 7 in the outpatient setting. Additional laboratory 
assessments may be performed per investigator discretion. 
 All 24-hour post-dose laboratory assessments (Chemistry and Hematology) may be taken 
within a +/- 1 hour window, if necessary. 
 For subjects who are hospitalized during subsequent dose escalations, Chemistry and 
Hematology laboratory tests will be collected and sent to local laboratories upon admission. 
Chemistry tests will be performed by local laboratory STAT at 0 hour (pre-dose, within 4 
hours before ABT-199 administration), 4, 8, 12 (+/- 30 minutes) and 24 (+/- 1 hour) hours 
post dose. These laboratory values must be reviewed in real time by the investigator. Pre-
dose laboratory values will be collected and used as baseline to assess potential electrolyte 
abnormalities occurring post ABT-199 administration. 
o IV hydration should be started with a target of approximately 2 L per day, or as 
clinically appropriate, for subjects who are hospitalized. 
o Hematology laboratory tests will be performed 24 hours post-dose.  
o The 24-hour post-dose laboratory results must be reviewed by the investigator prior to 
the subject leaving the hospital or receiving any additional doses of the study drug. 
 Chemistry and Hematology laboratory tests for all subjects treated in the outpatient 
setting must be collected within 72 hours prior to the first dose of ABT-199 of each dose 
escalation, and results must be reviewed by the investigator prior to each escalation. For 
subjects demonstrating any clinically significant laboratory abnormalities, additional 
prophylactic treatment should be administered prior to dosing (see Appendix B; 
Recommendations for Initial Management of Electrolyte Abnormalities and Prevention 
of Tumor Lysis Syndrome [TLS]). 
 
5.4 
General Concomitant Medication and Supportive Care Guidelines 
 
Participants will be instructed not to take any additional medications (including over-the-counter 
products) during the course of the study without prior consultation with the investigator. At each 
visit, the investigator will ask the participant about any new medications he/she is or has taken 
after the start of the study drug. 
Anti-emetics are permitted if clinically indicated. Standard supportive care medications are 
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start and after start of study drug, including physical therapy and blood transfusions, should be 
recorded. The following restrictions apply during the entire duration of the study: 
 
No other investigational therapy should be given to participants. 
 
No anticancer agents other than the study medication should be given to participants. If 
such agents are required for a patient then the patient must first be withdrawn from the 
study. 
 
Growth factors (i.e. G-CSF, GM-CSF, erythropoietin, platelets growth factors etc.) can 
be administered prophylactically, except to eligibility, and may be prescribed at the 
discretion of the treating physician for treatment-related hematologic events in 
accordance with ASCO guidelines, and to meet re-treatment criteria. 
 
Transfusions (red blood cells, platelets) can be administered to meet eligibility and for 
treatment-related hematologic events in accordance with ASCO guidelines, and to meet 
re-treatment criteria. 
 
Concurrent administration of ABT-199 and moderate or strong CYP3A4 inhibitors (such 
as clarithromycin, ketoconazole, itraconazole, and ritonavir) and inducers (such as 
rifampin and rifabutin) should be avoided. Alternatives should be sought if possible.  
During the ramp-up phase, moderate or strong CYP3A4 inhibitors and inducers are 
prohibited. 
o If subjects require use of moderate or strong CYP3A inhibitors after the ramp-up 
phase, use with caution and reduce the venetoclax dose by 50% for moderate 
inhibitors and at least 75% for strong inhibitors during co-administration.  After 
discontinuation of CYP3A inhibitor, wait for 2 to 3 days before increasing 
venetoclax dose back to maintenance/target dose. 
o If subject requires use of moderate or strong CYP3A inducers after the ramp-up 
phase and provided there is no alternative treatment available, the Principal 
Investigator should be consulted, and treatment should be administered with 
caution; patients should be closely monitored for potential lack of efficacy.  
Examples of moderate and strong CYP3A inhibitors and inducers are provided in Table 5-1.  
 
If venetoclax is co-administered with warfarin, the international normalized ratio (INR) 
should be monitored closely. 
 
Grapefruit and grapefruit juice affect CYP450 and P-glycoprotein activity and should 
therefore be avoided. 
 
In addition, patients should avoid Seville oranges and star fruit, as well as the juice of 
these fruits, which are potent CYP3A4-inhibitors. 
 
No green tea or foods/supplements containing green tea or extract. 
 
No chronic treatment with systemic steroids (at dosages equivalent to prednisone >20 
mg/day) or other immunosuppressive agents. Topical or inhaled corticosteroids are 
allowed. 
 
Inhibitors of CYP3A4 are defined as follows. Examples of moderate and strong CYP3A 
inhibitors and inducers are provided in Table 5-1.The general categorization into strong, 
moderate, and weak inhibitors according to the website is displayed below: 
 
A strong inhibitor is one that causes a >5-fold increase in plasma AUC values or >80% 
decrease in clearance. Strong inhibitors are capitalized in the list below.  


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 
A moderate inhibitor is one that causes a >2-fold increase in plasma AUC values or 50-80% 
decrease in clearance. 
 
A weak inhibitor is one that causes a >1.25-fold but <2-fold increase in plasma AUC values 
or 20-50% decrease in clearance. 
 
Table 5-1 Moderate and Strong Inhibitors and Inducers of CYP3A4/5 
 
Inhibitors of CYP3A4/5 
Inducers of CYP3A4/5 
Strong inhibitors: 
Boceprevir 
Clarithromycin 
Cobicistat 
Conivaptan 
Danoprevir/ritonavir 
Elvitegravir/ritonavir 
Idelalisib 
Indinavir 
Itraconazole 
Ketoconazole 
Mibefradil 
Lopinavir/ritonavir 
Nefazodone 
Nelfinavir 
Ritonavir 
Paritaprevir/ritonavir combinations 
Posaconazle 
Squinavir 
Telaprevir 
Telithromycin 
Tipranavir/ritonavir 
Voriconazole 
Strong CYP3A inducers: 
Avasimibe 
Carbamazepine 
Enzalutamine 
Mitotane 
Phenytoin 
Rifampin 
St. John’s wort 
 
Moderate CYP3A inducers: 
Bosentan 
Efavirenz 
Etravirine 
Modafinil 
Nafcillin 
Moderate inhibitors: 
Amprenavir 
Aprepitant 
Atazanavir 
Cimetidine 
Ciprofloxacin 
Clotrimazole 
Crizotinib 
Cyclosporine 
Darunavir/ritonavir 
Diltiazem 
Erythromycin 
Fluconazole 
Fosamprenavir 
Imatinib 
 


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Isavuconazole 
Tofisopam 
Verapamil 
 
Note that this is not an exhaustive list. For an updated list, see the following link: 
http://www.fda.gov/Drugs/DevelopmentApprovalProcess/DevelopmentResources/DrugInteractionsLabeling/ucm080499.h
tm  
 
In addition to the medications listed in this table, subjects receiving venetoclax should not consume grapefruit, 
grapefruit products, Seville oranges (including marmalade containing Seville oranges) or Star fruits.
 
5.5 
Criteria for Taking a Participant Off Protocol Therapy 
 
Duration of therapy will depend on individual response, evidence of disease progression and 
tolerance. In the absence of one of the above, treatment may continue for total drug study 
duration of 26 cycles (2 years), 25 cycles at the target dose, or until one of the following criteria 
applies: 
 
 
Confirmed disease progression or development of new signs or symptoms of disease;  
 
Development of symptomatic hyperviscosity 
 
Lack of response to signs or symptoms that prompted therapy after 12 weeks of therapy 
(defined as non-responder); 
 
Commencement of new anti-neoplastic therapy (including radiation therapy) for WM or 
other malignancy including myelodysplasia or WM disease transformation; 
 
Intercurrent illness or hold of study drug for any other reason for >28 days;  
 
Unacceptable adverse event(s); 
 
In the study team’s opinion, participant has demonstrated an inability or unwillingness to 
comply with the oral medication regimen and/or documentation requirements; 
 
Participant decides to withdraw from the study; 
 
General or specific changes in the participant's condition render the participant 
unacceptable for further treatment in the opinion of the treating investigator. 
 
Special mentions: 
 
For participants meeting criteria for disease progression (based on consensus panel criteria for IgM 
response) but are deemed by the investigator to be clinically benefiting from ABT-199, these 
individuals will be permitted to continue on protocol therapy at the principal investigator’s 
discretion. Documentation describing the rationale for continuing benefit shall be entered into the 
medical record. Clinical benefit will be determined by considering clinical data, such as overall 
participant performance and disposition, complete blood counts, and when necessary, results from 
bone marrow biopsies and/or CT scans. In such instances, any new nadir that may result with 
continued therapy will be used as the study nadir point for this patient. Patients must be on >2 
consecutive weeks of therapy for determination of a reliable IgM reading for response assessment 
purposes. 
 


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Participants will be removed from the protocol therapy when any of these criteria apply.  The 
reason for removal from protocol therapy, and the date the participant was removed, must be 
documented in the case report form (CRF). Alternative care options will be discussed with the 
participant. For Decentralized Subject Registrations, the Coordinating Center study staff updates 
the relevant Off Treatment/Off Study information in OnCore.  
In the event of unusual or life-threatening complications, treating investigators must immediately 
notify the Overall PI, Jorge J. Castillo at 617-632-6045. 
 
5.6 
Duration of Follow Up 
 
Participants will be followed up for the duration of the study treatment and for 2 years 
after completion of the study, or next therapy, whichever comes first. Patients will be seen 
every 6 months in the follow-up phase. Participants removed from study for unacceptable 
adverse events will be followed for 2 years or until next therapy. 
 
5.7 
Criteria for Taking a Participant Off Study 
 
Participants will be removed from study treatment, but will continue to be followed-up, when any 
of the criteria listed in Section 5.5 applies for up to 2 years or until the participant is lost to 
follow-up, withdraws consent, starts next therapy, or death. The reason for study removal and the 
date the participant was removed must be documented in the study-specific case report form 
(CRF). Alternative care options will be discussed with the participant. In the event of unusual or 
life-threatening complications, participating investigators must immediately notify the 
Principal Investigator, Jorge J. Castillo, MD, at 617-632-6045. 
 
The reason for taking a participant off study, and the date the participant was removed, must be 
documented in the case report form (CRF). 
 
For Decentralized Subject Registrations, the research team updates the relevant Off 
Treatment/Off Study information in OnCore.  
 
6. DOSING DELAYS/DOSE MODIFICATIONS 
 
Dose delays and modifications will be made as indicated in the following table(s). The 
descriptions and grading scales found in the revised NCI Common Terminology Criteria for 
Adverse Events (CTCAE) version 4.0 will be utilized for dose delays and dose modifications. A 
copy of the CTCAE version 4.0 can be downloaded from the CTEP website 
 http://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm.  
 
If possible, symptoms should be managed symptomatically. In the case of toxicity, appropriate 
medical treatment should be used (including anti-emetics, anti-diarrheals, etc.). All adverse 
events experienced by participants will be collected from the time of the first dose of study 
treatment, through the study and until the final study visit. Participants continuing to experience 
toxicity at the off study visit may be contacted for additional assessments until the toxicity has 
resolved or is deemed irreversible. 
 


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For patients who are unable to tolerate the protocol-specified dosing schedule, dose adjustments 
are permitted. If administration of ABT-199 must be interrupted because of unacceptable 
toxicity, drug dosing will be interrupted or modified according to rules described in Table 6-1.  
 
If dose reductions of ABT-199 are needed during the lead-in period, dose escalation should 
continue on a weekly basis to reach the targeted dose of 800 mg PO daily (e.g. if a participant 
cannot tolerate the 400mg dose escalation, they should be reduced back to 200mg for 1 week, 
and then re-challenged at 400mg the following week, etc). In this case, the lead-in period could 
last for >4 weeks.  Once at goal dose of 800 mg PO daily, dose reductions are permitted down to 
100 mg PO daily before a patient is taken off study. However, patients will remain on study to 
assess for progression. If a participant requires a dose delay of 28 days or more, then the 
participant must be discontinued from the study. 
 
Table 6-1. ABT-199 Dose Modification Guidelines Lead-in Phase Cohort 1 
 
Lead-in 
Phase ABT-
199 dosing 
ABT-199 
Dose 
level 1 
Dose 
level     
-1
Dose level -
2 
Dose level 
-3 
Dose Level   
-4 
Week 1 
starting dose 
200mg 
100mg 
- 
- 
- 
Week 2 1st 
dose 
escalation 
400mg 
200mg 
100mg 
- 
- 
Week 3+ 
Escalation to 
target dose 
and all cycles 
therafter 
800mg 
600mg 
400mg 
200mg 
100mg 
 
 
Table 6-2 ABT-199 Dose Modification Guidelines Lead-in Phase Cohort 2 
 
Post Lead-in 
Phase ABT-
199 dosing 
ABT-199 
Dose 
level 1 
Dose 
level     
-1
Dose level -
2 
Dose level 
-3 
Dose Level   
-4 
Week 1 
starting dose 
400mg 
200mg 
100mg 
- 
- 
Week 2+ 
Escalation to 
target dose 
and all cycles 
therafter 
800mg 
600mg 
400mg 
200mg 
100mg 
 


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Dosing will be held for any of the following conditions: 
 Grade 4 ANC (<500/μL) for >7 days (neutrophil growth factors are permitted). 
 Grade 4 Platelets (<25,000/μL) or in subjects with baseline thrombocytopenia, decrease of > 
75% from baseline or <20,000/ μL, whichever is higher. Hold until grade 3 unless active 
bleeding. 
 Grade 3 or 4 nausea, vomiting, or diarrhea (if persistent despite optimal antiemetic and/or 
antidiarrheal therapy). 
 Any other related grade 4 toxicities and any unmanageable non-hematologic Grade 3 
toxicities. 
 
Drug Modification/Discontinuation Actions for ABT-199-related events 
 
 1st Hold: ABT-199 until recovery from criteria to hold; may restart at original dose level. 
 2nd Hold: ABT-199 until recovery from criteria to hold; restart at -1 dose level. 
 3rd Hold: ABT-199 until recovery from criteria to hold; restart at -2 dose level (if applicable, 
see tables 6-1 and 6-2) 
 4th Hold: ABT-199 until recovery from criteria to hold; restart at -3 dose level (if applicable, 
see tables 6-1 and 6-2) 
 5th Hold: ABT-199 until recovery from criteria to hold; restart at -4 dose level (if applicable, 
see tables 6-1 and 6-2 
 6th Hold: Discontinue ABT-199 
 
If a participant has a drug hold, the schedule of assessments will not change.  If participants do 
not meet treatment criteria on Day 1 of the cycle, the cycle will not be delayed.  
  
7. ADVERSE EVENTS:  LIST AND REPORTING REQUIREMENTS  
 
Adverse event (AE) monitoring and reporting is a routine part of every clinical trial.  The 
following list of reported and/or potential AEs (Section 7.1) and the characteristics of an 
observed AE (Section 7.2) will determine whether the event requires expedited reporting in 
addition to routine reporting. 
 
7.1 
Expected Toxicities 
 
A list of the adverse events and potential risks associated with the agents administered in this 
study appear below and will determine whether dose delays and modifications will be made or 
whether the event requires expedited reporting in addition to routine reporting. 
 
7.1.1 
Adverse Events List 
 
7.1.1.1 
Adverse Event List(s) for ABT199 
 
Most subjects (89.6%) reported at least 1 adverse event. The most common adverse events were 
nausea (31.3%), diarrhea (29.2%), neutropenia (25.5%), fatigue (22.9%), and upper respiratory 
tract infection (22.4%). A summary of the treatment-emergent adverse events reported in > 10% 


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subjects treated with ABT-199 monotherapy, and relationship to study drug, is presented in 
Table 7-1. 
 
Table 7-1. Treatment-Emergent Adverse Events in >10% of Subjects Treated with ABT-
199 Monotherapy and Relationship to Study Drug 
 
 
 
A summary of adverse events NCI CTCAE grade 3 and above reported in more than 1% of the 
subjects treated with ABT-199 monotherapy, and relationship to study drug, is presented in 
Table 7-2. The most common adverse events grade 3 and above were neutropenia (21.9%) and 
anemia (12.0%). 
 
 
 
 
 


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Table 7-2. Treatment-Emergent Adverse Events NCI CTCAE Grade 3 and Above in > 1% 
of the Subjects Treated with ABT-199 Monotherapy and Relationship to Study Drug 
 
 
 
A summary of serious adverse events reported in more than 1% of the subjects treated with 
ABT-199 monotherapy, and relationship to study drug, is presented in Table 7-3. The most 
common serious adverse event was febrile neutropenia (4.2%). 


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Table 7-3. Treatment-Emergent Serious Adverse Events Reported in > 1% of the Subjects 
Treated with ABT-199 Monotherapy and Relationship to Study Drug 
 
 
 
Ten of 192 (5.2%) subjects treated with ABT-199 monotherapy experienced adverse events that 
led to death. The most common adverse event that led to death was malignant neoplasm 
progression (4 subjects, 2.1%). All other adverse events leading to death included small intestinal 
obstruction, multi-organ failure, sudden death (in the setting of TLS), pneumonia viral, mental 
status changes, and respiratory failure (0.5% each). No other deaths were attributed to ABT-199. 
 
Nineteen of 192 (9.9%) subjects treated with ABT-199 monotherapy experienced adverse events 
that led to study discontinuation. The most common event that led to study drug discontinuation 
was malignant neoplasm progression (in 3 subjects, 1.6%). All other adverse events leading to 
discontinuation were reported in 1 subject (0.5%) each. 
 
Tumor Lysis Syndrome 
 
TLS is considered an adverse event of special interest (AESI). 
 
There is a potential for TLS in subjects affected by hematologic malignancies, especially in those 
with bulky disease, elevated pretreatment lactate dehydrogenase (LDH) levels, elevated 
leukocyte count, renal dysfunction, and dehydration. The risk of TLS in patients with WM is, 
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literature (PubMed search performed on 02/10/2015 without date or language restriction using 
the keywords: “waldenstrom*” AND “tumor lysis”), and we have not observed the occurrence 
TLS in our database, which includes approximately 1,500 patients with WM. For these reasons, 
we do not believe the risk stratification criteria for TLS used for CLL, NHL and MM are 
applicable in WM patients. To err on the side of safety, we will take TLS precautionary measures 
in all patients enrolled in the present study. 
 
Based on nonclinical and clinical data available with ABT-199 administration, the identified and 
potential risks, besides TLS are nausea, diarrhea, hematological effects (including lymphopenia, 
neutropenia/febrile neutropenia, thrombocytopenia, and anemia), serious and/or opportunistic 
infections, and decreased spermatogenesis. In addition, as ABT-199 is being evaluated in 
subjects with relapsed/refractory disease and has potential immunomodulatory properties, the 
risks of Richter's Syndrome and secondary malignancies are closely monitored. 
 
Hematological Effects 
 
All hematological adverse events were identified via review of events reported in the Blood and 
Lymphatic Disorders System Organ Class (SOC). In particular, events of neutropenia/febrile 
neutropenia, anemia/hemoglobin decreased, and thrombocytopenia are reviewed and 
summarized below. Lymphopenia and opportunistic infections are discussed together. 
 
Neutropenia/Febrile Neutropenia 
 
Neutropenia and febrile neutropenia are potential risks of dosing with ABT-199 based on 
suspected Bcl-2 mechanism-based toxicity.  
 
One of 192 subjects (0.5%) treated with ABT-199 monotherapy experienced a serious adverse 
event of neutropenia (considered related to ABT-199); no serious adverse events were reported 
in the combination therapy studies. None of the events of neutropenia were considered serious or 
resulted in deaths or discontinuations. 
 
In ABT-199 monotherapy studies, 8 of 192 subjects (4.2%) experienced serious adverse events 
of febrile neutropenia; these events were considered related to ABT-199 treatment by the 
investigators in 7 subjects (3.6%). One monotherapy subject (0.5%) discontinued the study due 
to an adverse event of febrile neutropenia; there were no deaths due to febrile neutropenia. In the 
combination Study M13-365, 1 of 38 subjects (2.6%) experienced a serious adverse event of 
febrile neutropenia; this event was not considered related to ABT-199. Additionally, in the 
combination Study M12-630, 3 of 22 subjects (13.6%) experienced serious adverse events of 
febrile neutropenia; 2 of these (9.1%) were considered related to ABT-199 treatment. There were 
no deaths or discontinuations due to febrile neutropenia in any combination therapy studies. 
 
The events of neutropenia/febrile neutropenia were observed across all ABT-199 oncology 
studies; however, data are confounded by underlying advanced hematological malignancies and 
multiple prior therapies in these subject populations. Furthermore, the higher percentage of these 
events in combination studies is confounded by the coadministration with chemotherapeutic 
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which are known to be associated with neutropenia/febrile neutropenia. 
 
Based on clinical observations with the 1st generation Bcl-2 inhibitor, navitoclax and in vitro 
colony-forming assays to assess Bcl-2-selective inhibitor effects on granulocyte precursors, it is 
possible that subjects treated with ABT-199 might experience neutropenia. Subjects with a 
history of neutropenia, who have received multiple prior therapies and/or have significant bone 
marrow involvement, may be at particular high risk. If determined to be clinically indicated by 
the treating physician in compliance with ASCO guidelines, G-CSF may be administered during 
dosing of ABT-199. The use of G-CSF support is strongly recommended for subjects with Grade 
4 neutropenia (ANC <500/μL). If the subject presents with febrile neutropenia or Grade 4 
neutropenia for more than one week despite the use of optimal G-CSF support, ABT-199 dosing 
should be interrupted until ANC recovery to >500/μL. ABT-199 may then be re-initiated at a 
lower dose as defined in Table 6.1. Subjects not responding to G-CSF despite ABT-199 
interruption should undergo further evaluation to determine the etiology of the neutropenia. 
 
Anemia 
 
Only 1 of 192 subjects (0.5%) in the monotherapy studies experienced a serious adverse event of 
anemia; the event was considered to have a reasonable possibility of being related to ABT-199. 
Although the percentage of all adverse events of anemia was higher in combination studies when 
compared to monotherapy, the data are confounded by administration of chemotherapeutic 
agents. There were no serious adverse events of anemia in any of the combination therapy 
studies. None of the events resulted in deaths or discontinuations. 
 
Thrombocytopenia 
 
Thrombocytopenia is a mechanism-based toxicity of the first-generation Bcl-2/Bcl-XL dual 
inhibitor navitoclax (ABT-263). As a second-generation, Bcl-2-selective inhibitor, ABT-199 is 
not expected to exhibit this type of thrombocytopenia; nevertheless, adverse events of 
thrombocytopenia remain of interest as data are collected. 
 
In ABT-199 monotherapy studies, only 1 of 192 subjects (0.5%) experienced a serious adverse 
event of thrombocytopenia; this event was considered possibly related to ABT-199 (the subject 
was in the NHL arm of Study M12-175). One additional monotherapy subject (0.5%) 
discontinued the study due to a nonserious adverse event of thrombocytopenia, which was 
considered probably related to ABT-199. There were no deaths due to thrombocytopenia. In the 
combination therapy studies, there were no serious adverse events of thrombocytopenia, and no 
deaths or discontinuations due to thrombocytopenia. 
 
Additionally, 4 subjects in monotherapy studies (2.1%) reported autoimmune thrombocytopenia; 
3 of which (1.6%) were both grade 4 and serious. All events occurred in the CLL arm of Study 
M12-175. 
 
Lymphopenia and Opportunistic Infections 
 
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is one aspect of the therapeutic mechanism of action in the treatment of subjects with lymphoid 
malignancies. No subjects treated with ABT-199 as monotherapy or in combination with 
chemotherapy experienced a serious adverse event of lymphopenia. None of the events of 
lymphopenia resulted in deaths or discontinuations. Due to potential risk of opportunistic 
infections in subjects with lymphopenia, adverse events potentially related to opportunistic 
infections were identified using the Opportunistic Infections Product-Specific (Bcl-2 specific) 
Company MedDRA query (PMQ). In monotherapy studies, adverse events in 6 subjects (3.1%) 
were identified on the basis of this PMQ. These included 1 subject with an adverse event of 
nocardiosis (0.5%) and 5 subjects (2.6%) with events of oral candidiasis. 
 
There is a potential for clinically significant lymphopenia in this study. If clinically indicated, 
anti-infective prophylaxis should be implemented at the investigator's discretion, including 
appropriate prophylaxis for viral, fungal, bacterial or Pneumocystis infections. Potential for drug-
drug interactions should be considered. Most anti-fungals are excluded and other commonly used 
agents may be cautionary or prohibited due to drug-drug interactions. Please refer to Table 1, 
Table 2 and Appendix B for a description of excluded and cautionary medications.  
 
Serious Infections 
 
Adverse events potentially related to serious infections were identified using the Infections and 
Infestations SOC.  
 
A total of 22 of 192 subjects (11.5%) treated with ABT-199 monotherapy reported serious 
adverse events in the Infections and Infestations SOC. The most common serious adverse events 
for monotherapy were influenza and pneumonia (in 3 subjects, 1.6% each.) Of these, influenza 
was considered to have a reasonable possibility of being related to ABT-199 in 2 subjects 
(1.0%). One serious adverse event of pneumonia viral (0.5%) resulted in discontinuation of 
ABT-199 and subject death; this event occurred in the CLL arm of Study M12-175 at 400 mg 
ABT-199, and was considered not related to ABT-199 by the investigator. 
 
Additionally, in the combination therapy Study M13-365, five of 38 subjects (13.2%) 
experienced serious adverse events (bronchitis bacterial, influenza, lung infection, pneumonia 
haemophilus, and rotavirus infection, in 1 subject each). Bronchitis bacterial, pneumonia 
haemophilus, and rotavirus infection were considered to have a reasonable possibility of being 
related to ABT-199. And in the combination therapy Study M12-630, 1 serious adverse event of 
urinary tract infection was reported, it was considered to have no reasonable possibility of being 
related to ABT-199. None of the adverse events in combination therapy studies resulted in 
discontinuation or death. 
 
The types of infectious events observed were generally consistent with those anticipated in the 
population of heavily pretreated CLL/NHL subjects. 
 
Cardiac Function 
 
As a result of findings of mild reductions in myocardial contractility and cardiac output (but not 
blood pressure, heart rate, or ECG) observed following ABT-199 administration in the 


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anesthetized cardiovascular dog model at concentrations of ≥ 16 μg/mL (concentrations greater 
than the concentration of ABT-199 in humans [3.39 μg/mL at the 900 mg dose]). 
 
Pre- and post-dose left ventricular ejection fraction (LVEF) assessments (multi-gated acquisition 
scan/echocardiogram) were collected per protocol in monotherapy Study M12-175. As of 03 
February 2013, the mean baseline LVEF among 76 subjects for whom data were available is 
64.25 mmHg (SD: 6.72 mmHg; range: 43.00 to 80.00 mmHg). Pre- and post-dose ABT-199 
LVEF assessment is available for 14 subjects (all from Study M12-175). Of these 14 subjects, no 
subject had a decrease in LVEF of more than 10%. Additionally, there were no subjects with 
LVEF less than 40 mmHg (grade 3 post-dose). 
 
Medical review of all events retrieved using the Cardiac Failure (narrow) SMQ identified no 
treatment-emergent serious or non-serious events of cardiac failure/left ventricular function 
decrease that were related to ABT-199 or resulted in discontinuation or death. Events of edema 
peripheral were reported at a frequency of 8% or lower in monotherapy studies and combination 
Studies M13-365 and M12-630. One event each (2.6%) of left ventricular dysfunction and 
pulmonary edema was identified in Study M13-365; both events were considered to have no 
reasonable possibility of being related to ABT -199 by the investigator and were confounded by 
relevant past medical history. 
 
Thus, based on data to date, the Sponsor believes that there is no risk of decreased cardiac 
function/decrease in LVEF following ABT-199 administration. 
 
Richter's Syndrome (RS) due to disease progression 
 
The reported incidence of RS (the clinical pathologic transformation to an aggressive lymphoma) 
in the published literature ranges from approximately 2% to 3% to as high as 16%, depending on 
the characteristics of the population studied. The evolution to RS typically occurs via acquisition 
of new genetic alterations in the original clone or other mechanisms appearing to play a role in 
the minority of cases. 
 
Disease progression due to RS was reported for a total of 18 of 160 subjects (11.3%) in the ABT-
199 oncology clinical program. (This included 14 of 95 subjects in Study M12-175, 3 of 38 in 
Study M13-365, 1 of 17 in Study M13-982, and zero subjects in Genentech/Roche Studies 
GP28331 [N = 8] and GO28440 [N = 2]). Sixteen of 18 subjects (88.9%) had prior exposure to 
fludarabine. The median number of prior treatment regimens was 4 (range: 1 to 9). The majority 
of subjects (11 of 18, 61.1%) were diagnosed with CLL more than 5 years before study 
enrollment, with 7 (38.9%) being diagnosed more than 10 years before study enrollment. At the 
time of the RS diagnosis, 9 of 18 subjects (50.0%) were on study for less than 6 months, and 
most subjects (14 of 18, 77.8%) were on study for less than a year. Nine of 16 subjects (56.3%) 
with RS who were analyzed for 17p del status were positive for 17p del; this subject population 
was also heavily pretreated. The diagnoses were 17 subjects transformed to DLBCL, and 1 
subject transformed to classic Hodgkin's Lymphoma. 
 
The role of ABT-199 treatment in these cases is unclear. The frequency of RS cases observed to 
date in the ABT-199 oncology clinical program in subjects with CLL (11.3%) is within the range 


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of reported incidence for subjects with relapsed CLL previously treated with multiple prior 
therapies. Ongoing monitoring of subjects for the signs and symptoms of RS was implemented in 
ABT-199 clinical trials in the previous reporting period, including recommendations for 
performing a diagnostic biopsy to obtain pathology and examination for EBV and genetic 
markers, if possible. 
 
Treatment-Emergent Malignancies 
 
The risk of a secondary malignancy is increased in subjects with WM, particularly those who 
have undergone prior chemotherapy treatments. Additionally, due to the immunomodulatory 
mechanism of action of ABT-199, the risk of secondary malignancy cannot be ruled out. 
 
A total of 5 treatment-emergent secondary malignancies were identified following medical 
review of events retrieved using the SOC of neoplasms benign, malignant, and unspecified of the 
Malignancies SMQ: bladder transitional cell carcinoma recurrent, lung adenocarcinoma, 
esophageal adenocarcinoma, prostate cancer, squamous cell carcinoma, and squamous cell 
carcinoma of the lung in 1 subject (0.5%) each. None of these events in monotherapy and 
combination therapy studies were considered to have a reasonable possibility of being related to 
ABT-199. 
 
These events are consistent with that expected in an elderly population with relapsed 
hematological malignancies and a history of multiple prior therapies. 
 
7.2 
Adverse Event Characteristics 
 
 CTCAE term (AE description) and grade:  The descriptions and grading scales found 
in the revised NCI Common Terminology Criteria for Adverse Events (CTCAE) version 
4.0 will be utilized for AE reporting.  All appropriate treatment areas should have access 
to a copy of the CTCAE version 4.0.  A copy of the CTCAE version 4.0 can be 
downloaded from the CTEP web site 
http://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm. 
 
 For expedited reporting purposes only:   
- 
AEs for the agent(s) that are listed above should be reported only if the adverse event 
varies in nature, intensity or frequency from the expected toxicity information which 
is provided. 
- 
Other AEs for the protocol that do not require expedited reporting are outlined in the 
next section (Expedited Adverse Event Reporting) under the sub-heading of Protocol-
Specific Expedited Adverse Event Reporting Exclusions. 
 
 Attribution of the AE: 
- 
Definite – The AE is clearly related to the study treatment. 
- 
Probable – The AE is likely related to the study treatment. 
- 
Possible – The AE may be related to the study treatment. 
- 
Unlikely – The AE is doubtfully related to the study treatment. 
- 
Unrelated – The AE is clearly NOT related to the study treatment. 


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7.3 
Expedited Adverse Event Reporting  
 
7.3.1 Investigators must report to the Overall PI any serious adverse event (SAE) that occurs 
after the initial dose of study treatment, during treatment, or within 30 days of the last 
dose of treatment on the local institutional SAE form.  
 
7.3.2 For multi-institution studies where a DF/HCC investigator is serving as the Overall 
Principal Investigator, each participating institution must abide by the reporting 
requirements set by the DF/HCC. This applies to any medical event equivalent to an 
unexpected grade 2 or 3 with a possible, probable or definite attribution, all grade 4 
toxicities, and grade 5 (death) regardless of study phase or attribution. 
 
7.3.3 
DF/HCC Expedited Reporting Guidelines 
 
Investigative sites within DF/HCC will report AEs directly to the DFCI Office for 
Human Research Studies (OHRS) per the DFCI IRB reporting policy.  
 
Other investigative sites will report AEs to their respective IRB according to the local 
IRB’s policies and procedures in reporting adverse events. A copy of the submitted 
institutional AE form should be forwarded to the Overall PI within the timeframes 
detailed in the table below.   
 
 
 
 
Attribution 
DF/HCC Reportable AEs
Gr. 2 & 3 AE 
Expected 
Gr. 2 & 3 AE 
Unexpected 
Gr. 4 AE Expected
Gr. 4 AE 
Unexpected 
Gr. 5 AE 
Expected or 
Unexpected
Unrelated 
Unlikely 
Not required 
Not required 
5 calendar days# 
5 calendar days 
24 hours* 
Possible 
Probable 
Definite 
 
Not required 
 
5 calendar days 
 
5 calendar days# 
 
5 calendar days 
 
24 hours* 
# If listed in protocol as expected and not requiring expedited reporting, event does not need to be reported. 
 
* For participants enrolled and actively participating in the study or for AEs occurring within 30 days of the last 
intervention, the AE should be reported within 1 business day of learning of the event. 
 
 
The Overall PI will submit AE reports from outside institutions to the DFCI OHRS 
according to DFCI IRB policies and procedures in reporting adverse events.  
 
7.3.4 Protocol-Specific Expedited Adverse Event Reporting Exclusions 
 
For this protocol only, the AEs/grades listed below do not require expedited reporting to 
the Overall PI or the DFCI IRB.  However, they still must be reported through the routine 
reporting mechanism (i.e. case report form). 
 
 


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CTCAE SOC 
Adverse Event 
Grade 
Hospitalization/ 
Prolongation of 
Hospitalization 
Attribution 
Comments 
Investigations 
Neutrophil 
count 
decreased 
4 
No 
Related 
If hospitalization required, 
must be reported to DFCI 
IRB and PI 
 
 
7.4 
Expedited Reporting to the Food and Drug Administration (FDA) 
 
The Overall PI, as study sponsor, will be responsible for all communications with the FDA. The 
Overall PI will report to the FDA, regardless of the site of occurrence, any serious adverse event 
that meets the FDA’s criteria for expedited reporting following the reporting requirements and 
timelines set by the FDA. 
 
7.5 
Expedited Reporting to Hospital Risk Management 
 
Participating investigators will report to their local Risk Management office any participant 
safety reports or sentinel events that require reporting according to institutional policy.  
 
7.6 
Expedited Reporting to Abbvie Drug Safety Department 
Adverse Events; Pregnancy. In addition to compliance with all FDA reporting requirements 
pursuant to 21 C.F.R. § 312, the Principal Investigator shall: 
a. report all serious adverse events experienced by a study subject receiving an AbbVie 
product within 24 hours of learning of the event regardless of the relationship of the event 
to the AbbVie product.  Principal Investigator shall make available to AbbVie promptly 
such records as may be necessary and pertinent to investigate any such event, if 
specifically requested by AbbVie; and in addition; report all non-serious adverse events 
of tumor lysis syndrome for studies involving ABT-199. 
i. 
Serious AE (SAE) means any untoward medical occurrence that meets one of the 
following criteria: 
i. Results in death 
ii. Is life-threatening 
iii. Requires inpatient hospitalization for >24 hours or prolongation of 
hospitalization 
iv. Is a congenital anomaly 
v. Results in persistent or significant disability/incapacity 
vi. Other serious (Important Medical Events)  Events that do not fit the other 
outcomes but may require medical or surgical intervention to prevent one 
of the other outcomes.   
b. copy AbbVie on the submission to the FDA of events meeting the definition of IND 
safety reports at the time of submission to the Agency; and 


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c. notify AbbVie upon any subject receiving an AbbVie Product whose pregnancy has 
resulted in a negative outcome or untoward event during the course of pregnancy or upon 
delivery.   
AbbVie’s contact for reporting serious adverse drug experiences, pregnancy experiences, 
non-serious adverse events of tumor lysis syndrome, and communication of FDA 
submissions of IND safety reports shall be  PPDINDPharmacovigilance@abbvie.com  
 
7.7 
Routine Adverse Event Reporting 
 
All Adverse Events must be reported in routine study data submissions to the Overall PI on the 
toxicity case report forms.  AEs reported through expedited processes (e.g., reported to the 
IRB, FDA, etc.) must also be reported in routine study data submissions. 
8. PHARMACEUTICAL INFORMATION 
 
A list of the adverse events and potential risks associated with the investigational agent 
administered in this study can be found in Section 7.1. 
 
8.1 
ABT-199 
 
8.1.1 
Description 
 
ABT-199 has the molecular formula C45H50ClN7O7S and a molecular weight of 868.44. ABT-
199 is a light yellow to dark yellow powder, and is freely soluble in vinylpyrrolidone dimer; 
soluble in polyethylene glycol (PEG) 400; very slightly soluble in 1% (w/v) Cremophor RH40, 
and is practically insoluble in water. There are no optical isomers. 
 
8.1.2 
Form 
 
ABT-199 is provided as a yellow film-coated tablet in 50 and 100mg strength. 100mg tablets 
will be supplied for this study in 30 or 120 count bottles which must not be opened and re-
packaged.  It will be packaged in high density polyethylene (HDPE) plastic bottles to 
accommodate the study design.  Each bottle will be labeled per regulatory requirements.  Labels 
must remain affixed to the bottle. 
 
8.1.3 
Storage and Stability 
 
The ABT-199 tablets must be stored at 15° to 25°C (59° to 77°F). The investigational products 
are for investigational use only and are to be used only within the context of this study.  The 
study drug supplied for this study must be maintained under adequate security and stored under 
the conditions specified on the label. 
 
8.1.4 
Availability 
 
ABT-199 is provided to by Abbvie.  The study drug will be labeled and handled as open-label 
material, and packaging labels will fulfill all requirements specified by governing regulations. 


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8.1.5 
Administration 
 
ABT-199 should be self-administered daily by the participant and should be taken at 
approximately 30 minutes after breakfast or the first meal of the day, at approximately the same 
time each day. ABT-199 should be administered with 8 ounces (approximately 240 mL) of water 
(avoid GRAPEFRUIT JUICE due to CYP3A4 inhibition).  The tablets should be swallowed 
intact.  If a dose is missed, it can be taken up to 6 hours after the scheduled time with a return to 
the normal schedule the following day.  If it has been greater than 6 hours, the dose should not be 
taken and the participant should take the next dose at the scheduled time the next day.  The 
missed dose will not be made up and must be returned to the site at the next scheduled visit.   
 
Dietary habits around the time of ABT-199 intake should be as consistent as possible throughout 
the study. If the pills are vomited this should be noted on the diary, but a replacement dose 
should not be taken that day. A study diary will be used to aid with study drug administration 
compliance.   
 
Except for cycle 1 which may be longer, one cycle of ABT-199 is once daily, oral administration 
for 4 weeks ± 1 week. At each study visit, enough ABT-199 will be dispensed until the next 
cycle. For cycle 1, additional drug may be dispensed mid-cycle if necessary.  For visits occurring 
monthly (every 4 weeks ± 1 week), one cycle of pills (5 weeks of ABT-199 therapy) will be 
dispensed. For visits occurring every 12 weeks ± 2 weeks), three cycles of pills (14 weeks) will 
be dispensed. 
 
8.1.6 
Ordering 
 
ABT-199 is an investigational agent and will be supplied free-of-charge from AbbVie and 
Genentech/Roche. 
 
The contact for ordering is: 
iisoncologysupport@abbvie.com 
 
8.1.7 
Accountability 
 
The investigator, or a responsible party designated by the investigator, should maintain a careful 
record of the inventory and disposition of the agent using the NCI Drug Accountability Record 
Form (DARF) or another comparable drug accountability form.  (See the NCI Investigator’s 
Handbook for Procedures for Drug Accountability and Storage.) 
 
8.1.8 
Destruction and Return 
 
Unused ABT-199 tablets will be returned by the participant, collected and counted at each 
study visit, and will be returned to pharmacy for destruction. Unused supplies of ABT-199 
should be destroyed according to institutional policies. Destruction will be documented in the 
Drug Accountability Record Form. 
 


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9. BIOMARKER, CORRELATIVE, AND SPECIAL STUDIES 
 
9.1 
Biomarker Studies 
 
9.1.1 
Laboratory Correlative Studies 
 
Assessment of MYD88 L265P and CXCR4 WHIM genotyping. 
 
An allele-specific polymerase-chain-reaction (PCR) assay will be used to detect MYD88L265P 
mutations. CXCR4WHIM mutation status will be determined by means of Sanger sequencing, and 
allele-specific PCR will be used to detect CXCR4S338X C→G and C→A mutations in CD19-
selected bone marrow cells (Xu et al, 2013; Hunter et al,2014; Treon et al, 2014). For PCR 
assays two large lavender tops of bone marrow aspirate will be collected at the time of the 
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10. STUDY CALENDAR 
STUDY CALENDAR 
 
 
 
Screening
* 
 
 30 days 
from 
study 
entry 
Treatment Phase7
Off 
Treatment 
Assessment 
 
Within 4 
weeks of 
completion of 
or removal 
from study ± 2 
weeks 
Follow-Up 
Phase
Cycles 
1*(4 
weeks 
+2 
days), 2 
(4 weeks 
+/- 1 
week) 
Cycles 3, 6, 
9, etc. until 
study 
completion 
(12 weeks ± 
2 week) 
Post Treatment; 
Every 24 weeks 
± 2 weeks for 2 
years or until 
next therapy 
Physical exams1, vital 
signs (Temp, HR, RR, 
BP), weight, height 
X 
X 
X 
X 
X 
ECOG performance 
status (see Appendix A)
X 
X 
X 
X 
X 
CT of the chest & 
abdomen / pelvis2 
X 
 
X2
X2
X (if applicable) 
Bone marrow biopsy 
and aspiration3 
X 
 
X3 
X 
X  (if applicable) 
Serum immuno-
electropheresis 
X 
X
X 
X 
X 
IgM 
 
X*** 
 
 
 
Complete Blood Count 
plus differential1,4 
X 
X**
X 
X 
X 
Coagulation profile: 
PT, PTT, PT-INR5 
X 
 
 
 
 
Chemistry including: 
Electrolytes, Renal 
(BUN, Creatinine) and 
Hepatic function testing 
[ALT (SGPT), AST 
(SGOT), Alk phos, 
total Bilirubin], 
albumin, total protein 
X 
X**
X 
X 
X 
Tumor lysis labs: 
Potassium, Creatinine, 
Bicarbonate, Calcium, 
Phosphorus, LDH, uric 
acid 
X 
X** 
 
 
 
Magnesium 
X 
X
 
Beta-2 microglobulin, 
HIV, Von Willebrand 
X 
 
 
 
 
Pregnancy Test6 
X 
 
HBsAg, HBsAb, 
HBcAB 
X 
 
 
 
 
HCV Ab 
X 
 


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Response Assessment 
 
X
X
X
X 
Review patient diary  
 
X
X
 
Adverse event 
monitoring (see section 
6) 
 
X 
X 
X 
X 
* Physical exam, vital signs, and weight do not need to be repeated if Cycle 1, Day 1 is within 14 
days of Screening. Cycle 1, Day 1 labs, to be collected within 72 hours prior to first dose of 
ABT-199, do not need to re-confirm eligibility prior to administering first dose.  
 
**TLS monitoring and management will depend on criteria in section 5.1 Tumor Lysis 
Syndrome. All Chemistry and TLS laboratories will be drawn on dose escalation days at 0 hour, 
8 hours post dose, and 24 hours post dose until the target dose is reached.  Hematology labs 
should be done at 0 hours and 24 hours post dose until the target dose is reached.  At a minimum 
they will be drawn during. Cycle 1 on Days 1, 8, and 15 for the first six participants (cohort 1), 
and Cycle 1 Day 1 and 8 for all other participants (cohort 2). 
 
*** IgM will be monitored weekly for the first 6 weeks of study treatment for all participants 
(i.e. Days 1,8, 15, 22, 29, and 36 +/- 2 days) to evaluate the potential for IgM flare. 
 
1More frequent visits may be required at the discretion of the treating physician.  
 
2If CT scans of the chest, abdomen and pelvis have been collected and done within 90 days 
of C1D1 they will not be required at the screening visit. Scans will be repeated at 
cycles 6, 12, and EOT for participants with extramedullary disease at baseline 
defined as adenopathy >1.5 cm in any axis, and splenomegaly >15 cm in the 
craniocaudal axis. Scans will also be repeated to confirm a complete response if the 
participant has no detectable monoclonal protein and had extramedullary disease at 
baseline and at the discretion of the investigator. 
 
3If a bone marrow biopsy and aspiration was done within 90 days of C1D1, it will not be 
repeated. Bone marrow biopsy and aspiration are required at cycles 6, 12, and EOT. 
Bone marrow biopsy and aspiration may also be done at the investigator’s discretion, and 
at any time to confirm a complete response if the participant has no detectable 
monoclonal protein. MYD88 and CXCR4 mutational status will be assessed at each bone 
marrow biopsy. 
 
4For patients who demonstrate therapy-related hematoxicity, more frequent CBC evaluations are 
strongly recommended. 
 
5Coagulation profile. Prothrombin time (PT) will be performed at screening and repeated as 
clinically indicated. PT will be reported as well as the international normalized ratio 
(INR) and PTT.  
 
6For women of childbearing potential only: Serum pregnancy test is required at screening. 
 
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11. MEASUREMENT OF EFFECT 
 
For the purposes of this study, participants should be re-evaluated for response every 4 weeks ± 
1 week for cycles 1, 2, and 3 and thereafter every 12 weeks ± 2 weeks for the remaining cycles 
for a total of 4 years, and within 4 weeks ± 2 weeks from when a participant is removed from 
trial or when treatment is completed.  IgMs measured during Cycle 1 are only for evaluation of 
potential IgM flare and should not be used for response or nadir determination.  Post-treatment, 
patients will continue to be followed-up every 12 weeks ± 2 weeks for 2 years. Participants will 
be assessed for efficacy by consensus panel criteria according to section 11.1.1 below adopted 
from the Third International Workshop on WM (Anderson et al, 2012).  
 
 
11.1 
Antitumor Effect – Hematologic Tumors 
 
11.1.1 Definitions 
 
Evaluable for toxicity: All participants who receive at least one dose of study treatment will 
be evaluable for toxicity from the time of their first treatment. 
 
Evaluable for objective response: Only those participants who have measurable disease 
present at baseline, have received at least one cycle of therapy, and have had their disease 
re-evaluated will be considered evaluable for response. These participants will have their 
response classified according to the definitions stated below. (Note: Participants who 
exhibit objective disease progression or die prior to the end of cycle 1 will also be considered 
evaluable.) 
 
11.1.2 Response Criteria  
 
Complete Response (CR): A complete response (CR) is defined as having resolution of WM 
related symptoms, normalization of serum IgM levels with complete disappearance of IgM 
paraprotein by immunofixation, and resolution of any adenopathy or splenomegaly. A complete 
response requires reconfirmation demonstrating normal serum IgM levels, and absence of IgM 
paraprotein by immunofixation by a measurement repeated at least 2 weeks later. 
 
Very Good Partial Response (VGPR): is defined as > 90% reduction in serum IgM levels, or 
normalization of serum IgM levels. 
 
Partial Response (PR): Partial response (PR) is defined as achieving a > 50% reduction in 
serum IgM levels. 
 
Minor Response (MR): A minor response (MR) is defined 25-49% reduction in serum IgM 
levels. 
 
Progressive Disease (PD): Progressive disease (PD) is defined as occurring when a greater than 
25% increase in serum IgM level occurs with an absolute increase of at least 500 mg/dL from the 
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symptom(s). Reconfirmation of the initial IgM increase is required when IgM is the sole criterion 
for progressive disease confirmation.  Death from any cause or initiation of a new anti-neoplastic 
therapy will also be considered a progression event. For participants on active therapy who are 
on a drug hold for > 7 days, serum IgM levels will be considered unevaluable for response 
assessment. Patient must be on study drug for >2 consecutive weeks to be considered eligible for 
serum IgM response assessment. An increase of 1 cm in any axis for adenopathy, or 2 cm in the 
craniocaudal axis of the spleen will be considered evidence of progression of extramedullary 
disease. Development of Bing Neel syndrome, or other extramedullary disease manifestations, as 
well as disease transformation will be considered as progressive events. 
 
Stable Disease (SD): Stable disease is defined as having < 25% change in serum IgM levels, in 
the absence of new or increasing adenopathy or splenomegaly and/or other progressive signs or 
symptoms of WM. 
 
Overall Response Rate (ORR): Includes patients who achieved MR, PR, VGPR and CR. 
 
11.1.3 Confirmation of Response 
 
Confirmation of response will be done by bone marrow biopsy at cycles 6, 12, 24, 36 and 48 and in the case of 
extramedullary disease by CT scans at cycles 6, 12, 24, 36 and 48. 
 
11.1.4 Time-to-event definition 
 
 Progression-Free Survival (PFS) is defined as the duration of time from start of treatment to 
time of objective disease progression (including initiation of new therapy or death). Median, 
2-year and 4-year landmark PFS analysis will be determined. 
 Overall survival (OS) is defined as the duration of time from start of treatment to time of 
death or last follow-up. Median, 2-year and 4-year landmark OS analysis will be 
determined. 
 Time to Progression (TTP) for a given subject will be defined as the number of days from 
the date the subject started study drug to the date of the subject's tumor progression as 
defined in Section 11.1.1. Time to tumor progression may be collected up to 12 weeks 
following the last available tumor evaluation. All events of tumor progression will be 
included, regardless of whether the event occurred while the subject was still taking study 
drug, or after the subject discontinued study drug. If a subject has not progressed, then the 
data will be censored at the last study visit at which a tumor assessment was performed. 
 The duration of response (DOR) for a given subject will be defined as the number of days 
from the day the criteria are met for ORR to the date that PD is objectively documented. The 
reference for PD will be the smallest IgM measurements recorded since the treatment started. 
If a subject is still responding then the subject's data will be censored at the last study visit at 
which a tumor assessment was performed. 
 
12. DATA REPORTING / REGULATORY REQUIREMENTS 
 
Adverse event lists, guidelines, and instructions for AE reporting can be found in Section 7.0 
(Adverse Events: List and Reporting Requirements). 


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12.1 
Data Reporting 
 
12.1.1 Method 
 
 
The Office of Data Quality (ODQ) will collect, manage, and perform quality checks on the data 
for this study. 
 
 
12.1.2 Responsibility for Data Submission 
 
Investigative sites within DF/HCC or DF/PCC are responsible for submitting data and/or data 
forms to the Office of Data Quality in accordance with DF/HCC SOPs. 
 
 
12.2 
Data Safety Monitoring 
 
The DF/HCC Data and Safety Monitoring Committee (DSMC) will review and monitor toxicity 
and accrual data from this study. The committee is composed of clinical specialists with 
experience in oncology and who have no direct relationship with the study. Information that 
raises any questions about participant safety will be addressed with the Overall PI and study 
team. 
 
The DSMC will review each protocol up to four times a year or more often if required to review 
toxicity and accrual data. Information to be provided to the committee may include: up-to-date 
participant accrual; current dose level information; DLT information; all grade 2 or higher 
unexpected adverse events that have been reported; summary of all deaths occurring with 30 
days of intervention for Phase I or II protocols; for gene therapy protocols, summary of all deaths 
while being treated and during active follow-up; any response information; audit results, and a 
summary provided by the study team. Other information (e.g. scans, laboratory values) will be 
provided upon request.  
 
12.3 
Multicenter Guidelines 
 
This protocol will adhere to the policies and requirements of the DF/HCC Multi-Center Data and 
Safety Monitoring Plan.  The specific responsibilities of the Overall PI, Coordinating Center, and 
Participating Institutions and the procedures for auditing are presented in Appendix C. 
 The Overall PI/Coordinating Center is responsible for distributing all IND Action Letters 
or Safety Reports to all participating institutions for submission to their individual IRBs 
for action as required. 
 
 Mechanisms will be in place to ensure quality assurance, protocol compliance, and 
adverse event reporting at each site. 
 


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 Except in very unusual circumstances, each participating institution will order the study 
agent(s) directly from supplier.  A participating site may order the agent(s) only after the 
initial IRB approval for the site has been forwarded to the Coordinating Center. 
 
12.4 
Collaborative Agreements Language 
 
N/a 
 
13. STATISTICAL CONSIDERATIONS 
 
This is single arm, open label, Phase II study designed to evaluate the safety and efficacy of 
ABT-199 in previously treated, relapsed/refractory WM patients. Therapy will be administered 
daily to patients with WM, and patients will receive treatment until progression or unacceptable 
toxicity for 2 years after completion of the lead-in phase.  
 
Study Design/Endpoints 
 
The primary endpoint of the current study is: 
 
 To assess the overall response rate (ORR) of ABT-199 in symptomatic WM patients with 
relapsed/refractory disease. 
 
The final analysis for the primary endpoint, overall response rate (minor response or better), will 
be conducted at 6 months after the enrollment of the last subject, and will be based on the 
evaluable population. The evaluable population is defined as all enrolled subjects who have 
received at least 1 dose of study drug and who have at least 1 adequate post-baseline disease 
assessment. Adequate disease assessment is defined as having sufficient evidence to correctly 
indicate that progression has or has not occurred. Subjects who died due to progression are also 
considered to have had adequate assessment. 
 
13.1 
Study Design/Endpoints 
 
The primary endpoint of this study is to assess the Overall Response Rate (MR or better).  Major 
response rates (PR or better), and Very Good Partial Response/Complete Response (VGPR/CR) of 
ibrutinib in previously treated, symptomatic WM patients will also be evaluated.  The analysis for 
the primary endpoint, Overall response rate (MR or better), will be based on the evaluable 
population. The evaluable population will be defined as all enrolled participants. The overall 
response rate and its exact 95% confidence intervals (CI) will be calculated and the null 
hypothesis will be rejected if the lower bound of the 95% confidence interval exceeds 40%. The 
analysis for major response (PR or better) will be similarly evaluated. In addition, the number 
and percent of subjects by best overall response (CR, VGPR, PR, MR, SD, or PD) will be 
summarized.    
 
13.2 
Sample Size, Accrual Rate and Study Duration 
 
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previous experience on single-agent efficacy in patients with WM), and an alternative (H1) ORR 
of 70%, a total of 30 evaluable patients need to be accrued to show the proposed difference with 
an alpha (type I error) of 0.04 and a power (1-beta or type II error) of 90%, based on a binomial 
model (STATA version 13.1). 3 participants were determined to be non-evaluable, so a total of 
33 participants will be enrolled.  Therefore, if less than 18 patients achieved at least a minor 
response, the null hypothesis cannot be rejected and further research with ABT-199 in patients 
with WM should not be pursued. On the other hand, if 18 or more patients achieve at least a 
minor response (18/30 patients ORR 60%, 95% CI 42-75%), the null hypothesis will be rejected 
and further research with ABT-199 in patients with WM would be warranted.  The expected 
accrual rate is 2-4 participants per month, for a an expected accrual time of 9-12 months. 
 
 
13.3 
Stratification Factors 
 
 
 
No stratification factors will be applied to any analysis. 
 
13.4 
Interim Monitoring Plan 
 
Refer to section 13.6 
 
13.5 
Analysis of Primary Endpoints 
 
Refer to section 13.6 
 
13.6 
Analysis of Secondary Endpoints 
 
The secondary endpoints are: 
 
 To assess the safety and tolerability of ABT-199 in symptomatic WM patients with 
relapsed/refractory disease. 
 To evaluate the rate of CR, very good partial response (VGPR), partial response (PR), 
minimal response (MR), stable disease (SD) and progressive disease (PD)  
 To evaluate the median, 2-year and 4-year PFS and OS, and median duration of response 
(DOR) 
 To evaluate the toxicity profile of ABT-199 in patients with relapsed/refractory WM 
 To determine the MYD88 L265P mutational status in response to ABT-199 in patients with 
relapsed/refractory WM 
 To evaluate the association between depth of response and quantification of MYD88 L265P 
burden by PCR 
 To evaluate the association between presence of CXCR4-WHIM-like mutations and response 
to ABT-199 
 
DOR, PFS and OS analysis will be performed using the Kaplan-Meier methodology, and 
participants will be censored at the time of last relevant assessment if they have not demonstrated 
the event of interest by the end of the study. Analysis of TTP, DOR, PFS and OS analysis will be 


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conducted at the same cutoff as the overall response rate, and an update of these endpoints will 
be provided at the end of the study. 
 
In recent studies, the MYD88 and CXCR4 mutational status are predictive of clinical status, 
response to therapy and survival outcomes (Cao 2013, Treon 2013, Treon 2014). Activating 
MYD88 as well as nonsense and frameshift WHIM-like CXCR4 somatic mutations are common 
in Waldenström macroglobulinemia. CXCR4 nonsense mutations are present in aggressive cases 
including hyperviscosity syndrome, and MYD88 status is a determinant of survival. The MYD88 
L265P mutational analysis by allele-specific PCR and CXCR4 mutational analysis by Sanger 
sequencing will be performed by the Bing Center for Waldenström Macroglobulinemia in 
Boston, MA. 
13.7 
Reporting and Exclusions 
 
13.7.1 Evaluation of Toxicity 
 
All participants who receive at least one dose of any test material during the study will be 
included in the safety analysis.    
 
13.7.2 Evaluation of the Primary Efficacy Endpoint 
 
All participants included in the study must be assessed for response to treatment, even if there 
are major protocol treatment deviations or if they are ineligible. Each participant should be 
assigned a response category based on the response criteria in Section 11.1.1.  
 
All participants who met the eligibility criteria and were enrolled in the trial will be included in 
the main analysis of the response rate. All conclusions will be based on all eligible participants. 
 
14. PUBLICATION PLAN 
 
Any formal presentation or publication of data from this trial may be published after review and 
comment by Abbvie, Inc. prior to any outside submission. Abbvie, Inc. must receive copies of 
any intended communication in advance of publication (at least fifteen working days for 
presentational materials and abstracts and thirty working days for manuscripts). These 
requirements acknowledge Abbvie, Inc.’s responsibility to provide peer input regarding the 
scientific content and conclusions of such publications or presentations. Principal 
Investigation/Institution shall have the final authority to determine the scope and content of its 
publications, provided such authority shall be exercised with reasonable regard for the interests 
of Abbvie, Inc. and, in accord with the trial contract and shall not permit disclosure of Abbvie, 
Inc. confidential or proprietary information.  
 
Abstracts will be submitted, and presented if accepted as poster or oral presentation, at the ASH 
Annual Meeting and at the EHA Annual Meeting on a yearly basis while the study is ongoing. 
The final manuscript will be compiled and submitted for publication in approximately 2 years of 
the end date of all data collection with an updated publication at 4-year landmark analysis. 
 


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REFERENCES 
 
Bajwa N, Liao C, Nikolovska-Coleska Z. Inhibitors of the anti-apoptotic Bcl-2 proteins: a patent 
review. Expert Opin Ther Pat 2012; 22: 37-55. 
 
Cao Y, Hunter ZR, Liu X, et al. The WHIM-like CXCR4(S338X) somatic mutation activates 
AKT and ERK, and promotes resistance to ibrutinib and other agents in the treatment of 
Waldenstrom’s Macroglobulinemia. Leukemia 2014 [Epub ahead of print] 
 
Castillo JJ, Olszewski AJ, Cronin AM, et al. Survival trends in Waldenström macroglobulienia: 
an analysis of the Surveillance, Epidemiology and End Results database. Blood 2014; 123(25): 
3999-4000. 
 
Davids MS, Seymour JF, Gerecitano JF, et al. Phase I study of ABT-199 (GDC-199) in patients 
with relapsed/refractory (R/R) non-Hodgkin lymphoma (NHL): Responses observed in diffuse 
large B-cell (DLBCL) and follicular lymphoma (FL) at higher cohort doses. J Clin Oncol 
(Meeting Abstracts) 2104; 32(15_s): 8522. 
 
Fesik SW. Promoting apoptosis as a strategy for cancer drug discovery. Nat Rev Cancer 2005; 
5(11): 876-85. 
 
Gertz MA, Geyer SM, Badros A et al. Early results of a phase I trial of oblimersen sodium for 
relapsed or refractory Waldenstrom's macroglobulinemia. Clin Lymphoma 2005; 5: 282-284. 
 
Hatjiharissi E, Mitsiades CS, Bryan CT et al. Comprehensive Molecular Characterization of 
Malignant and Microenvironmental Cells in Waldenstrom's Macroglobulinemia by Gene 
Expression Profiling. ASH Annual Meeting Abstracts 2007; 110: 3174-. 
 
Hunter ZR, Xu L, Yang G, et al. The genomic landscape of Waldenstrom macroglobulinemia is 
characterized by highly recurring MYD88 and WHIM-like CXCR4 mutations, and small somatic 
deletions associated with B-cell lymphomagenesis. Blood 2014; 123(11): 1637-46. 
 
Kyle RA, Treon SP, Alexanian R, et al. Prognostic markers and criteria to initiate therapy in 
Waldenstrom's macroglobulinemia: consensus panel recommendations from the Second 
International Workshop on Waldenstrom's Macroglobulinemia. Semin Oncol 2003; 30(2): 116-
20. 
 
Leleu X, Soumerai J, Roccaro A et al. Increased incidence of transformation and 
myelodysplasia/acute leukemia in patients with Waldenstrom macroglobulinemia treated with 
nucleoside analogs. J Clin Oncol 2009; 27: 250-255. 
 
Ogmundsdottir HM, Einarsdottir HK, Steingrimsdottir H, Haraldsdottir V. Familial 
predisposition to monoclonal gammopathy of unknown significance, Waldenstrom's 
macroglobulinemia, and multiple myeloma. Clin Lymphoma Myeloma 2009; 9: 27-29. 
 
Owen RG, Treon SP, Al-Katib A, et al. Clinicopathological definition of Waldenström’s 


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Macroglobulinemia: consensus panel recommendations from the Second International Workshop 
on Waldenström’s Macroglobulinemia. Semin Oncol 2003; 30(2): 110-115. 
 
Owen RG, Kyle RA, Stone MJ, et al. Response assessment in Waldenström 
macroglobulinaemia: update from the VIth International Workshop. Br J Haematol 2013; 160(2): 
171-6. 
 
Paulus A, Chitta K, Akhtar S et al. AT-101 downregulates BCL2 and MCL1 and potentiates the 
cytotoxic effects of lenalidomide and dexamethasone in preclinical models of multiple myeloma 
and Waldenstrom macroglobulinaemia. Br J Haematol 2014; 164: 352-365. 
 
San Miguel JF, Vidriales MB, Ocio E et al. Immunophenotypic analysis of Waldenstrom's 
macroglobulinemia. Semin Oncol 2003; 30: 187-195. 
 
Sekhar J, Sanfilippo K, Zhang Q, et al. Waldenström macroglobulinemia: a Surveillance, 
Epidemiology, and End Results database review from 1988 to 2005. Leuk Lymphoma 2012; 
53(8): 1625-6. 
 
Seymour JF, Davids MS, Pagel JM, et al. ABT-199 (GDC-199) in relapsed/refractory (R/R) 
chronic lymphocytic leukemia (CLL) and small lymphocytic lymphoma (SLL): High complete 
response rate and durable disease control. J Clin Oncol (Meeting Abstracts) 2014; 32(15_s): 
7015. 
 
Souers AJ, Leverson JD, Boghaert ER et al. ABT-199, a potent and selective BCL-2 inhibitor, 
achieves antitumor activity while sparing platelets. Nat Med 2013; 19: 202-208. 
 
 
Swerdlow SH, Berger F, Pileri SA et al. Lymphoplasmacytic lymphoma. In Swerdlow SH, 
Campo E, Harris NL et al. (eds): WHO Classification of Tumours of Haematopoietic and 
Lymphoid Tissues. Lyon, France: IARC 2008; 194-195. 
 
Treon SP. How I treat Waldenström macroglobulinemia. Blood. 2009;114(12):2375-85. 
 
Treon SP, Xu L, Yang G, et al. MYD88 L265P somatic mutation in Waldenström's 
macroglobulinemia. N Engl J Med 2012; 367(9): 826-33. 
 
Treon SP, Tripsas CK, Yang G, et al. A prospective multicenter study of the Bruton’s Tyrosine 
Kinase inhibitor ibrutinib in patients with relapsed or refractory Waldenstrom’s 
Macroglobulinemia. ASH Annual Meeting Abstracts 2013; 122(21): 251. 
 
Treon SP, Cao Y, Xu L, et al. Somatic mutations in MYD88 and CXCR4 are determinants of 
clinical presentation and overall survival in Waldenstrom’s macroglobulinemia. Blood 2014; 
123(18): 2791-6. 
 
Yang G, Zhou Y, Liu X, et al. A mutation in MYD88 (L265P) supports the survival of 
lymphoplasmacytic cells by activation of Bruton tyrosine kinase in Waldenstrom 
macroglobulinemia. Blood 2013; 122(7): 1222-32.


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


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APPENDIX B: Recommendations for Initial Management of Electrolyte Abnormalities and 
Prevention of Tumor Lysis Syndrome (TLS) 
 
Section 1: First Dose of ABT-199 or Dose Escalation 
 
 Within the first 24 hours after either the first dose or dose escalation, if any laboratory 
criteria below are met, the patient should be hospitalized for monitoring and the investigator 
notified. No additional ABT-199 doses should be administered until resolution. Rapidly 
rising serum potassium is a medical emergency. 
 Nephrology (or other acute dialysis service) should be contacted/consulted (per institutional 
standards to ensure emergency dialysis is available) on admission for any subject 
hospitalized prophylactically or in response to laboratory changes. 
 IV fluids (e.g., D5 1/2 normal saline) should be initiated at a rate of at least 1 mL/kg/hr 
rounded to the nearest 10 mL (target 150 to 200 mL/hr; not < 50 mL/hr). Modification of 
fluid rate should also be considered for individuals with specific medical needs. 
 Monitor for symptoms or signs of TLS (e.g., fever, chills, tachycardia, nausea, vomiting, 
diarrhea, diaphoresis, hypotension, muscle aches, weakness, paresthesias, mental status 
changes, confusion and seizures). If any clinical features are observed, recheck potassium, 
phosphorus, uric acid, calcium and creatinine within 1 hour STAT. 
 Vital signs should be taken at time of all blood draws or any intervention. 
 The management recommendations below focus on the minimum initial responses required. 
If a diagnosis of TLS is established, ongoing intensive monitoring and multi-disciplinary 
management will be per institutional protocols. 
 
In addition to the recommendations in the table below, for subjects receiving the first dose of 
ABT-199: 
 
 For potassium increase ≥ 0.5 mmol/L from baseline, or any value > 5.0 mmol/L, recheck 
potassium, phosphorus, uric acid, calcium and creatinine within 1 hour STAT and follow first 
guideline. 
 For phosphorus increase of > 0.5 mg/dL AND > 4.5 mg/dL, administer phosphate binder and 
recheck potassium, phosphorus, uric acid, calcium and creatinine within 1 hour STAT. 
 
Abnormality 
Management recommendation 
Hyperkalemia (Including rapidly rising 
potassium) 
 
Potassium ≥ 0.5 mmol/L increase from prior 
value (even if potassium within normal limits 
[WNL]) 
 Recheck potassium, phosphorus, uric acid, 
calcium and creatinine in 1 hour STAT. If 
further ≥ 0.2 mmol/L increase in potassium, 
but still < upper limit of normal 
 (ULN), manage as per potassium ≥ ULN. 
Otherwise recheck in 1 hour. 
 Resume per protocol testing if change in 
potassium is < 0.2 mmol/L, and potassium 
< ULN, and no other evidence of tumor 


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lysis. 
 At the discretion of the investigator, may 
recheck prior to hospitalization. If stable or 
decreased, and still WNL, hospitalization is 
at the discretion of the investigator. 
 Potassium, phosphorus, uric acid, calcium 
and creatinine must be rechecked within 24 
hours.
Potassium > upper limit of normal 
 Perform STAT ECG and commence 
telemetry. 
 Nephrology (or other acute dialysis 
service) notification with consideration of 
initiating dialysis. 
 Administer Kayexalate 60 g (or Resonium 
A 60 g). 
 Administer furosemide 20 mg IV × 1. 
 Administer calcium gluconate 100 to 200 
mg/kg IV slowly if there is ECG/telemetry 
evidence of life-threatening arrhythmias. 
 Recheck potassium, phosphorus, uric acid, 
calcium and creatinine in 1 hour STAT. 
 If potassium < ULN 1 hour later, repeat 
potassium, phosphorus, uric acid, calcium 
and creatinine 1, 2 and 4 hrs., if no other 
evidence of tumor lysis. 
Potassium ≥ 6.0 mmol/L (6.0 mEq/L) and/or 
symptomatic (e.g., muscle cramps, weakness, 
paresthesias, nausea, vomiting, diarrhea) 
 Perform STAT ECG and commence 
telemetry. 
 Nephrology (or other acute dialysis 
service) assessment with consideration of 
initiating dialysis. 
 Administer Kayexalate 60 g (or Resonium 
A 60 g). 
 Administer furosemide 20 mg IV × 1. 
 Administer insulin 0.1 U/kg IV + D25 2 
mL/kg IV. 
 Administer sodium bicarbonate 1 to 2 
mEq IV push. 
 If sodium bicarbonate is used, rasburicase 
should not be used as this may exacerbate 
calcium phosphate precipitation. 
 Administer calcium gluconate 100 to 200 
mg/kg IV slowly if there is ECG/telemetry 
evidence of life-threatening arrhythmias. 
Do not administer in same IV line as 
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 Recheck potassium, phosphorus, uric acid, 
calcium and creatinine every hour STAT.
Hyperuricemia 
 
Uric acid ≥ 8.0 mg/dL (476 μmol/L) 
 Consider rasburicase (dose based on local 
guidelines and/or institutional standards). 
 If rasburicase is used, sodium bicarbonate 
should not be used as this may exacerbate 
calcium phosphate precipitation. 
 Recheck potassium, phosphorus, uric acid, 
calcium and creatinine in 1 hr STAT.
Uric acid ≥ 10 mg/dL (595 μmol/L) 
 
OR 
 
Uric acid ≥ 8.0 mg/dL (476 μmol/L) with 25% 
increase and creatinine increase ≥ 0.3 mg/dL (≥ 
0.027 mmol/L) from pre-dose level 
 Administer rasburicase (dose based on 
local guidelines and/or institutional 
standards). 
 When rasburicase is used, sodium 
bicarbonate should not be used as this may 
exacerbate calcium phosphate 
precipitation. 
 Notify nephrology (or other acute dialysis 
service). 
 Recheck potassium, phosphorus, uric acid, 
calcium and creatinine in 1 hour STAT. 
 If uric acid < 8.0 mg/dL 1 hour later, 
repeat potassium, phosphorus, uric acid, 
calcium and creatinine 2 and 4 hrs. later, if 
no other evidence of tumor lysis. 
Hypocalcemia 
Calcium ≤ 7.0 mg/dL 
(1.75 mmol/L) 
AND 
Patient symptomatic (e.g., muscle 
cramps, hypotension, tetany, 
cardiac arrhythmias) 
 Administer calcium gluconate 50 to 100 
mg/kg IV slowly with ECG monitoring. 
 Telemetry. 
 Recheck potassium, phosphorus, uric acid, 
calcium and creatinine in 1 hr STAT. 
 If calcium normalized 1 hour later, repeat 
potassium, phosphorus, uric acid, calcium 
and creatinine 2 and 
 4 hrs. later, if no other evidence of tumor 
lysis. 
 Calculate corrected calcium and check 
ionized calcium if albumin low. 
Hyperphosphatemia 
Phosphorus ≥ 5.0 mg/dL 
(1.615 mmol/L) with ≥ 0.5 mg/dL 
(0.16 mmol/L) increase 
 Administer a phosphate binder (e.g., 
aluminum hydroxide, calcium carbonate, 
sevelamer hydroxide, or lanthanum 
carbonate). 

Nephrology (or other acute dialysis 


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service) notification (dialysis required for 
phosphorus ≥ 10 mg/dL). 
 Recheck potassium, phosphorus, uric acid, 
calcium and creatinine in 1 hr STAT 
 If phosphorus < 5.0 mg/dL 1 hour later, 
repeat potassium, phosphorus, uric acid, 
calcium and creatinine 2 and 4 hrs., later, 
if no other evidence of tumor lysis.
Creatinine 
Increase ≥ 25% from baseline 
 Start or increase rate of IV fluids. 
 Recheck potassium, phosphorus, uric acid, 
calcium and creatinine in 1 to 2 hours 
STAT.
 
Section 2: Ongoing Dosing of ABT-199 
 
Management of electrolyte changes from last value at intervals > 24 hours after either the first 
dose or dose escalation (e.g., 48 or 72 hours) are as below. 
 
Note: If the patient is hospitalized, no additional ABT-199 doses should be administered until 
resolution. 
 
 For potassium, admit patient for any increase ≥ 1.0 mmol/L (1.0 mEq/L), or any level > 
upper limit of normal. 
 Refer to the management guidelines for electrolyte changes observed within the first 24 
hours after either the first dose or dose escalation (see prior table). 
 If a smaller potassium increase is observed that does not meet the criteria for admission 
above, recheck potassium, phosphorus, uric acid, calcium and creatinine in 24 hours and 
confirm no evidence of tumor lysis prior to further ABT-199 dosing. 
 For uric acid, calcium, phosphorus and creatinine, refer to the management guidelines for 
electrolyte changes observed within the first 24 hours after either the first dose or dose 
escalation (see prior table). 
 
 
 
 
 
 
 
 
 
 
 
 


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APPENDIX C.  DEFINITIONS OF LABORATORY AND CLINICAL TUMOR LYSIS SYNDROME 
 
 
 
Metabolic     
Criteria for Classification of                        Criteria for Classification of 
Abnormality                 Laboratory Tumor Lysis Syndrome             Clinical Tumor Lysis Syndrome 
 
 
Hyperruricemia              Uric acid > 8.0 mg/dl (475.8µmol/liter)   
                                        in adults or above the upper limit of the 
                                        normal range for age in children  
 
Hyperphosphatemia       Phosphorus > 4.5 mg/dl (1.5mmol/liter)  
                                        in adults or > 6.5 mg/dl (2.1 mmol/liter) 
   
                                       in children 
 
Hyperkalemia                 Potassium > 6.0 mmol/liter                             Cardiac  dysrhythmia or sudden death                                            
 
       
                                                                      probably or definitely caused by                                
 
 
 
 
                          hyperkalemia 
 
 
Hypocalcemia               Corrected calcium < 7.0 mg/dl                        Cardiac dysrhythmia, sudden death,  
  
                  (1.75 mmol/liter) or ionized calcium              seizure, neuromuscular irritability  
 
                  <1.12 (0.3 mmol/liter) † 
     
    (tetany, paresthesias, muscle twitching, 
 
 
 
 
 
    Carpopedal spasm, Trousseau’s sign,  
 
 
 
 
                          Chvostek’s sign, laryngospasm, or 
 
 
 
 
 
    bronchospasm), hypotension, or heart 
 
 
 
 
 
    failure probably or definitely caused by 
 
 
 
 
 
    hypocalcemia. 
 
Acute kidney injury‡      Not Applicable                        
     Increase in the serum creatinine   level 
of  0.3 mg/dl (26.5 µmol/liter) (or a               
single value > 1.5 times the upper limit of 
the age-appropriate normal range if no 
baseline creatinine measurement is 
available) or the presence of oliguria, 
defined as an average urine output < 0.5 
ml/kg/hr for 6 hrs 
 
 
 
†     The corrected calcium level in milligrams per deciliter = measured calcium level in milligrams per deciliter + 0.8 × (4-  
albumin in grams per deciliter). 
‡      Acute kidney injury is definited as an increase in the creatinine level of at least 0.3 mg per deciliter (26.5 µmol per liter) or 
a period of oliguia lasting 6 hours or more. By definition, if acute kidney injury is present, the patient has clinical tumor lysis 
syndrome. Data about acute kidney injurt from Levin at al. 
 
Note:       In laboratory tumor lysis syndrome, two or more metabolic abnormalities must be present during the same 
24-hour period within 3 days before the start of therapy or up to 7 afterward. Clinical tumor lysis syndrome requires 
the presence of laboratory tumor lysis syndrome plus an increased creatinine level, seizures, cardiac dysrhythmia, or 
death. 


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APPENDIX D 
MULTICENTER GUIDELINES 
 
 
DFCI IRB Protocol #: 15-491 
 
 
 
 
 
APPENDIX D 
 
Dana-Farber/Harvard Cancer Center 
Multi-Center Data and Safety Monitoring Plan 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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TABLE OF CONTENTS 
15. 
INTRODUCTION .............................................................................................................55 
15.1 
Purpose ...................................................................................................................55 
15.2 
Multi-Center Data and Safety Monitoring Plan Definitions ..................................55 
16. 
GENERAL ROLES AND RESPONSIBILITIES .............................................................56 
16.1 
DF/HCC Sponsor ...................................................................................................56 
16.2 
Coordinating Center ...............................................................................................57 
16.3 
Participating Institution ..........................................................................................57 
17. 
DF/HCC REQUIREMENTS FOR MULTI-CENTER PROTOCOLS..............................58 
17.1 
Protocol Distribution ..............................................................................................58 
17.2 
Protocol Revisions and Closures ...........................................................................58 
17.3 
Informed Consent Requirements ...........................................................................59 
17.4 
IRB Documentation ...............................................................................................59 
17.5 
IRB Re-Approval ...................................................................................................59 
17.6 
Participant Confidentiality and Authorization Statement ......................................60 
17.7 
DF/HCC Multi-Center Protocol Registration Policy .............................................60 
17.8 
DF/HCC Protocol Case Number ............................................................................61 
17.9 
Safety Assessments and Toxicity Monitoring .......................................................63 
17.10  Data Management ..................................................................................................63 
18. 
REQUISITIONING INVESTIGATIONAL DRUG..........................................................64 
19. 
MONITORING: QUALITY CONTROL ..........................................................................64 
19.1 
Ongoing Monitoring of Protocol Compliance .......................................................64 
19.2 
Monitoring Reports ................................................................................................65 
19.3 
Accrual Monitoring ................................................................................................66 
20. 
AUDITING: QUALITY ASSURANCE ...........................................................................66 
20.1 
Audit Plan: NCI Sponsored Trials .........................................................................66 
20.2 
Audit Plan: DF/HCC Sponsored Trials..................................................................66 
20.3 
Audit Notification ..................................................................................................66 
20.4 
Audit Reports .........................................................................................................66 
20.5 
Participating Institution Performance ....................................................................67 
 
  
 


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15. INTRODUCTION 
 
The Dana-Farber/Harvard Cancer Center Multi-Center Data and Safety Monitoring Plan 
(DF/HCC DSMP) outlines the procedures for conducting a DF/HCC Multi-Center research 
protocol. The DF/HCC DSMP should serve as a reference for any sites external to DF/HCC 
that will be participating in the research protocol. 
 
15.1 Purpose 
 
To establish standards that will ensure that a Dana-Farber/Harvard Cancer Center Multi-
Center protocol will comply with Federal Regulations, Health Insurance Portability and 
Accountability Act (HIPAA) requirements and applicable DF/HCC Standard Operating 
Procedures.        
 
15.2 Multi-Center Data and Safety Monitoring Plan Definitions 
 
DF/HCC Multi-Center Protocol:  A research protocol in which one  or more outside 
institutions are collaborating with Dana-Farber/Harvard Cancer Center where  a DF/HCC 
investigator is the sponsor. DF/HCC includes Dana-Farber/Partners Cancer Care (DF/PCC) 
Network Clinical Trial Affiliates.  
 
Lead Institution:  One of the Dana-Farber/Harvard Cancer Center consortium members 
(Dana-Farber Cancer Institute (DFCI), Massachusetts General Hospital (MGH), Beth 
Israel Deaconess Medical Center (BIDMC), Boston Children’s Hospital (BCH), Brigham 
and Women’s Hospital (BWH)) responsible for the coordination, development, 
submission, and approval of a protocol as well as its subsequent amendments per the 
DFCI IRB and applicable regulatory guidelines (CTEP, Food and Drug Administration 
(FDA), Office of Biotechnology Activities (OBA) etc.).  The Lead Institution is typically 
the home of the DF/HCC Sponsor. The Lead Institution also typically serves as the 
Coordinating Center for the DF/HCC Multi-Center Protocol.   
 
DF/HCC Sponsor:  The person sponsoring the submitted Multi-Center protocol.  Within 
DF/HCC, this person is the Overall Principal Investigator who takes responsibility for 
initiation, management and conduct of the protocol at all research locations. In applicable 
protocols, the DF/HCC Sponsor will serve as the single liaison with any regulatory 
agencies (FDA). The DF/HCC Sponsor has ultimate authority over the protocol and is 
responsible for the conduct of the study at DF/HCC and all Participating Institutions. In 
most cases the DF/HCC Sponsor is the same person as the DF/HCC Overall Principal 
Investigator; however, both roles can be filled by two different people.  
 
Participating Institution:  An institution that is outside the DF/HCC and DF/PCC 
consortium that is collaborating with DF/HCC on a protocol where the sponsor is a 
DF/HCC Investigator.  The Participating Institution acknowledges the DF/HCC Sponsor 
as having the ultimate authority and responsibility for the overall conduct of the study.    


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Coordinating Center: The entity (i.e. Lead Institution, Medical Monitor, Contract 
Research Organization (CRO), etc) that provides administrative support to the DF/HCC 
Sponsor in order that he/she may fulfill the responsibilities outlined in the protocol 
document and DSMP, and as specified in applicable regulatory guidelines (i.e. CTEP 
Multi-Center Guidelines). In general, the Lead Institution is the Coordinating Center for 
the DF/HCC Multi-Center Protocol. Should the DF/HCC Sponsor decide to use a CRO, 
the CRO will be deemed the Coordinating Center.   
 
DF/HCC Office of Data Quality/Clinical Trial Research Informatics Office: Groups 
within DF/HCC responsible for registering human subjects for trials, ensuring high-quality 
standards are used for data collection and the ongoing management of clinical trials, 
auditing, and data and safety monitoring. ODQ also coordinates quality assurance efforts 
related to multi-center clinical research. 
 
16. GENERAL ROLES AND RESPONSIBILITIES 
For DF/HCC Multi-Center Protocols, the DF/HCC Sponsor, the Coordinating Center, and 
the Participating Institutions are expected to adhere to the following general 
responsibilities:  
 
16.1 DF/HCC Sponsor 
 
The DF/HCC Sponsor, Jorge J. Castillo, will accept responsibility for all aspects of 
conducting a DF/HCC Multi-Center protocol which includes but is not limited to:  
 Oversee the coordination, development, submission, and approval of the protocol 
as well as subsequent amendments.  
 Ensure that the investigators, study team members, and Participating Institutions 
are qualified and appropriately resourced to conduct the protocol.   
 Include the Multi-Center Data and Safety Monitoring Plan as an appendix to the 
protocol. 
 Ensure all Participating Institutions are using the correct version of the protocol. 
 Ensure that each participating investigator and study team member receives 
adequate protocol training and/or a Site Initiation Visit prior to enrolling 
participants and throughout trial’s conduct as needed. 
 Ensure the protocol will be provided to each participating site in a language 
understandable to all applicable site personnel when English is not the primary 
language.  
 Monitor progress and overall conduct of the study at all Participating Institutions.  
 Ensure all DFCI Institutional Review Board (IRB), DF/HCC and other applicable 
(i.e. FDA) reporting requirements are met.  
 Review data and maintain timely submission of data for study analysis.  
 Act as the single liaison with FDA (investigator-held IND trials, as applicable. 
 Ensure compliance with all requirements as set forth in the Code of Federal 
Regulations, applicable DF/HCC requirements, HIPAA requirements, and the 
approved protocol. 


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 Commit to the provision that the protocol will not be rewritten or modified by 
anyone other than the DF/HCC Sponsor. 
 Identify and qualify Participating Institutions and obtain accrual commitments 
prior to extending the protocol to that site. 
 Monitor accrual and address Participating Institutions that are not meeting their 
accrual requirements.  
 
16.2 Coordinating Center  
 
The general responsibilities of the Coordinating Center may include but are not limited to: 
 Assist in protocol development.  
 Maintain FDA correspondence, as applicable. 
 Review registration materials for eligibility and register participants from 
Participating Institutions with OnCore 
 Distribute protocol and informed consent document updates to Participating 
Institutions as needed. 
 Oversee the data collection process from Participating Institutions. 
 Maintain documentation of Serious Adverse Event (SAE) reports and 
deviations/violation submitted by Participating Institutions and provide to the 
DF/HCC Sponsor for timely review.   
 Distribute serious adverse events reported to the DF/HCC Sponsor that fall under 
the DFCI IRB Adverse Event Reporting Policy to all Participating Institutions. 
 Provide 
Participating 
Institutions 
with 
information 
regarding 
DF/HCC 
requirements that they will be expected to comply with. 
 
 Carry out plan to monitor Participating Institutions either by on-site or remote 
monitoring.  
 Maintain Regulatory documents of all Participating Institutions which includes but 
is not limited to the following: local IRB approvals/notifications from all 
Participating Institutions, confirmation of Federalwide Assurances (FWAs) for all 
sites,  all SAE submissions, Screening Logs for all sites, IRB approved consents 
for all sites 
 Conduct regular communications with all Participating Institutions (conference 
calls, emails, etc) and maintain documentation all relevant communications. 
 
16.3 Participating Institution 
 
Each Participating Institution is expected to comply with all applicable federal regulations 
and DF/HCC requirements, the protocol and HIPAA requirements.  
 
The general responsibilities for each Participating Institution may include but are not 
limited to: 
 Document the delegation of research specific activities to study personnel. 
 Commit to the accrual of participants to the protocol. 
 Submit protocol and/or amendments to their local IRB. 
 Maintain regulatory files as per sponsor requirements. 


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 Provide the Coordinating Center with regulatory documents or source documents 
as requested. 
 Participate in protocol training prior to enrolling participants and throughout the 
trial as required (i.e. teleconferences). 
 Update Coordinating Center with research staff changes on a timely basis. 
 Register participants through the Coordinating Center prior to beginning research 
related activities.  
 Submit Serious Adverse Event (SAE) reports to local IRB per local requirements 
and to the Coordinating Center, in accordance with DF/HCC requirements.   
 Submit protocol deviations and violations to local IRB per local requirements and 
to the DF/HCC Sponsor in accordance with DF/HCC requirements. 
 Order, store and dispense investigational agents and/or other protocol mandated 
drugs per federal guidelines and protocol requirements. 
 Have office space, office equipment, and internet access that meet HIPAA 
standards. 
 Participate in any quality assurance activities and meet with monitors or auditors at 
the conclusion of a visit to review findings. 
 Promptly provide follow-up and/or corrective action plans for any monitoring 
queries or audit findings. 
 
17. DF/HCC REQUIREMENTS FOR MULTI-CENTER PROTOCOLS 
 
The following section will clarify DF/HCC Requirements and further detail the expectations 
for participating in a DF/HCC Multi-Center protocol.  
 
17.1 Protocol Distribution 
 
The Coordinating Center will distribute the final DFCI IRB approved protocol and any 
subsequent amended protocols to all Participating Institutions.    
 
17.2 Protocol Revisions and Closures 
 
The Participating Institutions will receive notification of protocol revisions and closures 
from the Coordinating Center.  It is the individual Participating Institution’s responsibility 
to notify its IRB of these revisions. 
 
 Non life-threatening revisions: Participating Institutions will receive written 
notification of protocol revisions regarding non life-threatening events from the 
Coordinating Center. Non-life-threatening protocol revisions must be IRB 
approved and implemented within 90 days from receipt of the notification. 
 
 Revisions for life-threatening causes: Participating Institutions will receive 
immediate notification from the Coordinating Center concerning protocol revisions 
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protocol revisions will be implemented immediately followed by IRB request for 
approval. 
 
 Protocol closures and temporary holds: Participating Institutions will receive 
notification of protocol closures and temporary holds from the Coordinating 
Center. Closures and holds will be effective immediately.  In addition, the 
Coordinating Center, will update the Participating Institutions on an ongoing basis 
about protocol accrual data so that they will be aware of imminent protocol 
closures. 
 
17.3 Informed Consent Requirements 
 
The DF/HCC approved informed consent document will serve as a template for the 
informed consent for Participating Institutions. The Participating Institution consent form 
must follow the consent template as closely as possible and should adhere to specifications 
outlined in the DF/HCC Guidance Document on Model Consent Language for PI-Initiated 
Multi-Center Protocols.  This document will be provided separately to each Participating 
Institution. 
 
Participating Institutions are to send their version of the informed consent document and 
HIPAA authorization, if a separate document, to the Coordinating Center for review and 
approval prior to submission to their local IRB. The approved consent form must also be 
submitted to the Coordinating Center after approval by the local IRB for all consent 
versions. 
 
The Principal Investigator (PI) at each Participating Institution will identify the physician 
members of the study team who will be obtaining consent and signing the consent form 
for therapeutic protocols. Participating institutions must follow the DF/HCC requirement 
that only attending physicians obtain informed consent and re-consent to interventional 
trials (i.e. drug and/or device trials).   
 
17.4 IRB Documentation 
 
The following must be on file with the Coordinating Center: 
 Initial approval letter of the Participating Institution's IRB.  
 Copy of the Informed Consent Form(s) approved by the Participating Institution’s 
IRB.  
 Participating Institution’s IRB approval for all amendments. 
 Annual approval letters by the Participating Institution's IRB. 
 
 
17.5 IRB Re-Approval 
 
Verification of IRB re-approval from the Participating Institutions is required in order to 
continue research activities.  There is no grace period for continuing approvals. 
 


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The Coordinating Center will not register participants if a re-approval letter is not received 
from the Participating Institution on or before the anniversary of the previous approval 
date.   
 
 
17.6 Participant Confidentiality and Authorization Statement 
 
In 1996, congress passed the first federal law covering the privacy of health information 
known as the Health Insurance Portability and Accountability Act (HIPPA). Any 
information, related to the physical or mental health of an individual is called Protected 
Health Information (PHI). HIPAA outlines how and under what circumstances PHI can be 
used or disclosed.  
 
In order for covered entities to use or disclose protected health information during the 
course of a study, the study participant must sign an authorization statement.  This 
authorization statement may or may not be separate from the informed consent document.  
The Coordinating Center, with the approval from the DFCI IRB, will provide a consent 
template, with information regarding authorization for the disclosure of protected health 
information.  
 
The DF/HCC Sponsor will use all efforts to limit its use of protected health information in 
its trials. However, because of the nature of these trials, certain protected health 
information must be collected. DF/HCC has chosen to use authorizations, signed by the 
participant in the trial, rather than limited data sets with data use agreements. 
 
17.6.1  DF/HCC Multi-Center Protocol Confidentiality 
 
All documents, investigative reports, or information relating to the participant are strictly 
confidential. Whenever reasonably feasible, any participant specific reports (i.e. Pathology 
Reports, MRI Reports, Operative Reports, etc.) submitted to the Coordinating Center 
should be de-identified. It is recommended that the assigned DF/HCC ODQ/OnCore case 
number (as described below) be used for all participant specific documents. Participant 
initials may be included or retained for cross verification of identification.  
 
17.7 DF/HCC Multi-Center Protocol Registration Policy 
 
17.7.1  Participant Registration and Randomization  
To register a participant, the following documents should be completed by the 
Participating 
Institution 
and 
faxed 
(617-632-6752) 
or 
e-mailed 
(kirsten_meid@dfci.harvard.edu) to the Coordinating Center  
 Copy of serum protein electropheresis, CBC with diff, Chemistries, CT C/A/P, 
bone marrow biopsy 
 Screening visit note 
 Signed informed consent document 
 HIPAA authorization form (if separate from the informed consent document) 
 Eligibility Checklist 


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The Eligibility Checklist should be filled out by a clinical study staff member and the 
“Screening Staff” section must be signed by them.  Study staff at the Coordinating 
Center will review the eligibility documentation and sign as the “Enrollment Monitor.” 
 
The Coordinating Center will review the submitted documents in order to verify 
eligibility and consent. To complete the registration process, the Coordinator will follow 
DF/HCC Standard Operating Procedure for Human Subject Research Titled Subject 
Protocol Registration (SOP #: REGIST-101B) and register the participant on the protocol 
in OnCore.  The coordinator will fax or e-mail the participant study number, and if 
applicable the dose treatment level, to the participating site.  The coordinator will also call 
the research nurse or data manager at the participating site and verbally confirm 
registration 
 
 
Treatment may not begin without confirmation from the Coordinating Center 
that the participant has been registered.  
 
Randomization can only occur during normal business hours, Monday through Friday 
from 8:00 AM to 5:00 PM Eastern Time. 
 
17.7.2  Initiation of Therapy 
 
Participants must be registered with the DF/HCC ODQ before receiving treatment.  
Treatment may not be initiated until the Participating Institution receives confirmation of 
the participant’s registration from the Coordinating Center. The DF/HCC Sponsor and 
DFCI IRB must be notified of any violations to this policy. 
 
17.7.3  Eligibility Exceptions 
 
The DF/HCC ODQ will make no exceptions to the eligibility requirements for a protocol 
without DFCI IRB approval. The DF/HCC ODQ requires each institution to fully comply 
with this requirement. 
 
17.8 DF/HCC Protocol Case Number 
 
At the time of registration, ODQ/OnCore requires the following identifiers for all subjects: 
initials, date of birth, gender, race and ethnicity. Once eligibility has been established and 
the participant successfully registered, the participant is assigned a unique protocol case 
number.  Participating Institutions should submit all de-identified subsequent 
communication and documents to the Coordinating Center, using this case number to 
identify the subject.   
 
17.8.1 Protocol Deviations, Exceptions and Violations 
 


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Federal Regulations require an IRB to review proposed changes in a research activity to 
ensure that researchers do not initiate changes in approved research without IRB review 
and approval, except when necessary to eliminate apparent immediate hazards to the 
participant. DF/HCC requires all departures from the defined procedures set forth in the 
IRB approved protocol to be reported to the DF/HCC Sponsor, who in turn is responsible 
for reporting to the DFCI IRB. 
 
 
For reporting purposes, DF/HCC uses the terms “violation”, “deviation” and “exception” 
to describe departures from a protocol. All Participating Institutions must adhere to these 
requirements for reporting to the DF/HCC Sponsor and will follow their institutional 
policy for reporting to their local IRB. 
 
17.8.2  Definitions 
 
Protocol Deviation: Any departure from the defined procedures set forth in the IRB-
approved protocol which is prospectively approved prior to its implementation. 
 
Protocol Exception:  Any protocol deviation that relates to the eligibility criteria, e.g. 
enrollment of a participant who does not meet all inclusion/exclusion criteria. 
 
 
 
Protocol Violation: Any protocol deviation that was not prospectively approved by the 
IRB prior to its initiation or implementation.  
 
 
17.8.3  Reporting Procedures 
 
DF/HCC Sponsor: is responsible for ensuring that clear documentation is available in the 
medical record and/or regulatory documents to describe all protocol exceptions, deviations 
and violations. The DF/HCC Sponsor will also be responsible for ensuring that all 
protocol violations/deviations are promptly reported per DFCI IRB guidelines.  
 
Participating Institutions: Protocol deviations require prospective approval from the DFCI 
IRB. The Participating Institution must submit the deviation request to the Coordinating 
Center who will then submit the deviation request to the DFCI IRB. Upon DFCI IRB 
approval the deviation is submitted to the Participating Institution IRB, per institutional 
policy. A copy of the Participating Institution’s IRB report and determination will be 
forwarded to the Coordinating Center within 10 business days after the original 
submission.  
 
All protocol violations must be sent to the Coordinating Center in a timely manner.  
 
Coordinating Center:  Upon receipt of the violation/deviation report from the Participating 
Institution, the Coordinating Center will submit the report to the DF/HCC Sponsor for 
review. Subsequently, the Participating Institution’s IRB violation/deviation report will be 
submitted to the DFCI IRB for review per DFCI IRB reporting guidelines. DF/HCC will 
forward all violation reports to CTEP via an internal DF/HCC process, as applicable. 
 


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17.9 Safety Assessments and Toxicity Monitoring 
 
The study teams at all participating institutions are responsible for protecting the safety, 
rights and well-being of study participants. Recording and reporting of adverse events that 
occur during the course of a study help ensure the continuing safety of study participants.  
 
All participants receiving investigational agents and/or other protocol mandated treatment 
will be evaluated for safety. The safety parameters include all laboratory tests and 
hematological abnormalities, physical examination findings, and spontaneous reports of 
adverse events reported by participants.  All toxicities encountered during the study will 
be evaluated according to the NCI criteria specified in the protocol. Life-threatening 
toxicities must be reported immediately to the DF/HCC Sponsor via the Coordinating 
Center.  
 
Additional safety assessments and toxicity monitoring will be outlined in the protocol. 
 
17.9.1 Guidelines for Reporting Serious Adverse Events  
 
Guidelines for reporting Adverse Events (AEs) and Serious Adverse Events (SAEs) are 
detailed in protocol section 7. 
 
 
 
 
 
 
Participating Institutions must report the SAEs to the DF/HCC Sponsor and the 
Coordinating Center following the DFCI IRB Adverse Event Reporting Policy.  
 
The Coordinating Center will maintain documentation of all Participating Institution 
Adverse Event reports and be responsible for communicating to all participating 
investigators, any observations reportable under the DFCI IRB Reporting Requirements.  
Participating Institutions will review and submit to their IRB according to their 
institutional policies and procedures 
 
 
17.9.2 Guidelines for Processing IND Safety Reports  
 
The DF/HCC Sponsor will review all IND Safety Reports and ensure that all IND Safety 
Reports are distributed to the Participating Institutions. Participating Institutions will 
review and submit to their IRB according to their institutional policies and procedures. 
 
 
 
 
17.10 Data Management 
 
The DF/HCC CTRIO develops case report forms (CRF/eCRFs), for use with the protocol.  
These forms are designed to collect data for each study. The DF/HCC CTRIO provides a 
web based training for eCRF users. 
   
17.10.1 Data Forms Review 
 


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Data submissions are monitored for timeliness and completeness of submission. 
Participating Institutions are notified of their data submission delinquencies in accordance 
with the following: 
 
Incomplete or Questionable Data 
If study forms are received with missing or questionable data, the submitting institution 
will receive a written or electronic query from the DF/HCC CTRIO Data Analyst, 
Coordinating Center or designee.  Responses to all queries should be completed and 
submitted within 14 calendar days.  Responses may be returned on the written query or on 
an amended paper case report form, or in the case of electronic queries, within the 
electronic data capture (eDC) system. In the case of a written query for data submitted on 
a paper case report form, the query must be attached to the specific data being re-
submitted in response.   
 
Missing Forms 
If study forms are not submitted on schedule, the Participating Institution will receive a 
Missing Form Report from the Coordinating Center noting the missing forms.  These 
reports are compiled by the DF/HCC QACT and distributed on a monthly basis.  
 
18. REQUISITIONING INVESTIGATIONAL DRUG 
 
 
The ordering of investigational agent is specified in the protocol section 8.1.6. 
 
Participating Institutions should order their own agent regardless of the supplier.  
 
If the agent is investigational, ensure that the pharmacy will be able to receive and store the 
agent according to state and federal requirements. The local IRB should be kept informed 
of who will supply the agent so that any regulatory responsibilities can be met in a timely 
fashion.  
 
19. MONITORING: QUALITY CONTROL 
 
 
The quality control process for a clinical trial requires verification of protocol compliance 
and data accuracy. The Coordinating Center, with the aid of the ODQ provides quality 
control oversight for the protocol. 
 
19.1 Ongoing Monitoring of Protocol Compliance 
  
 
The Participating Institutions may be required to submit participant source documents to 
the Coordinating Center for monitoring. Participating Institution may also be subject to 
on-site monitoring conducted by the Coordinating Center.  
 
The Coordinating Center will implement on-site as well as virtual ongoing monitoring 
activities to ensure that Participating Institutions are complying with regulatory and 


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protocol requirements, data quality, and participant safety. Monitoring will occur before 
the clinical phase of the protocol begins, continue during protocol performance and 
through study completion. Additional monitoring practices may include but are not limited 
to; source verification, review and analysis of the following: eligibility requirements of all 
participants, informed consent procedures, adverse events and all associated 
documentation, study drug administration/treatment, regulatory files, protocol departures, 
pharmacy records, response assessments, and data management.  
 
Additionally, regular and ongoing communication with Participating Institutions will be 
accomplished by holding all site teleconferences at quarterly until enrollment is completed 
and the last participant in has been on study for at least 6 months.  After this there will be 
teleconferences every 6 months until all participants are off treatment.  Additional 
teleconferences will take place as needed for significant events (i.e. change in accrual, 
event involving participant, etc.)  The Lead Institution will keep in close touch with the 
Participating Institutions via email and phone. Source documents from Participating 
Institutions, will be collected at specific data points that support the primary and or 
 
Remote Monitoring 
 
Participating Institutions will be required to forward de-identified copies of participants’ 
medical record and source documents to the Coordinating Center to aid in source data 
verification.  Each participant’s initial consent and eligibility will be reviewed within 30 
days of enrollment.  Study visits and corresponding CRFs will be reviewed every 6 
months for protocol compliance, AEs, SAEs, study drug administration, dose 
modifications, and follow-up of action items.  Pharmacy records will be remotely 
reviewed every 6 months. 
 
On-Site Monitoring 
 
Participating Institutions will have annual on-site visits to for a Pharmacy site review, 
Regulatory binder review, and to meet with the site PI (if available).   
 
Closeout Monitoring 
 
Closeout monitoring will be done remotely at the end of the study. 
 
 
19.2 Monitoring Reports 
 
The DF/HCC Sponsor will review all monitoring reports for on-site and remote 
monitoring of Participating Institutions to ensure protocol compliance. The DF/HCC 
Sponsor may increase the monitoring activities at Participating Institutions that are unable 
to comply with the protocol, DF/HCC Sponsor requirements or federal and local 
regulations. Participating Institutions may also be subject to an audit as determined by the 
DF/HCC Sponsor. 
 


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19.3 Accrual Monitoring 
 
Prior to extending a protocol to an external site, the DF/HCC Sponsor will establish 
accrual requirements for each participating institution. Accrual will be monitored for each 
participating institution by the DF/HCC Sponsor or designee. Sites that are not meeting 
their accrual expectations may be subject to termination. Due to the small patient 
population, the accrual minimum requirement is at least 1 patient every two years. 
 
20. AUDITING: QUALITY ASSURANCE 
 
Auditing is a method of Quality Assurance. Its main focus is to measure whether standards 
and procedures were followed. Auditing is the systematic and independent examination of 
all trial related activities and documents.  Audits determine if evaluated activities were 
appropriately conducted and whether data was generated, recorded and analyzed, and 
accurately reported per the protocol, Standard Operating Procedures (SOPs), and the Code 
of Federal Regulations (CFR). 
 
 
20.1 Audit Plan: DF/HCC Sponsored Trials 
 
One on-site audit will be scheduled by ODQ, assuming at least three participants have 
been treated on protocol at the site. Approximately 3-4 participants would be audited at 
the site over a 2 day period.  If violations which impact participant safety or the integrity 
of the study are found, more participant records may be audited.  
 
20.2 Audit Notification 
 
It is the Participating Institution’s responsibility to notify the Coordinating Center of all 
scheduled audit dates (internal or NCI) and re-audit dates (if applicable), which involve 
this protocol. All institutions will forward a copy of final audit and/or re-audit reports and 
corrective action plans (if applicable) to the Coordinating Center, within 12 weeks after 
the audit date.  
 
20.3 Audit Reports  
 
The DF/HCC Sponsor will review all final audit reports and corrective action plans if 
applicable. The Coordinating Center, must forward these reports to the DF/HCC ODQ per 
DF/HCC policy for review by the DF/HCC Audit Committee. Based upon the audit 
assessments the DF/HCC Audit Committee could accept or conditionally accept the audit 
rating and final report. Conditional approval could require the DF/HCC Sponsor to 
implement recommendations or require further follow-up.  For unacceptable audits, the 
DF/HCC Audit Committee would forward the final audit report and corrective action plan 
to the DFCI IRB as applicable. 
 
20.4 Participating Institution Performance 
 


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The DF/HCC Sponsor, DFCI IRB, is charged with considering the totality of an 
institution’s performance in considering institutional participation in the protocol. 
 
20.5 
Corrective Actions 
 
Participating Institutions that fail to meet the performance goals of accrual, submission of 
timely and accurate data, adherence to protocol requirements, and compliance with state 
and federal regulations, may be recommended for a six-month probation period. Such 
institutions must respond with a corrective action plan and must demonstrate during the 
probation period that deficiencies have been corrected, as evidenced by the improved 
performance measures. Participating Institutions that fail to demonstrate significant 
improvement will be considered by the DF/HCC Sponsor for revocation of participation. 
A DF/HCC Sponsor and/or the DFCI IRB may terminate a site’s participation if it is 
determined that a site is not fulfilling its responsibilities as described above.