Conditions: Recurrent Transformed B-Cell Non-Hodgkin Lymphoma Refractory Transformed B-Cell Non-Hodgkin Lymphoma
Keywords: Non-Hodgkin Lymphoma
Allocation: NA | Intervention model: SINGLE_GROUP
Enrollment: 20
Healthy volunteers: no

Brief summary:
This pilot phase II trial studies ibrutinib in treating patients with transformed indolent (a type of cancer that grows slowly) B-cell non-Hodgkin lymphoma that have returned after a period of improvement (relapsed) or do not respond to treatment (refractory). Ibrutinib may stop the growth of cancer cells by blocking some of the enzymes (proteins) needed for cell growth.

Detailed description:
OUTLINE:

Patients receive ibrutinib orally (PO) once daily (QD) in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed up every 3 months for up to 5 years.

Arms:
arm 1: Patients receive ibrutinib PO QD in the absence of disease progression or unacceptable toxicity.

Interventions: intervention 1: Ibrutinib intervention 2: Laboratory Biomarker Analysis
Intervention descriptions: intervention 1: Given PO intervention 2: Correlative studies

Protocol document:
Prot_SAP_000.pdf: 
9107
PROTOCOL 
A Pilot Study of Single-Agent Ibrutinib in Relapsed or Refractory Transformed 
Indolent B-Cell Non-Hodgkin Lymphoma
Trial of the Fred Hutchinson Cancer Center (FHCC) and the University of Washington (UW)
Supported in part by Janssen Scientific Affairs, LLC
Protocol Version Date: 07/18/2022
Previous Version Date: 04/23/2020
SPONSOR-INVESTIGATOR: 
Lead Sub-Investigator:   
Ajay K Gopal, MD
Solomon A Graf, MD
Professor, UW
Acting Instructor, UW
Member, FHCC
Fred Hutchinson Cancer Center
Fred Hutchinson Cancer Center
825 Eastlake Ave. E. 
825 Eastlake Ave. E. 
Seattle, WA  98109
Seattle, WA  98109
Telephone: (206) 277-6829
Telephone: (206) 606-2037
Fred Hutch IRB
Approved 
6/28/2023


 Protocol 9107
Version 7.0  Dated 07/18/2022
Page 2 of 34
PROTOCOL ACTIVITY
Accrual Activated:
Protocol Revision Record:
Original Version:
Version 3, Dated 06/17/2014
Amendment #1: 
Version 4, Dated 10/23/2015
Amendment #2:
Version 5, Dated 02/27/2019
Amendment #3: 
Version 6.0, Dated 04/23/2020
Amendment #4: 
Version 7.0, Dated 07/18/2022
Fred Hutch IRB
Approved 
6/28/2023


 Protocol 9107
Version 7.0  Dated 07/18/2022
Page 3 of 34
SCHEMA
Registration
Ibrutinib 560 mg PO taken daily continuously on a 21-day cycle 
Continued until intolerance, progressive disease, or the discretion of patient / clinician
Stop ibrutinib
Routine clinical follow-up for up to 5 years
Fred Hutch IRB
Approved 
6/28/2023


 Protocol 9107
Version 7.0  Dated 07/18/2022
Page 4 of 34
TABLE OF CONTENTS:
1.0
Objectives .................................................................................................................5
2.0
Background and Rationale.........................................................................................5
3.0
Drug Information .......................................................................................................6
4.0
Staging Criteria..........................................................................................................9
5.0
Eligibility Criteria .....................................................................................................9
6.0
Registration ...............................................................................................................12
7.0
Treatment Plan ..........................................................................................................12
8.0
Dosage Modifications ...............................................................................................13
9.0
Study Calendar ..........................................................................................................16
10.0
Criteria for Evaluation and Endpoint Definitions......................................................17
11.0
Statistical Considerations...........................................................................................18
12.0
Study Monitoring and Reporting Procedures ............................................................19
13.0
Elements of Informed Consent .................................................................................26
14.0
References..................................................................................................................27
 
Fred Hutch IRB
Approved 
6/28/2023


 Protocol 9107
Version 7.0  Dated 07/18/2022
Page 5 of 34
1.0
OBJECTIVES
1.1
Primary objectives
1.1.1
Perform a preliminary assessment of the efficacy of single-agent ibrutinib, 
based on overall response rate, in subjects with relapsed or refractory 
transformed indolent B-cell non-Hodgkin lymphoma (R/R TIL).
1.2
Secondary objectives
1.2.1
To determine the tolerability of chronic ibrutinib therapy in this patient 
population.
1.2.2
To determine the disease control rate of this regimen.
1.2.3
Evaluate the complete response rate, overall survival, and progression-free 
survival to single-agent ibrutinib in this patient population.
1.2.4
Determine response rate relative to the underlying B-cell histology.
2.0
BACKGROUND
2.1
Transformed indolent B-cell non-Hodgkin lymphoma
Indolent B-cell non-Hodgkin lymphomas are comprised of several histologic subtypes, 
including follicular lymphoma (FL), chronic lymphocytic leukemia (CLL), and marginal 
zone lymphoma (MZL). As a disease class, it is incurable short of allogeneic 
transplantation and shows a variable natural history. The course is typically slowly 
progressive at the outset and responsive to cytotoxic and immunologic therapies. Most 
patients eventually relapse with a disease phenotype that is increasingly resistant to 
treatment, with shorter intervals of response, over time [1, 2]. At a rate of approximately 
3% per year, indolent B-cell non-Hodgkin lymphomas transform into more aggressive 
malignancies that share a clonal relationship with the original disease [3]. 
Transformed indolent B-cell non-Hodgkin lymphoma (TIL) is classically diagnosed with 
histologic demonstration of an increased proportion, compared with the original specimen, 
of large neoplastic cells. Though typically transformation is to DLBCL, other subtypes, 
including to unclassifiable B cell lymphoma (BCLU), lymphoblastic lymphoma, and acute 
lymphocytic leukemia (ALL) also occur [4]. Clinically, transformation is often reflected 
by a rapid rise in LDH, discordant localized nodal growth, or new B-type symptoms [4, 5]. 
Treatment paradigms for TIL are dictated by prior therapies and patient characteristics. 
High dose therapy (HDT) followed by consolidation with autologous stem cell 
transplantation (ASCT) appears to benefit select patients, with estimates of 5-year overall 
survival ranging from 37 – 65% [6-9], but this procedure is generally limited to a subset of 
patients with chemotherapy-sensitive disease and in good physical condition. Involved-
field radiotherapy is beneficial in the subset of patients with early stage disease. For cases 
of relapsed or refractory TIL (R/R TIL), few therapeutic strategies of proven benefit are 
available. Radioimmunotherapy has activity in a subset of patients with R/R TIL and is 
approved for this indication; however its role is not yet clearly defined [10].
Fred Hutch IRB
Approved 
6/28/2023


 Protocol 9107
Version 7.0  Dated 07/18/2022
Page 6 of 34
2.2
Ibrutinib in lymphoma 
The B-cell antigen receptor (BCR) transmits proliferation signals during normal B cell 
development and its signaling activity has been shown to play a role in a variety of B cell 
malignancies, including follicular lymphoma [11, 12]. The Bruton’s tyrosine kinase (BTK) 
is an essential component of the BCR pathway; its absence results in the arrest of normal 
peripheral B cell maturation and, consequently, low levels of circulating immunoglobulin 
[13, 14]. Ibrutinib (PCI-32765) is a small molecule that selectively and covalently inhibits 
BTK and has shown activity in several B cell malignancies, including previously treated 
mantle cell lymphoma and chronic lymphocytic leukemia, for which its administration is 
FDA approved [15]. Early data also suggest a benefit in FL, with an overall response rate 
in 6 of 11 patients treated on PCYC-04753, and in DLBCL [16]. Ibrutinib is not currently 
FDA approved for these diseases nor for RR/TIL. Ibrutinib has been shown to modulate 
B-cell chemotaxis and migration and promote apoptosis [17]. It is taken orally and, to date, 
has demonstrated a very good safety profile with reported adverse events mostly grade 1 
and 2 in severity and typically self-limited in duration [15, 18].
2.3
Summary
R/R TIL presents a great therapeutic challenge and requires novel strategies. Ibrutinib has 
shown significant promise in treating several B-cell malignancies, and its oral 
administration and favorable toxicity profile make it an especially attractive candidate in 
advanced, previously treated disease. We hypothesize that its use will achieve significant 
and durable responses in a subset of patients with R/R TIL, thus adding to the limited 
selection of therapeutic options for this disease.
3.0
DRUG INFORMATION
  
3.1
General Information
Ibrutinib is an orally-administered, covalently-binding small molecule inhibitor of 
Bruton’s tyrosine kinase, currently being co-developed by Pharmacyclics, Inc. and 
Janssen Scientific Affairs, LLC in B-cell malignancies.
3.2
Administration 
Each capsule contains 140 mg of ibrutinib. The capsules are to be taken once daily 
around the same time each day. They should be swallowed whole and should not 
be opened, broken, or chewed. If a dose of ibrutinib is not taken at the scheduled 
time, it can be taken as soon as possible on the same day with a return to the normal 
schedule the following day. Extra capsules of ibrutinib should not be taken to make 
up for the missed dose.
3.3
Toxicity
3.3.1
Adverse events
Refer to the current FDA-approved package insert or the Physician Desk Reference. 
The most common adverse reactions (≥20%) in patients with MCL were 
thrombocytopenia, diarrhea, neutropenia, anemia, fatigue, musculoskeletal
Fred Hutch IRB
Approved 
6/28/2023


 Protocol 9107
Version 7.0  Dated 07/18/2022
Page 7 of 34
pain, peripheral edema, upper respiratory tract infection, nausea, bruising, dyspnea, 
constipation, rash, abdominal pain, vomiting and decreased appetite.
The most common adverse reactions (≥20%) in patients with CLL were 
thrombocytopenia, diarrhea, bruising, neutropenia, anemia, upper respiratory
tract infection, fatigue, musculoskeletal pain, rash, pyrexia, constipation, peripheral 
edema, arthralgia, nausea, stomatitis, sinusitis, and dizziness. 
3.3.2
Hemorrhage
Five percent of patients with MCL and 6% of patients with CLL had Grade 3 or 
higher bleeding events (subdural hematoma, ecchymoses, gastrointestinal bleeding, 
and hematuria). Overall, 4 bleeding events including bruising of any grade occurred 
in 48% of patients with MCL treated with 560 mg daily and 63% of patients with 
CLL treated at 420 mg daily. The mechanism for the bleeding events is not well 
understood. Ibrutinib may increase the risk of hemorrhage in patients receiving 
antiplatelet or anticoagulant therapies. Consider the benefit-risk of withholding 
ibrutinib for at least 3 to 7 days pre and postsurgery depending upon the type of 
surgery and the risk of bleeding.Subjects in the current study will be monitored 
closely for hemorrhagic adverse events. Guidance on use of antiplatelet agents and 
anticoagulants is provided in Section 3.4.3. 
3.3.3
Other Malignancies 
Other malignancies have occurred in 5% of patients with MCL and 10% of patients 
with CLL who have been treated with ibrutinib. Four percent of patients with MCL, 
had skin cancers and 1% had other carcinomas. Eight percent of patients with CLL 
had skin cancers and 2% had other carcinomas.It is not clear whether or not these 
events are attributable to ibrutinib. 
3.4
Drug Interactions
3.4.1 Metabolism
Ibrutinib is metabolized primarily by CYP3A. In healthy volunteers, co-
administration of ketoconazole, a strong CYP3A inhibitor, increased Cmax and 
AUC of ibrutinib by 29- and 24-fold, respectively. The highest ibrutinib dose 
evaluated in clinical trials was 12.5 mg/kg (actual doses of 840 – 1400 mg) given 
for 28 days with single dose AUC values of 1445 ± 869 ng ⋅ hr/mL which is 
approximately 50% greater than steady state exposures seen at the highest indicated 
dose (560 mg). Avoid concomitant administration of ibrutinib with strong or 
moderate inhibitors of CYP3A. For strong CYP3A inhibitors used short-term (e.g., 
antifungals and antibiotics for 7 days or less, e.g., ketoconazole, itraconazole, 
voriconazole, posaconazole, clarithromycin, telithromycin) consider interrupting 
ibrutinib therapy during the duration of inhibitor use. Avoid strong CYP3A 
inhibitors that are needed chronically. If a moderate CYP3A inhibitor must be used, 
reduce the ibrutinib dose. Patients taking concomitant strong or moderate CYP3A4 
inhibitors should be monitored more closely for signs of ibrutinib toxicity. Avoid 
grapefruit and Seville oranges during ibrutinib treatment, as these contain moderate 
inhibitors of CYP3A. 
Fred Hutch IRB
Approved 
6/28/2023


 Protocol 9107
Version 7.0  Dated 07/18/2022
Page 8 of 34
Administration of ibrutinib with strong inducers of CYP3A decrease ibrutinib 
plasma concentrations by approximately 10-fold. Avoid concomitant use of strong 
CYP3A inducers (e.g., carbamazepine, rifampin, phenytoin and
St. John’s Wort). Consider alternative agents with less CYP3A induction. 
Appendix C outlines some of the inhibitors and inducers of CYP3A.
 
3.4.3 Concomitant Use of Ibrutinib and Antiplatelet Agents and Anticoagulants 
There have been reports of hemorrhagic events in subjects treated with ibrutinib, 
both with and without thrombocytopenia. These include minor hemorrhagic events 
such as contusion, epistaxis and petechiae; and major hemorrhagic events including 
gastrointestinal bleeding, intracranial hemorrhage, and hematuria. Also, patients 
with congenital bleeding diathesis have not been studied. Warfarin or vitamin K 
antagonists should not be administered concomitantly with ibrutinib. Supplements 
such as fish oil and vitamin E preparations should be avoided. Ibrutinib should be 
withheld at least 3 to 7 days pre- and post-surgery depending upon the type of 
surgery and the risk of bleeding (see Section 5.3). Ibrutinib should be used with 
caution in subjects requiring other anticoagulants or medications that inhibit 
platelet function. It is possible that treatment with ibrutinib may increase the risk of 
bruising or bleeding, particularly in subjects receiving antiplatelet agents or 
anticoagulants. Subjects receiving antiplatelet agents in conjunction with ibrutinib 
should be observed closely for any signs of bleeding and ibrutinib should be held 
in the event of major bleeding events defined as adverse event of special interest 
(Section 12). 
3.5
Lymphocytosis
MCL:
Upon initiation of ibrutinib a temporary increase in lymphocyte counts (ie >= 50% 
increase from baseline and above absolute lymphocyte count of 5,000/mcL) 
occurred in 33% of patients in the MCL study. The onset of isolated lymphocytosis 
occurs during the first few weeks of ibrutinib therapy and resolves by a median of 
8 weeks.
Patients with MCL who develop lymphocytosis greater than 400,000/mcL have 
developed intracranial hemorrhage, lethargy, gait instability, and headache. 
However, some of these cases were in the setting of disease progression.
CLL:
Upon initiation of ibrutinib a temporary increase in lymphocyte counts (ie >= 50% 
increase from baseline and above absolute lymphocyte count of 5,000/mcL) in 77% 
of patients in the CLL study. The onset of isolated lymphocytosis occurs during the 
first month of ibrutinib therapy and resolves by a median of 23 weeks (range 1 - 
104+ weeks).
3.6
Supplier 
Ibrutinib used under this study will be provided by Janssen Scientific Affairs and 
will be identical to the commercially marketed product.
Fred Hutch IRB
Approved 
6/28/2023


 Protocol 9107
Version 7.0  Dated 07/18/2022
Page 9 of 34
3.7
Drug Accountability  
The sponsor-investigator, or a responsible party designated by the sponsor-
investigator, must maintain a careful record of the receipt, disposition, and return 
of all drugs received for this study using the study specific Investigational Agent 
Accountability Record form or NCI Drug Accountability form.
Return of unused ibrutinib
Patients will be instructed to return unused ibrutinib to the SCCA pharmacy. 
All unused drug will be destroyed per Investigational Drug Services policy.
4.0
STAGING CRITERIA
4.1
When applicable, the Ann Arbor staging criteria (see Appendix A) will be used; 
staging should be the highest stage established, either at diagnosis or relapse of 
disease.  
4.2
For patients from whom data are available, the international prognostic score at the 
time of diagnosis and enrollment will be documented  as detailed below: 
1.
Age > 60 years
2.
Ann Arbor stage III or IV
3.
Elevated serum LDH
4. 
ECOG PS (see Appendix B) > 1
5. 
More than 1 extra-nodal side of disease
5.0
ELIGIBILITY CRITERIA
5.1
Inclusion Criteria
5.1.1
Patients must have histologically confirmed transformed indolent B-cell 
non-Hodgkin lymphoma that is relapsed or refractory to at least one line of 
therapy.
5.1.2
Patients must have a CT (preferred) or MRI scan of the chest, abdomen, and 
pelvis within 28 days of enrollment. 
5.1.3
Patients must have measurable disease defined as lesions greater than 1.5 
cm that can be accurately measured in two dimensions by CT (preferred), 
or MRI. 
5.1.4
Patients must have a PET scan within 56 days of enrollment. 
5.1.5
Patients must have an ECOG performance status of 0 to 2 (See Appendix 
B).  
5.1.6
Patients must be 18 years of age or older. 
Fred Hutch IRB
Approved 
6/28/2023


 Protocol 9107
Version 7.0  Dated 07/18/2022
Page 10 of 34
5.1.7
Hematology values must be within the following limits independent of 
growth factor or transfusion support:  
5.1.7.1 Absolute neutrophil count (ANC)  1000/mm3 or  750/ mm3 in the 
setting of marrow involvement by disease.
5.1.7.2 Platelets 50,000/mm3  or  30,000 /mm3 in the setting of marrow 
involvement by disease or splenomegaly due to disease.
5.1.8
Biochemical values within the following limits:
5.1.8.1 Alanine aminotransferase (ALT) and aspartate aminotransferase 
(AST) ≤ 3 x upper limit of normal (ULN)
5.1.8.2 Total bilirubin ≤ 1.5 x ULN unless bilirubin rise is due to Gilbert’s 
syndrome or of non-hepatic origin
5.1.8.3 Creatinine clearance (Clcr) > 25 mL/min
5.1.9
Patients must be anticipated to complete 2 cycles of therapy in the opinion 
of the treating physician.
5.1.10 Women of childbearing potential and men who are sexually active must 
affirm they are practicing a highly effective method of birth control during 
and after the study consistent with local regulations regarding the use of 
birth control methods for subjects participating in clinical trials. Men must 
agree to not donate sperm during or after the study. For females, these 
restrictions apply for 1 month after the last dose of study drug. For males, 
these restrictions apply for 3 months after the last dose of the study drug.
5.1.11 Women of childbearing potential must have a negative serum (beta-human 
chorionic gonadotropin [-hCG]) or urine pregnancy test at Screening. 
Women who are pregnant or breastfeeding are ineligible for this study.
5.1.12 Sign (or their legally-acceptable representatives must sign) an informed 
consent document in accordance with institutional and federal guidelines 
indicating that they understand the investigational nature of and procedures 
required for the study, including biomarkers, and are willing to participate 
in and comply with  the guidelines of the study.
5.2
Exclusion Criteria
5.2.1
Known history of human immunodeficiency virus (HIV) or active Hepatitis 
C Virus or active Hepatitis B Virus infection or any uncontrolled active 
systemic infection.
5.2.2
Major surgery or a wound that has not fully healed within 4 weeks of 
initiation of therapy.
5.2.3
Known central nervous system lymphoma. 
Fred Hutch IRB
Approved 
6/28/2023


 Protocol 9107
Version 7.0  Dated 07/18/2022
Page 11 of 34
5.2.4
History of stroke or intracranial hemorrhage within 6 months of screening.
5.2.5
Requires anticoagulation with warfarin or equivalent vitamin K      
antagonists (e.g., phenprocoumon).
5.2.6
Requires chronic treatment with strong CYP3A inhibitors.
5.2.7
Clinically significant cardiovascular disease such as uncontrolled or 
symptomatic arrhythmias, congestive heart failure, or myocardial infarction 
within 6 months of screening, or any Class 3 (moderate) or Class 4 (severe) 
cardiac disease as defined by the New York Heart Association Functional 
Classification.
5.2.8
Vaccinated with live, attenuated vaccines within 4 weeks of initiation of 
therapy.
5.2.9
Any life-threatening illness, medical condition, or organ system dysfunction 
which, in the investigator’s opinion, could compromise the subject’s safety, 
interfere with the absorption or metabolism of ibrutinib capsules, or put the 
study outcomes at undue risk.
5.2.10 Patients with other prior malignancies except for adequately treated basal 
cell carcinoma, squamous cell carcinoma of the skin, breast or cervical 
cancer in situ, or other cancer from which the patient has been disease-free 
for 5 years or greater, unless approved by the protocol Sponsor-Investigator 
/ Lead-Sub-Investigator.
5.2.11 Patients that previously were treated with ibrutinib for > 7 days.
5.2.12 Previous chemotherapy, immunotherapy, biologically targeted therapy, 
other investigational agent, or radiation therapy within 3 weeks of initiation 
of ibrutinib therapy or radio-immunotherapy within 12 weeks of initiation 
of ibrutinib therapy.
5.2.13 Prior allogeneic transplant with GVHD requiring immunosuppressive 
therapy. 
5.3
Restrictions: The following guidance should be considered during the perioperative 
period for subjects who require surgical intervention (including oral surgery) or an 
invasive procedure while receiving ibrutinib:
5.3.1 For any planned surgery or invasive procedure requiring sutures or staples 
for closure, ibrutinib should be held at least 7 days prior to the intervention 
and should be held at least 7 days after the procedure, and restarted at the 
discretion of the investigator when the surgical site is reasonably healed 
without serosanguineous drainage or the need for drainage tubes.  
5.3.2 For planned minor procedures (such as a central line placement, needle 
biopsy, thoracentesis, or paracentesis) ibrutinib should be held for at least 3 
days prior to the procedure and should not be restarted for at least 3 days 
after the procedure. For bone marrow biopsies that are performed while the 
subject is on ibrutinib, it is not necessary to hold ibrutinib for these 
procedures.
Fred Hutch IRB
Approved 
6/28/2023


 Protocol 9107
Version 7.0  Dated 07/18/2022
Page 12 of 34
5.3.3
For emergency procedures, ibrutinib should be held after the procedure until 
the surgical site is reasonably healed, for at least 7 days after the urgent 
surgical procedure or at the discretion of the investigator.
6.0
REGISTRATION
6.1
Patients must be registered prior to the start of protocol therapy.  A completed 
eligibility checklist with source documentation, a copy of the signed consent form 
and a signed HIPAA authorization are required for registration.  All of the 
eligibility requirements according to Section 5.0 must have been met.
7.0
TREATMENT PLAN
7.1
For treatment or dose-modification related questions, please contact Dr. Graf at 
(206) 606-2195 or Dr. Gopal at (206) 606-2037.  (MedCon may also be used to 
contact MDs at 206-543-5300.)
7.2
Administration of ibrutinib.  Ibrutinib is taken orally at a dose of 560 mg daily.
Drug
Dose 
Route
Days
Duration
Ibrutinib
560 mg
PO
Once daily
Until disease 
progression, 
intolerance, or 
decision of patient or 
treating physician
Post Protocol Follow-up
 Long-term follow-up will assess survival and disease progression; subjects will be contacted 
until death, subject withdrawal of consent, lost to follow-up, or study termination by the 
sponsor-investigator, whichever occurs first.
7.3
Prophylaxis
No prophylaxis is needed for ibrutinib and supportive care should be administered 
as needed.
7.4 
Criteria for removal from protocol treatment:
7.4.1 Documented progression of disease (see section 10.6). 
7.4.2   Development of any related non-hematologic grade ≥ 4 toxicity or other 
serious adverse event as defined in section 12.0 will qualify for 
consideration from removal from protocol treatment
7.4.3 Development of any other unacceptable toxicity
Fred Hutch IRB
Approved 
6/28/2023


 Protocol 9107
Version 7.0  Dated 07/18/2022
Page 13 of 34
7.4.4
Delay of treatment for more than 21 days due to adverse events.
7.4.5
The patient may withdraw from the treatment at any time for any reason.
7.4.5
Taking prohibited medications concurrent with ibrutinib therapy may result 
in removal from protocol treatment.
7.5
Continuation of therapy after disease progression
Anecdotal reports indicate that cessation of ibrutinib in patients with B-NHL may 
contribute to rapid tumor progression. Consequently, it may be beneficial for 
patients to begin a new treatment regimen after a minimal interval off ibrutinib. 
To facilitate this, ibrutinib may be continued for up to 4 weeks after 
documentation of disease progression provided that all other criteria for 
continuation of treatment re met. Ibrutinib must be stopped at least 24 hours prior 
to the initiation of the new B-NHL treatment regimen.
8.0       DOSAGE MODIFICATIONS
8.1
Dose Modification and Dose Delay
Treatment with ibrutinib should be held for any of the toxicities listed below:
8.1.1
Grade 4 neutropenia (ANC < 500/mm3) 
8.1.2
Grade 3 thrombocytopenia (platelets < 50,000/mm3) in the presence of 
significant bleeding (≥ Grade 2 bleeding) 
8.1.3
Grade 4 thrombocytopenia (platelets < 25,000/mm3) 
8.1.4
 Grade 3 or Grade 4 nausea, vomiting or diarrhea (if persistent despite optimal 
antiemetic or antidiarrheal therapy) or any other Grade 4 or unmanageable Grade 3 
drug-related toxicities.
The following actions should be taken for drug-related toxicities: 
Occurrence of the 
Same Adverse Event 
Action 
First 
Hold ibrutinib until recovery to Grade ≤1 or baseline; may 
restart at original dose level
Second 
Hold ibrutinib until recovery to Grade ≤1 or baseline; 
restart at 1 dose level lower (420 mg daily) 
Third 
Hold ibrutinib until recovery to Grade ≤1 or baseline; 
restart at 1 dose level lower (280 mg daily) 
Fourth 
Discontinue ibrutinib 
Ibrutinib may be held for a maximum of 21 consecutive days. Ibrutinib should 
be discontinued if the treatment cannot be resumed within 21 days. Once the
ibrutinib dose is reduced because of toxicity, it cannot be re-escalated. No dose 
escalation of ibrutinib (above 560 mg) is allowed in this study. Refer to section 
3.4 for subjects requiring the initiation of anticoagulants while receiving study 
Fred Hutch IRB
Approved 
6/28/2023


 Protocol 9107
Version 7.0  Dated 07/18/2022
Page 14 of 34
drug and for instructions on dose modification or temporary hold during 
concomitant administration of CYP3A inhibitors or inducers.  Refer to section 5.3 
for guidance on dose delays during the perioperative period for subjects who 
require surgical intervention or an invasive procedure while receiving study drug.
If there is a rapid increase in disease burden leading to an "apparent" response of 
PD after the study drug has been held for at least 7 consecutive days, an 
assessment response of tumor flare may be assigned instead of PD. Should this 
occur the patient may remain on study drug if they otherwise meet criteria to 
continue until the next restaging exam unless there is ongoing evidence of 
progressive disease before that time despite ongoing treatment. If there is further 
documented PD on or before the next restaging evaluation the patient will be 
considered to have PD and the date of PD will be assigned to the initial date 
tumor flare.
 
8.2
Dose Modifications for Adverse Reactions
For adverse reactions listed in Table 1, interrupt IMBRUVICA therapy. Once the 
adverse reaction has improved to Grade 1 or baseline (recovery), follow the 
recommended dosage modifications. 
Table 1.  Recommended Dosage Modifications for Adverse Reactions
Adverse Reactiona,b
Occurrence
Dose Modification for 
MCL and MZL After 
Recovery
Starting Dose = 560 mg
Dose Modification for 
CLL/SLL, WM, and 
cGVHD After Recovery
Starting Dose = 420 mg 
First
Restart at 420 mg dailyc
Restart at 280 mg dailyc
Second
Restart at 280 mg dailyc
Restart at 140 mg dailyc
Grade 2 cardiac failure
Third
Discontinue IMBRUVICA
Discontinue IMBRUVICA
First
Restart at 420 mg dailyc
Restart at 280 mg dailyc 
Grade 3 cardiac arrhythmias
Second
Discontinue IMBRUVICA
Discontinue IMBRUVICA
Grade 3 or 4 cardiac failure 
Grade 4 cardiac arrhythmias 
First
Discontinue IMBRUVICA
Discontinue IMBRUVICA
First
Restart at 420 mg daily
Restart at 280 mg daily
Second
Restart at 280 mg daily
Restart at 140 mg daily
Other Grade 3 or 4 non-
hematological toxicitiesd
Grade 3 or 4 neutropenia 
with infection or fever
Grade 4 hematological 
toxicities
Third
Discontinue IMBRUVICA
Discontinue IMBRUVICA
    a See Warnings and Precautions.
b Grading based on National Cancer Institute-Common Terminology Criteria for Adverse Events (NCI-CTCAE) criteria, or 
International Workshop on Chronic Lymphocytic Leukemia (iwCLL) criteria for hematologic toxicities in CLL/SLL.
c Evaluate the benefit-risk before resuming treatment.
Fred Hutch IRB
Approved 
6/28/2023


 Protocol 9107
Version 7.0  Dated 07/18/2022
Page 15 of 34
d For Grade 4 non-hematologic toxicities, evaluate the benefit-risk before resuming treatment. These updated dosage 
modification recommendations may reduce the occurrence of additional serious events and are intended to improve 
tolerability for continued Imbruvica treatment. 
 
Summary of updated dosage modification recommendations:

Resume ibrutinib treatment at a reduced dose for patients who experience 
specific non-hematologic and hematologic adverse drug reactions, including 
Grade 2 cardiac failure and Grade 3 cardiac arrhythmias, as outlined in Table 
1

Evaluate the benefit-risk before resuming ibrutinib treatment following Grade 
2 cardiac failure, Grade 3 cardiac arrhythmias, or other Grade 4 non-
hematological adverse reactions

Discontinue treatment for patients who experience adverse drug reactions of 
Grade 3 or 4 cardiac failure or Grade 4 cardiac arrhythmia
8.3
Concomitant Therapy
8.3.1
Medications used during the course of the study should be documented.
8.3.2
Prohibited Concomitant Therapy: 
The administration of concurrent medications intended to treat the primary 
cancer is not allowed during protocol therapy.  This includes any 
chemotherapy, investigational agent, biologic agent or other anti-tumor 
agents.  Radiation therapy is also prohibited. 
8.3.3
Patients should be strongly discouraged from taking any “alternative” or 
“naturopathic” medications since these agents may interact with study 
treatment. Any use of these medications should be at the judgment of the 
treating physician and should be documented in the patient’s medical 
record.
8.3.4 Hematopoietic growth factors and transfusions are allowed. 
Fred Hutch IRB
Approved 
6/28/2023


 Protocol 9107
Version 7.0  Dated 07/18/2022
Page 16 of 34
 9.0
STUDY CALENDAR 
Required Studies
Screening
(within 4 weeks of initiation of 
treatment)
During 
treatment
Post 
Therapy
Follow-
up
Physical
Medical History
X
Physical Exam
X
X4
X6
X7
Performance Status
X
X4
X6
Clinical Disease Assessment
X
X4
X6
Adverse Event Assessment
X
X4
X6
EKG
X
Lab
CBC and differential
X
X4
X6
Serum creatinine, total bilirubin, 
SGOT (AST), electrolytes, glucose 
X
X4
X6
Albumin, LDH
X
X6
Bone marrow studies
X1
X1
Pregnancy test
X2
Pathologic studies
X
Radiology
CT (preferred) or MRI Chest, 
abdomen and pelvis
X
X5
X6
FDG-PET (skull base to proximal 
femur)
X3
X5
1 Bone marrow studies include aspirate and unilateral or bilateral biopsy and should be performed at screening unless approved by 
the Sponsor-Investigator or Lead Sub-Investigator.  If all bone marrow studies are negative at screening, these do not need to be 
repeated.  If bone marrow status is unknown or positive at screening, patients will need to a have bone marrow study to confirm a 
suspected CR.
2  Pregnancy test is only required in women of childbearing potential.
3 May be obtained up to 8 weeks in advance of initiation of therapy (provided no additional anti-cancer therapies are administered 
during the interval). A Deauville score should be assigned [19].
4 At the beginning of therapy (within 3 days), on completion of every cycle (+/- 3 days) during first 9 cycles, then on completion 
of every 4 cycles (+/- 6 days thereafter. For the first day of therapy, pre-entry H&P, PS, disease assessment, and adverse event 
assessment may be used (these do not need to be repeated within 3 days) and labs done within 14 days are acceptable.
5 During treatment restaging CT (preferred) or MRI will be performed on completion of every 3 cycles of therapy (+/- 6 days) 
during the first 9 cycles and on completion of every 8 cycles of therapy (+/- 12 days) thereafter, or as indicated to evaluate clinical 
suspicion of disease progression. Restaging PET/CT will be performed once during therapy on completion of the first 6 cycles (+/- 
6 days). A Deauville score should be assigned [19] when restaging PET is performed.
6 Post therapy studies should be done within 28 days after the last dose of ibrutinib. A CT (preferred) or MRI will be obtained if 
prior imaging was > 21 days of therapy’s completion.
7 Routine, long-term follow-up should be done approximately every 3 months or as clinically indicated. This can be done in 
conjunction with the patient’s local MD; patients do not need to return to the SCCA. Long-term follow-up will assess survival and 
disease progression for up to 5-years after completion of treatment; subjects will be contacted until death, subject withdrawal of 
consent, lost to follow-up, or study termination by the sponsor-investigator, whichever occurs first.
Fred Hutch IRB
Approved 
6/28/2023


 Protocol 9107
Version 7.0  Dated 07/18/2022
Page 17 of 34
10.0
CRITERIA FOR EVALUATION AND ENDPOINT DEFINITIONS
Definitions of Disease, Criteria for Evaluation and Endpoint Definitions – response will be 
based on standard criteria for lymphoid malignancies .
10.1 
Selection of Indicator (Target) Lesions
Up to six of the largest dominant nodes or tumor masses selected according to all 
of the following: 
• Clearly measurable in at least two perpendicular dimensions 
Abnormal lymph nodes are those that are either 
>15 mm in the greatest transverse diameter (GTD) regardless of the 
short axis diameter, or 
> 10 mm in short axis diameter regardless of long axis
• If possible, they should be from disparate regions of the body 
• Should include mediastinal and retroperitoneal areas of disease whenever these 
sites are involved 
• Extranodal lesions within the liver or spleen must be at least 1.0 cm in two 
perpendicular dimensions.
10.2 
PET Scans
Visual assessment currently is considered adequate for determining whether a 
PET scan is positive. A Deauville score should be reported. In brief, a positive 
scan is defined as focal or diffuse FDG uptake above background in a location 
incompatible with normal anatomy or physiology. 
10.3 
Response Criteria
For measurement of response, standard 2014 criteria as described in 
“Recommendations for Initial Evaluation, Staging, and Response Assessment of 
Hodgkin and Non-Hodgkin Lymphoma: The Lugano Classification” will be used 
(see Appendix D) [20].
10.4 
If a subject who had radiological evidence of PD is clinically stable or improving 
or exhibiting signs of tumor flare without confirmation of PD by PET or biopsy, 
the subject may continue treatment with ibrutinib upon approval by the sponsor-
investigator.. If tumor flare is suspected, the PI may continue ibrutinib and obtain 
additional radiological and clinical evaluation at a subsequent disease evaluation 
visit within 6 weeks, with a determination as to whether ibrutinib should be 
discontinued (in subjects with evidence of further progression at repeat 
evaluation) or further treatment provided (in subjects with signs of subsequent 
tumor shrinkage or stable disease without clinical deterioration).
10.5
Progression-free survival (PFS): PFS will be measured as time from first study 
drug administration to the first occurrence of disease progression or death from 
any cause. Data for subjects without disease progression or death will be censored 
at the date of the last tumor assessment and before the initiation of alternative 
Fred Hutch IRB
Approved 
6/28/2023


 Protocol 9107
Version 7.0  Dated 07/18/2022
Page 18 of 34
anticancer therapy. The estimates will be formed using the all treated population. 
Progression-free survival will be calculated using assessments by investigators. 
Kaplan-Meier methodology will be used to estimate event-free curves and 
corresponding quartiles (including the median).
10.6
Assessment inadequate, objective status unknown: Progression has not been 
documented and one or more target lesions or other sites of disease have not been 
assessed or inconsistent methods of assessment were used.
10.7
Bone Marrow Status: Bone marrow status is evaluated as follows: 
Positive: Unequivocal cytological or architectural evidence of malignancy.  
Negative: No aggregates or only a few well-circumscribed lymphoid 
aggregates.  
Indeterminate:  Does not qualify for either Positive or Negative Status.  *Note this 
typically consists of increased number or size of aggregates without cytological or 
architectural atypia.
11.0 
STATISTICAL CONSIDERATIONS
11.1
The primary objective is to gain a preliminary (pilot) assessment of the efficacy of 
this regimen based on overall response rate (ORR) (see section 10.2).  Analyses of 
secondary endpoints will be primarily descriptive. Patients with R/R TIL have a 
poor prognosis and short median survival; therefore an ORR of ≥ 30%, a disease 
control rate of ≥ 50% (defined as ORR plus stable disease, as defined in section 
10.2), or a median PFS of ≥ 6 months will be considered a success.
11.2 
Anticipated accrual: We anticipate that accrual will take 1-2 years.     
11.3
Estimated* distribution of study population by gender and race and ethnicity:
Ethnic Category
Females
Males
American Indian/Alaska Native
Asian
1
1
Native Hawaiian or Other Pacific Islander
Black or African American
1
1
White
8
8
More than one race
Unknown or not reported
Racial Categories: Total of all subjects
10
10
*The exact sample size is not known since it is dependent on the number of 
evaluable patients, but we estimate the total enrollment will be 20.   
Fred Hutch IRB
Approved 
6/28/2023


 Protocol 9107
Version 7.0  Dated 07/18/2022
Page 19 of 34
11.4
If treatment efficacy meets predefined success rate of 30% overall response rate 
(combined CR + PR) then a recommendation may be made to expand the study to 
accrue an additional 20 patients.
12.0 
STUDY MONITORING AND REPORTING PROCEDURES
12.1
Adverse Event Reporting 
Complete and timely reporting of adverse events (AEs) is required to ensure the 
safety of patients.  Reporting requirements are determined by the characteristics of 
the adverse event including the grade (severity), the relationship to the study 
therapy (attribution), and the prior experience (expectedness) of the adverse 
event, and whether the event is of interest to Janssen Scientific Affairs.  The 
guidelines outlined in this section, as well as the specific direction on each report 
form must be followed.  The NCI Common Terminology Criteria for Adverse 
Events v4.0 (CTCAE) will be used to classify and grade toxicities.
12.2 
Definitions and descriptions of terms used in adverse event reporting.
12.2.1 Adverse Event (AE)
An adverse event is defined as any unfavorable and unintended sign (including an 
abnormal laboratory finding), symptom, or disease temporally associated with the 
use of a medical treatment or procedure.
12.2.2 Serious Adverse Event (SAE) or Adverse Drug Reaction (ADR)
A Serious Adverse Event or Adverse Drug Reaction means any AE/ADR 
occurring at any dose that results in:

Death;

A life-threatening AE/ADR (i.e, the patient/subject was, in the view of the 
initial reporter/investigator, at immediate risk of death from the AE as it 
occurred. It does not refer to an AE that hypothetically might have caused 
death if more severe);

Inpatient hospitalization or prolongation of existing hospitalization (i.e, 
hospitalization was required to treat or diagnose the AE/ADR: excludes 
hospitalization for unrelated reasons (e.g., social reasons such as pending 
placement in long-term care facility) OR surgery or procedure planned 
before entry into the study (must be documented in the CRF). Note: 
Hospitalizations that were planned before the signing of the ICF, and 
where the underlying condition for which the hospitalization was planned 
has not worsened, will not be considered serious adverse events. Any 
adverse event that results in a prolongation of the originally planned 
hospitalization is to be reported as a new serious adverse event;
Fred Hutch IRB
Approved 
6/28/2023


 Protocol 9107
Version 7.0  Dated 07/18/2022
Page 20 of 34

A persistent or significant disability or incapacity (disability here means 
that there is a substantial disruption of a person's ability to conduct normal 
life functions;

A congenital anomaly/birth defect;

An important medical event (i.e., AEs/ADRs that might not be 
immediately life-threatening, or result in death or hospitalization might be 
considered serious when, based upon appropriate medical and scientific 
judgment, they might jeopardize the patient/subject or might require 
medical or surgical intervention to prevent one of the other serious 
outcomes listed above);

Any suspected transmission via a medicinal product of an infectious agent.
Sponsor-Investigator shall use his/her judgment to determine the relationship 
between the Serious Adverse Drug Experience and the Study Drug.
Disease progression should not be recorded as an adverse event or serious adverse 
event term; instead, signs and symptoms of clinical sequelae resulting from disease 
progression/lack of efficacy will be reported if they fulfill the serious adverse event 
definition.
12.2.3 Adverse Events of Special Interest
Specific adverse events or groups of adverse events will be followed as part of 
standard safety monitoring activities. These events will be reported to Janssen 
Scientific Affairs within 24 hours of awareness irrespective of seriousness (ie, 
serious and nonserious adverse events) following the procedure described above 
for serious adverse events and will require enhanced data collection.  Specific 
adverse events of interest include:
1. Major Hemorrhage
Major hemorrhage is defined as any hemorrhagic event that is Grade 3 or greater 
in severity or that results in 1 of the following: intraocular bleeding causing loss 
of vision, the need for a transfusion of 2 or more units of red cells or an equivalent 
amount of whole blood, hospitalization, or prolongation of hospitalization.
2. Intracranial Hemorrhage
Any intracranial hemorrhage adverse event, including subdural 
hematoma/hemorrhage, epidural hematoma/hemorrhage and intracerebral 
hemorrhage, of any grade severity, will be captured as an event of special interest.
3. Other Malignancies 
In addition to all routine AE reporting, all new malignant tumors, including solid 
tumors, skin malignancies and hematologic malignancies, are to be reported for 
Fred Hutch IRB
Approved 
6/28/2023


 Protocol 9107
Version 7.0  Dated 07/18/2022
Page 21 of 34
the duration of study treatment and during any protocol-specified follow-up 
periods including post-progression follow-up for overall survival.
12.2.4 Pregnancy 
All initial reports of pregnancy must be reported to Janssen Scientific Affairs by 
the study-site personnel within 24 hours of their knowledge of the event. 
Abnormal pregnancy outcomes (eg, spontaneous abortion, stillbirth, and 
congenital anomaly) are considered serious adverse events and must be reported 
as a Serious Adverse Event. Any subject who becomes pregnant during the study 
must discontinue further study treatment. 
Because the effect of the study drug on sperm is unknown, pregnancies in partners 
of male subjects included in the study will be reported by the study-site personnel 
within 24 hours of their knowledge of the event. 
Follow-up information regarding the outcome of the pregnancy and any postnatal 
sequelae in the infant will be required.
12.2.5 Grade
Grade is defined as the severity of the adverse event.  The CTCAE Version 4.0 
must be used to determine the grade of the adverse event. If toxicity is not listed 
in the CTCAE use the following general criteria for grading.  
0 – No adverse event or within normal limits
1 – Mild adverse event
2 – Moderate adverse event
3 – Severe adverse event
4 – Life-threatening or disabling adverse event
5 – Fatal adverse event
12.2.6 Attribution
Attribution is defined as the determination of whether an adverse event is related 
to a medical treatment or procedure.  Attribution categories are as follows:

Unrelated The adverse event is clearly NOT related to therapy

Unlikely
The adverse event is doubtfully related to therapy

Possible
The adverse event may be related to therapy

Probable The adverse event is likely related to therapy

Definite
The adverse event is clearly related to therapy
12.2.7 Unexpected Adverse Event
An adverse event is considered unlisted (unexpected) if the nature or severity is 
not consistent with the applicable product reference safety information. For 
ibrutinib, the expectedness of an adverse event will be determined by whether or 
not it is listed in the Investigator's Brochure and US package insert. 
Fred Hutch IRB
Approved 
6/28/2023


 Protocol 9107
Version 7.0  Dated 07/18/2022
Page 22 of 34
12.2.8 Product Quality Complaint
A product quality complaint may allege an injury or malfunction associated with 
the use of the drug product. It may involve the design, literature, packaging, 
advertising, availability, physical appearance or promotion of the drug product. It 
may also involve any discrete concern that questions the identity, quality, 
durability, reliability, safety, efficacy or intended performance of a drug product.
12.2.9 J&J Medicinal Product
J&J medicinal product includes the specific drug under study and other J&J 
medicinal product.
12.3
Routine Reporting
Routine reporting is required for all adverse events.  
All applicable adverse events and special reporting situations, whether serious or 
non-serious, will be reported from the time a signed and dated ICF is obtained 
until30 days following the last dose of study drug.  Serious adverse events, 
including those spontaneously reported to the investigator within 30 days after the 
last dose of study drug, must be reported. 
All events that meet the definition of a serious adverse event will be reported as 
serious adverse events, regardless of whether they are protocol-specific 
assessments.
All adverse events, regardless of seriousness, severity, or presumed relationship to 
study drug, must be recorded using medical terminology in the source document 
and the CRF. Whenever possible, diagnoses should be given when signs and 
symptoms are due to a common etiology (eg, cough, runny nose, sneezing, sore 
throat, and head congestion should be reported as "upper respiratory infection"). 
Investigators must record in the CRF their opinion concerning the relationship of 
the adverse event to study therapy. All measures required for adverse event 
management must be recorded in the source document.
The sponsor-investigator assumes responsibility for appropriate reporting of 
adverse events to the regulatory authorities. The sponsor will also report to Janssen 
Scientific Affairs all serious adverse events that are unlisted (unexpected) and 
associated with the use of the study drug. The sponsor must report these events to 
the appropriate IRB that approved the protocol unless otherwise required and 
documented by the IRB.
12.4
Expedited Reporting 
All unexpected adverse events, serious adverse events, and adverse events of 
interest which may be due to study treatment or intervention, must be reported to 
the Sponsor-Investigor as soon as possible. Expedited reporting will be conducted 
Fred Hutch IRB
Approved 
6/28/2023


 Protocol 9107
Version 7.0  Dated 07/18/2022
Page 23 of 34
in accordance with FHCRC/Cancer Consortium IRB policies, applicable FDA 
regulations, and agreements with Janssen Scientific Affairs.
Expedited reporting additionally applies to any death occurring during protocol 
therapy or within 30 days of completing protocol therapy and any death that occurs 
more than 30 days after completing protocol treatment that is thought to be 
treatment-related and is not due to disease recurrence. Expedited reporting further 
applies to the occurrence of pregnancy or, new diagnosis of cancer during treatment 
or within 30 days of the last dose of study drug, or overdose of study drugs 
(regardless of adverse outcome).
     
12.5
     Follow-up of serious adverse events
All serious adverse events that have not resolved by the end of the study, or that 
have not resolved upon discontinuation of the subject's participation in the study, 
must be followed until any of the following occurs:

The event resolves

The event stabilizes

The event returns to baseline, if a baseline value/status is available

The event can be attributed to agents other than the study drug or to factors 
unrelated to study conduct

It becomes unlikely that any additional information can be
obtained (subject or health care practitioner refusal to provide additional 
information, lost to follow-up after demonstration of due diligence with follow-
up efforts)
12.6
     Reporting to Janssen Scientific Affairs
All serious adverse events and adverse events of interest occurring during the study 
must be reported to Janssen Scientific Affairs by the sponsor-investigator within 24 
hours of learning of the event.
The Sponsor-Investigator will initially notify Janssen Scientific Affairs within 24 
hours, by facsimile or e-mail, upon learning of the occurrence during the Study of:
All serious AE/ADRs, regardless of causality (see 12.2);
AEs of special interest (see 12.2.3, 12.2.4);
Special reporting situations (see 12.11);
Product quality complaints (see 12.13);
Any exposure of a pregnant Study participant to the Study Drug within thirty 
(30) days of exposure;
A female partner of a male Study participant becoming pregnant within thirty 
(30) days of exposure;   
Any medical event which may reasonably be believed to impair the integrity, 
validity or ongoing viability of the Study. 
Fred Hutch IRB
Approved 
6/28/2023


 Protocol 9107
Version 7.0  Dated 07/18/2022
Page 24 of 34
All such occurrences listed in this section shall be reported in final form to Janssen 
Scientific Affairs using a MedWatch form.  An aggregate listing of all SAEs and 
AEs will also be sent yearly and at the end of the study to Janssen Scientific Affairs 
electronically.
In the event the IRB requests additional safety information from the investigator, 
the investigator shall notify Janssen Scientific Affairs of such request within one 
(1) business day of learning of the request.
12.7
    Maintenance of Safety Information
Safety information will be maintained in a clinical database/repository in a 
retrievable format. At a minimum, at the end of the treatment phase as well as the 
end of the follow-up phase of the Study, the Sponsor-Investigator shall provide all 
adverse events, both serious and non-serious, in report format. However, in certain 
circumstances more frequent review of the safety data may be necessary.
12.8
     Reconciliation of SAEs
At a minimum, on a quarterly basis and at the end of the Study, Janssen Scientific 
Affairs will provide to the Sponsor-Investigator, a listing of all SAEs reported to 
Janssen Scientific Affairs.  The Sponsor-Investigator will review this listing and 
provide any discrepancies to Janssen Scientific Affairs.
Upon request, the Sponsor-Investigator shall provide Janssen Scientific Affairs 
with a summary list of all SAEs, and AEs of Special Interest and Special Reporting 
Situation reports to date, for reconciliation purposes.
12.9
     Dissemination of Safety Information from Janssen Scientific Affairs to 
theSponsor-Investigator
Janssen Scientific Affairs will provide to the Sponsor-Investigator IND safety 
reports/SUSAR (Serious Unexpected Suspect Adverse Reaction) reports generated 
by the Janssen Scientific Affairs for the Study Product as they become available 
until all subjects in the Protocol have completed their last Study visit according to 
the Protocol  (i.e. Last Subject Last Visit has occurred).
12.10 Reporting to the IRB
Guidelines of the local IRB will be followed for reporting serious adverse events in 
a timely manner.  
12.11 Special Reporting Situations
Special reporting situations should be recorded in the CRF. Any special reporting 
situation that meets the criteria of a serious adverse event should be recorded on the 
Fred Hutch IRB
Approved 
6/28/2023


 Protocol 9107
Version 7.0  Dated 07/18/2022
Page 25 of 34
serious adverse event page of the CRF. Safety events of interest on a Johnson & 
Johnson medicinal product that may require expedited reporting and/or safety 
evaluation include, but are not limited to:

Overdose of a Johnson & Johnson medicinal product 

Pregnancy exposure (maternal and paternal)

Exposure to a medicinal product from breastfeeding 

Suspected abuse/misuse of a medicinal Johnson & Johnson product

Inadvertent or accidental exposure to a medicinal Johnson & Johnson product 

Any failure of expected pharmacological action (i.e., lack of effect) of a 
Johnson & Johnson medicinal product

Unexpected therapeutic or clinical benefit from use of a Johnson & Johnson 
medicinal product

Medication error involving a Johnson & Johnson product (with or without 
patient exposure to the medicinal Johnson & Johnson product, e.g., name 
confusion)

Suspected transmission of any infectious agent via a medicinal product.
12.12 Data Safety and Monitoring Plan
All serious adverse events are communicated to the study Sponsor-Investigator,  
and regulatory agencies as described above.  A status report including accrual, 
adverse events, and death information will be reviewed by the Sponsor-Investigator 
every 6 months and the Fred Hutchinson Cancer Research Center (FHCRC) 
Protocol Data Monitoring Committee (PDMC) annually.  In addition, the study will 
be monitored by the Research Trials Office according to the Fred Hutchinson 
Cancer Research Center monitoring plan.
12.13  Product quality complaint handling
All initial PQCs must be reported to Janssen Scientific Affairs by the study-site 
personnel within 24 hours after being made aware of the event.
If the defect is combined with a serious adverse event, the study-site personnel must 
report the PQC to Janssen Scientific Affairs according to the serious adverse event 
reporting timelines.  A sample of the suspected product should be maintained for 
further investigation if requested by Janssen Scientific Affairs.
 12.14 Required Records and Materials
Original signed informed consent form will be retained with the study records.  A 
copy will be sent to the clinical chart and to the patient.  
Data will be collected on patient characteristics, disease characteristics, protocol 
therapy, response to treatment, adverse events and follow-up for relapse and 
Fred Hutch IRB
Approved 
6/28/2023


 Protocol 9107
Version 7.0  Dated 07/18/2022
Page 26 of 34
survival.  Copies of the patient’s medical record including history and physical 
exams, documentation of protocol therapy, labs, scans, x-rays, hospitalizations, 
operative reports, pathology reports etc. are required. Case report forms will be 
completed by the study staff.
13.0
ELEMENTS OF INFORMED CONSENT
All Institutional, NCI, State and Federal regulations concerning informed consent and peer 
judgment will be fulfilled.  Written consent will be obtained from all patients entering the 
study.
Fred Hutch IRB
Approved 
6/28/2023


 Protocol 9107
Version 7.0  Dated 07/18/2022
Page 27 of 34
14.0
REFERENCES:
1.
Bernstein SH, Burack WR. The incidence, natural history, biology, and treatment of 
transformed lymphomas. Hematology Am Soc Hematol Educ Program 2009; 532-541.
2.
Horning SJ, Rosenberg SA. The natural history of initially untreated low-grade non-
Hodgkin's lymphomas. N Engl J Med 1984; 311: 1471-1475.
3.
Al-Tourah AJ, Gill KK, Chhanabhai M et al. Population-based analysis of incidence and 
outcome of transformed non-Hodgkin's lymphoma. J Clin Oncol 2008; 26: 5165-5169.
4.
Lossos IS, Gascoyne RD. Transformation of follicular lymphoma. Best Pract Res Clin 
Haematol 2011; 24: 147-163.
5.
Wong E, Dickinson M. Transformation in follicular lymphoma: biology, prognosis, and 
therapeutic options. Curr Oncol Rep 2012; 14: 424-432.
6.
Eide MB, Lauritzsen GF, Kvalheim G et al. High dose chemotherapy with autologous 
stem cell support for patients with histologically transformed B-cell non-Hodgkin lymphomas. A 
Norwegian multi centre phase II study. Br J Haematol 2011; 152: 600-610.
7.
Sabloff M, Atkins HL, Bence-Bruckler I et al. A 15-year analysis of early and late 
autologous hematopoietic stem cell transplant in relapsed, aggressive, transformed, and 
nontransformed follicular lymphoma. Biol Blood Marrow Transplant 2007; 13: 956-964.
8.
Villa D, Crump M, Panzarella T et al. Autologous and allogeneic stem-cell 
transplantation for transformed follicular lymphoma: a report of the Canadian blood and marrow 
transplant group. J Clin Oncol 2013; 31: 1164-1171.
9.
Williams CD, Harrison CN, Lister TA et al. High-dose therapy and autologous stem-cell 
support for chemosensitive transformed low-grade follicular non-Hodgkin's lymphoma: a case-
matched study from the European Bone Marrow Transplant Registry. J Clin Oncol 2001; 19: 
727-735.
10.
Fisher RI, Kaminski MS, Wahl RL et al. Tositumomab and iodine-131 tositumomab 
produces durable complete remissions in a subset of heavily pretreated patients with low-grade 
and transformed non-Hodgkin's lymphomas. J Clin Oncol 2005; 23: 7565-7573.
11.
Advani RH, Buggy JJ, Sharman JP et al. Bruton tyrosine kinase inhibitor ibrutinib (PCI-
32765) has significant activity in patients with relapsed/refractory B-cell malignancies. J Clin 
Oncol 2013; 31: 88-94.
12.
Irish JM, Czerwinski DK, Nolan GP, Levy R. Altered B-cell receptor signaling kinetics 
distinguish human follicular lymphoma B cells from tumor-infiltrating nonmalignant B cells. 
Blood 2006; 108: 3135-3142.
13.
Ansell SM. Two targets for the price of one. Blood 2013; 122: 2529-2531.
14.
de Rooij MF, Kuil A, Geest CR et al. The clinically active BTK inhibitor PCI-32765 
targets B-cell receptor- and chemokine-controlled adhesion and migration in chronic 
lymphocytic leukemia. Blood 2012; 119: 2590-2594.
15.
Wang ML, Rule S, Martin P et al. Targeting BTK with ibrutinib in relapsed or refractory 
mantle-cell lymphoma. N Engl J Med 2013; 369: 507-516.
16.
Wilson WH, et al. The Bruton's Tyrosine Kinase (BTK) Inhibitor, Ibrutinib (PCI-32765), 
Has Preferential Activity in the ABC Subtype of Relapsed/Refractory De Novo Diffuse Large B-
Cell Lymphoma (DLBCL): Interim Results of a Multicenter, Open-Label, Phase 2 Study ASH 
Annual Meeting 2012.
17.
Ponader S, Chen SS, Buggy JJ et al. The Bruton tyrosine kinase inhibitor PCI-32765 
thwarts chronic lymphocytic leukemia cell survival and tissue homing in vitro and in vivo. Blood 
2012; 119: 1182-1189.
Fred Hutch IRB
Approved 
6/28/2023


 Protocol 9107
Version 7.0  Dated 07/18/2022
Page 28 of 34
18.
Byrd JC, Furman RR, Coutre SE et al. Targeting BTK with ibrutinib in relapsed chronic 
lymphocytic leukemia. N Engl J Med 2013; 369: 32-42.
19.
Barrington SF, Qian W, Somer EJ et al. Concordance between four European centres of 
PET reporting criteria designed for use in multicentre trials in Hodgkin lymphoma. Eur J Nucl 
Med Mol Imaging 2010; 37: 1824-1833.
20.
Cheson BD, Fisher RI, Barrington SF et al. Recommendations for initial evaluation, 
staging, and response assessment of Hodgkin and non-Hodgkin lymphoma: the Lugano 
classification. J Clin Oncol 2014; 32: 3059-3068.
Fred Hutch IRB
Approved 
6/28/2023


 Protocol 9107
Version 7.0  Dated 07/18/2022
Page 29 of 34
Appendix A: Ann Arbor staging system for lymphomas
Principal stages
The principal stage is determined by location of the tumor:
Stage I indicates that the cancer is located in a single region, usually one lymph node and the 
surrounding area. Stage I often will not have outward symptoms.
Stage II indicates that the cancer is located in two separate regions, an affected lymph node or 
organ and a second affected area, and that both affected areas are confined to one side of the 
diaphragm - that is, both are above the diaphragm, or both are below the diaphragm.
Stage III indicates that the cancer has spread to both sides of the diaphragm, including one organ 
or area near the lymph nodes or the spleen.
Stage IV indicates diffuse or disseminated involvement of one or more extralymphatic organs, 
including any involvement of the liver, bone marrow, or nodular involvement of the lungs.
These letters can be appended to some stages:
A or B: the absence of constitutional (B-type) symptoms is denoted by adding an "A" to the 
stage; the presence is denoted by adding a "B" to the stage.
E: is used if the disease is "extranodal" (not in the lymph nodes) or has spread from lymph nodes 
to adjacent tissue.
X: is used if the largest deposit is >10 cm large ("bulky disease").
S: is used if the disease has spread to the spleen.
Fred Hutch IRB
Approved 
6/28/2023


 Protocol 9107
Version 7.0  Dated 07/18/2022
Page 30 of 34
Appendix B: ECOG Performance Status
0 – Asymptomatic (Fully active, able to carry on all predisease activities without restriction)
1 – Symptomatic but completely ambulatory (Restricted in physically strenuous activity but 
ambulatory and able to carry out work of a light or sedentary nature. For example, light 
housework, office work)
2 – Symptomatic, <50% in bed during the day (Ambulatory and capable of all self care but 
unable to carry out any work activities. Up and about more than 50% of waking hours)
3 – Symptomatic, >50% in bed, but not bedbound (Capable of only limited self-care, confined to 
bed or chair 50% or more of waking hours)
4 – Bedbound (Completely disabled. Cannot carry on any self-care. Totally confined to bed or 
chair)
5 – Death
Fred Hutch IRB
Approved 
6/28/2023


 Protocol 9107
Version 7.0  Dated 07/18/2022
Page 31 of 34
Appendix C: Inhibitors and Inducers of CYP3A
Inhibitors of CYP3A are defined as follows. This list may not be all inclusive. A comprehensive list of 
inhibitors can be found at the following website: http://medicine.iupui.edu/clinpharm/ddis/table.aspx. The 
general categorization into strong, moderate, and weak inhibitors according to the website is displayed 
below. 
Inhibitors of CYP3A
Inducers of CYP3A
STRONG
Carbamazepine
INDINAVIR
Efavirenz
NELFINAVIR
Nevirapine
RITONAVIR
Barbiturates
CLARITHROMYCIN
Glucocorticoids
ITRACONAZOLE
Modafinil
KETOCONAZOLE
Oxcarbarzepine
NEFAZODONE
Phenobarbital
SAQUINAVIR
Phenytoin
SUBOXONE
Pioglitazone
TELITHROMYCIN
Rifabutin
Rifampin
MODERATE
WEAK
St. John’s Wort
aprepitant
cimetidine
Troglitazone
erythromycin
diltiazem
fluconazole
grapefruit juice
Seville orange juice
verapamil
ALL OTHER INHIBITORS
amiodarone
NOT azithromycin
chloramphenicol
boceprevir
ciprofloxacin
delaviridine
diethyl-dithiocarbamate
fluvoxamine
gestodene
imatinib
mibefradil
mifepristone
norfloxacin
norfluoxetine
star fruit
telaprevir
troleandomycin
voriconazole
Source: http://medicine.iupui.edu/clinpharm/ddis/table.aspx
Fred Hutch IRB
Approved 
6/28/2023


 Protocol 9107
Version 7.0  Dated 07/18/2022
Page 32 of 34
Appendix D: The Lugano Response Classification [20]
Response and 
Site
PET-CT–Based Response
CT-Based Response
Complete
Complete metabolic response
Complete radiologic response (all of 
the following)
Score 1, 2, or 3* with or without a residual mass on 5PS†
Target nodes/nodal masses must regress 
to ≤ 1.5 cm in LDi
Lymph nodes and 
extralymphatic 
sites
It is recognized that in Waldeyer's ring or extranodal sites 
with high physiologic uptake or with activation within 
spleen or marrow (eg, with chemotherapy or myeloid 
colony-stimulating factors), uptake may be greater than 
normal mediastinum and/or liver. In this circumstance, 
complete metabolic response may be inferred if uptake at 
sites of initial involvement is no greater than surrounding 
normal tissue even if the tissue has high physiologic 
uptake
No extralymphatic sites of disease
    
Nonmeasured 
lesion
Not applicable
Absent
Organ 
enlargement
Not applicable
Regress to normal
New lesions
None
None
Bone marrow
No evidence of FDG-avid disease in marrow
Normal by morphology; if 
indeterminate, IHC negative
Partial
Partial metabolic response
Partial remission (all of the following)
Lymph nodes and 
extralymphatic 
sites
Score 4 or 5† with reduced uptake compared with baseline 
and residual mass(es) of any size
≥ 50% decrease in SPD of up to 6 target 
measurable nodes and extranodal sites
At interim, these findings suggest responding disease
When a lesion is too small to measure 
on CT, assign 5 mm × 5 mm as the 
default value
At end of treatment, these findings indicate residual 
disease
When no longer visible, 0 × 0 mm
For a node > 5 mm × 5 mm, but smaller 
than normal, use actual measurement 
for calculation
    
Nonmeasured 
lesions
Not applicable
Absent/normal, regressed, but no 
increase
Organ 
enlargement
Not applicable
Spleen must have regressed by > 50% 
in length beyond normal
New lesions
None
None
Bone marrow
Residual uptake higher than uptake in normal marrow but 
reduced compared with baseline (diffuse uptake 
compatible with reactive changes from chemotherapy 
Not applicable
Fred Hutch IRB
Approved 
6/28/2023


 Protocol 9107
Version 7.0  Dated 07/18/2022
Page 33 of 34
Response and 
Site
PET-CT–Based Response
CT-Based Response
allowed). If there are persistent focal changes in the 
marrow in the context of a nodal response, consideration 
should be given to further evaluation with MRI or biopsy 
or an interval scan
No response or 
stable disease
No metabolic response
Stable disease
Target 
nodes/nodal 
masses, 
extranodal lesions
Score 4 or 5 with no significant change in FDG uptake 
from baseline at interim or end of treatment
< 50% decrease from baseline in SPD 
of up to 6 dominant, measurable nodes 
and extranodal sites; no criteria for 
progressive disease are met
    
Nonmeasured 
lesions
Not applicable
No increase consistent with progression
Organ 
enlargement
Not applicable
No increase consistent with progression
New lesions
None
None
Bone marrow
No change from baseline
Not applicable
Progressive 
disease
Progressive metabolic disease
Progressive disease requires at least 1 
of the following
    
Individual target 
nodes/nodal 
masses
Score 4 or 5 with an increase in intensity of uptake from 
baseline and/or
PPD progression:
    
Extranodal 
lesions
New FDG-avid foci consistent with lymphoma at interim 
or end-of-treatment assessment
An individual node/lesion must be 
abnormal with:
LDi > 1.5 cm and
Increase by ≥ 50% from PPD nadir and
An increase in LDi or SDi from nadir
0.5 cm for lesions ≤ 2 cm
1.0 cm for lesions > 2 cm
In the setting of splenomegaly, the 
splenic length must increase by > 50% 
of the extent of its prior increase beyond 
baseline (eg, a 15-cm spleen must 
increase to > 16 cm). If no prior 
splenomegaly, must increase by at least 
2 cm from baseline
New or recurrent splenomegaly
    
Nonmeasured 
lesions
None
New or clear progression of preexisting 
nonmeasured lesions
New lesions
New FDG-avid foci consistent with lymphoma rather than 
another etiology (eg, infection, inflammation). If uncertain 
regarding etiology of new lesions, biopsy or interval scan 
may be considered
Regrowth of previously resolved lesions
A new node > 1.5 cm in any axis
A new extranodal site > 1.0 cm in any 
axis; if < 1.0 cm in any axis, its 
presence must be unequivocal and must 
Fred Hutch IRB
Approved 
6/28/2023


 Protocol 9107
Version 7.0  Dated 07/18/2022
Page 34 of 34
Response and 
Site
PET-CT–Based Response
CT-Based Response
be attributable to lymphoma
Assessable disease of any size 
unequivocally attributable to lymphoma
Bone marrow
New or recurrent FDG-avid foci
New or recurrent involvement
Fred Hutch IRB
Approved 
6/28/2023