MRD-Guided Abbreviation of Bendamustine and Rituximab Chemotherapy in Combination With Copanlisib in Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma
Phase: PHASE2
Conditions: Lymphoid Leukemia, Non-Hodgkin's Lymphoma, Chronic Lymphocytic Leukemia, Small Lymphocytic Lymphoma
Sponsor: University of Washington

Protocol version 3.0 dated 16 October 2020 
 
Page 1 of 40 
UNIVERSITY OF WASHINGTON SCHOOL OF MEDICINE 
FRED HUTCHINSON CANCER RESEARCH CENTER 
SEATTLE CANCER CARE ALLIANCE 
 
 
RG1005103 
MRD-guided abbreviation of bendamustine and rituximab chemotherapy in 
combination with copanlisib in chronic lymphocytic leukemia/small lymphocytic 
lymphoma 
 
Protocol Version 3.0 Dated 16 October 2020 
 
Sponsor/Principal Investigator:   
 
 
 
 
 
  
Ryan Lynch, MD 
Assistant Professor, University of Washington 
Assistant Member, Fred Hutchinson Cancer Research Center 
Seattle Cancer Care Alliance 
825 Eastlake Ave. E, CE3-300 
Seattle, WA  98109 
Telephone: (206) 606-1739 
 
 
Statistical Consultant 
Ted A. Gooley, Ph.D. 
Full Member, Clinical Research Division 
Fred Hutchinson Cancer Research Center 
1100 Fairview Ave. N., M2-B230 
Seattle, WA  98109 
This trial is supported by a grant from X  
Tracking Number:  X 
 
 
Previous Protocol Version (Dates): 
1.0 (06 December 2018) 
2.0 (03 September 2019) 
 
 
IRO REC'D NOV 16 2020
FHCRC IRB Approval  
DEC 17 2020 
Document Released Date

 Protocol version 3.0 dated 16 October 2020 
 
Page 2 of 40 
 
SCHEMA 
Registration: CLL/SLL without del 17p, and any of: 1) untreated with CIRS ≥ 7, 2) age ≥65, or  
3) previously treated 
 
Cycle 1 
Copanlisib 60 mg IV days 1, 8, 15 
Rituximab 375 mg/m2 IV day 1 
Bendamustine 90 mg/m2 IV day 1, 2 
Cycle length: 28 days 
 
 
 
Cycle 2-4 
Copanlisib 60 mg IV days 1, 8, 15 
Rituximab 500 mg/m2 IV day 1 
Bendamustine 90 mg/m2 IV day 1, 2 
Cycle length: 28 days 
 
 
 
Bone marrow minimal residual disease (MRD) testing and International Workshop on CLL (IWCLL) 
2018 assessment1  
 
 
 
MRD-negative subjects undergo observation       MRD-positive (who achieve at least a PR) subjects   
continue on treatment 
 
 
 
 
 
 
 
 
Cycle 5-6 
 
 
 
 
 
 
 
Copanlisib 60 mg IV days 1, 8, 15 
Rituximab 500 mg/m2 IV day 1 
Bendamustine 90 mg/m2 IV day 1, 2 
Cycle length: 28 days 
          Repeat MRD assessment 1 year after 
                          start of therapy 
 
Cycle 7-12 
Copanlisib 60 mg IV Day 1, 15 
                 Follow up for 3 years for                                  Cycle length 28 days 
             survival and remission status 
 
 
Bone marrow MRD assessment and IWCLL response 
assessment, followed by observation or additional treatment 
off protocol 
 
 
 
Follow up for 3 years for survival and remission status 

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Table of Contents 
1.0 
OBJECTIVES .......................................................................................................... 4 
2.0 
BACKGROUND/RATIONALE .............................................................................. 4 
3.0 
DRUG INFORMATION ......................................................................................... 5 
4.0 
STAGING CRITERIA AND RISK STRATIFICATION ....................................... 7 
5.0 
ELIGIBILITY CRITERIA ....................................................................................... 7 
6.0 
REGISTRATION ................................................................................................... 11 
7.0 
TREATMENT PLAN ............................................................................................ 11 
8.0 
DOSAGE MODIFICATIONS ............................................................................... 15 
9.0 
STUDY CALENDAR ............................................................................................ 23 
10.0       STUDY PROCEDURES ........................................................................................ 26 
11. 0      CRITERIA FOR EVALUATION AND ENDPOINT DEFINITIONS ................. 28 
12.0       STATISTICAL CONSIDERATIONS ................................................................... 28 
13.0  
STUDY MONITORING AND REPORTING PROCEDURES ............................ 29 
14.0 
ELEMENTS OF INFORMED CONSENT ........................................................... 34 
15.0  
ADMINISTRATIVE AND REGULATORY CONSIDERATIONS .................... 34 
Appendix 1: ECOG Performance Status .............................................................................. 39 
Appendix 2: Common Terminology Criteria for Adverse Events V5.0 (CTCAE) .............. 39 
 
 
 
  
 

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1.0 
OBJECTIVES 
 
1.1 
Primary objective: Estimate the marrow minimal residual disease (MRD)-
negative rate by high sensitivity flow cytometry at the end of 4 cycles of therapy 
 
1.2 
Secondary objective: Estimate the 1-year marrow MRD-negative rate, 1-year 
and 3-year PFS, and response rate by IWCLL criteria1. We will also assess the 
MRD conversion rate among those who are MRD-positive after 4 cycles who 
then complete 12 total cycles of treatment. Estimate safety of this regimen as 
defined by the proportion of subjects who experience grade 3+ immune-
mediated adverse events or any grade 5 adverse event possibly related to 
copanlisib 
 
2.0 
BACKGROUND/RATIONALE 
 
Chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL) is a B-cell 
lymphoid neoplasm that is considered to be incurable by standard therapies2. 
Combination chemoimmunotherapy is preferred for the upfront management of 
symptomatic patients without 17p deletion3,4. While treatment with FCR (fludarabine, 
cyclophosphamide, and rituximab) is associated with superior PFS than RB 
(bendamustine, rituximab), FCR is associated increased toxicity3. Moreover, there was 
no observed overall survival (OS) difference between the two with a median 37.1 
months of follow up. MRD by high sensitivity flow cytometry has been found to be an 
independent predictor of PFS in CLL patients treated with chemoimmunotherapy3,5. 
Marrow MRD-negative rates for previously untreated patients treated with RB were 
63% in the CLL10 trial3, and were 7-23% with RB in the relapsed refractory setting6,7. 
In a phase II study of untreated patients with CLL who received up to 6 cycles of RB, 
58% of patients were MRD-negative at the end of the study, and with a median follow 
up of 27 months, median event-free survival (EFS) had not been reached8.  
 
There are several new very effective drugs that have been currently Federal Drug 
Administration FDA approved for the treatment of relapsed/refractory CLL, including 
ibrutinib (BTK-inhibitor)9, venetoclax (BCL2-inhibitor)10, and idelalisib (PI3Kd-
inhibitor)11. Unfortunately, long term treatment with idelalisib has been associated 
with severe cases of immune-mediated grade 3-4 colitis and hepatotoxicity, 
particularly in the front line setting12. In addition, all of these agents are approved for 
treatment until progression, requiring patients to potentially take these agents for years 
with associated cost and toxicity. 
 
In relapsed/refractory CLL patients, the addition of idelalisib to RB was associated 
with improved outcomes.13 With median follow up of 14 months, the idelalisib arm 
had a median progression free survival of 20.8 months vs. 11.1 months in the placebo 
arm. However, serious adverse events like febrile neutropenia, pyrexia, and 
pneumonia were more common in the idelalisib arm. Newer agents like duvelisib14 
and umbralisib15 that target the PI3K pathway are being developed to replicate or 

 Protocol version 3.0 dated 16 October 2020 
 
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improved upon the efficacy of idelalisib with potentially less short and long term 
toxicity. 
 
Copanlisib is a selective pan-class I PI3K inhibitor that has been tested in 
relapsed/refractory non-Hodgkin lymphomas16 and is (FDA) approved for relapsed 
follicular lymphoma. Alterations in PI3K signaling that lead to increased tumor 
growth and survival have been found in numerous malignancies, including 
lymphomas17. Copanlisib is active in relapsed/refractory lymphomas including 
CLL/SLL, and is not associated with colitis and hepatotoxicity like idelalisib16,18,19. 
Efforts are underway to combine copanlisib with standard chemoimmunotherapy in 
relapsed/refractory indolent non-Hodgkin lymphomas20.  
 
Rationale for the Combination of C-RB and abbreviated (4-cycle) therapy in MRD-
negative patients 
 
The combination of copanlisib + RB (C-RB) in a safety run-in study in relapsed 
indolent non-Hodgkin lymphoma (NHL) did not result in any dose limiting toxicities 
(DLTs)21. The standard copanlisib 60 mg dose was recommended for the phase III 
CHRONOS-4 study which is ongoing.  
 
6 cycles of RB has been associated with neutropenia, thrombocytopenia, and 
infections. In addition, prolonged lymphodepletion, including sustained declines in 
CD4+ T cells have been observed22. A randomized trial combining RB with idelalisib 
versus placebo in relapsed CLL found that the idelalisib combination was associated 
with a superior median PFS (20.8 months vs. 11.1 months), but with higher rates of 
grade 3-4 infections (39% vs. 25%)13. Incorporation of MRD analysis may permit 
patient-specific attenuation of chemotherapy risk while preserving efficacy since 
higher MRD-negative rates are associated with improved outcomes8. 
 
Combining copanlisib with a less toxic upfront chemoimmunotherapy regimen like 
RB may improve outcomes while avoiding toxicity associated with more intensive 
regimens like FCR. 
 
Summary of Background/Rationale 
 
Most CLL/SLL patients can achieve durable responses to chemoimmunotherapy and/or 
targeted agents. However, emerging data suggests that patients who attain MRD-
negativity have superior outcomes. However, most targeted agents require indefinite 
treatment which can lead to additional costs and toxicities for patients. We propose a 
combination of the novel PI3K inhibitor copanlisib with the established regimen of 
rituximab and bendamustine which may permit high MRD-negative rates and improved 
patient outcomes.  
 
3.0 DRUG INFORMATION 
 
3.1 Copanlisib   

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3.1.1 Mechanism of action –  
Copanlisib is a novel, selective pan-class I phosphatidylinositol 3-kinase 
(PI3K) inhibitor with predominant activity against the p110α and p110δ-
isoforms23. The PI3K/serine/threonine kinase (AKT)/mammalian target 
of rapamycin (mTOR) pathway has been shown to be involved in cellular 
growth and survival.  Its constitutive activation leads to increased tumor 
growth and survival in numerous malignancies, including lymphomas 
 
3.1.2 Summary of toxicities 
Please refer to the current FDA-approved package inserts or prescriber 
information for complete about possible side effects and instructions for 
preparation, handling, dosing and storage of copanlisib. Common non-
hematologic side effects include hyperglycemia (54%), diarrhea (36%), 
hypertension (35%), and lower respiratory infection (21%). 
 
3.2 Rituximab 
 
3.2.1 Mechanism of action 
 
Rituximab is a monoclonal antibody directed against the CD20 antigen 
on the surface of B-lymphocytes. CD20 regulates cell cycle initiation; 
and, possibly, functions as a calcium channel. Rituximab binds to the 
antigen on the cell surface, activating complement-dependent B-cell 
cytotoxicity; and to human Fc receptors, mediating cell killing through 
an antibody-dependent cellular toxicity 
 
3.2.2 Summary of toxicities 
 
The most common toxicities seen with rituximab are infusion related 
reactions (58%). 7-9% of patients experience Grade 3 or 4 infusion 
reactions. 
 
3.3 Bendamustine 
 
3.3.1 Mechanism of action 
Bendamustine is an alkylating agent (nitrogen mustard derivative) with 
a benzimidazole ring (purine analog) which demonstrates only partial 
cross-resistance (in vitro) with other alkylating agents. It leads to cell 
death via single and double strand DNA cross-linking. Bendamustine is 
active against quiescent and dividing cells. 
 
3.3.2 Summary of toxicity 

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Hematologic toxicity is common, with grade 3-4 adverse events seen in 
98% of patients. Other common side effects include nausea (up to 75%), 
and fatigue (up to 57%). 
 
4.0 
STAGING CRITERIA AND RISK STRATIFICATION 
 
4.1 
The Rai24 and Binet25 Scoring systems will be used to stage patients prior to 
initiation of therapy. Absence of del 17p must be confirmed by testing performed 
before study entry, and after the last line of therapy for relapsed/refractory pts 
(see section 5.2). 
5.0 
ELIGIBILITY CRITERIA 
 
5.1 
Inclusion Criteria 
1. Histologically confirmed, non-17p del CLL/SLL with any of the three 
following conditions: 
a. No prior CLL/SLL directed therapy and Cumulative Illness Rating 
Scale (CIRS) score ≥ 7 
b. Age ≥ 65 
c. At least one prior CLL/SLL directed therapy with any CIRS score 
2. CLL/SLL requiring treatment as defined by at least one of the following 
criteria based on IWCLL 2018 guidelines:  
a. Evidence of progressive marrow failure as manifested by the 
development of, or worsening of, anemia and/or thrombocytopenia  
b. Massive (> 6 cm below left costal margin), progressive or symptomatic 
splenomegaly  
c. Massive nodes (> 10 cm in longest diameter), or progressive or 
symptomatic lymphadenopathy  
d. Progressive lymphocytosis with an increase of > 50% over a 2-month 
period or lymphocyte-doubling time of < 6 months. Lymphocyte-
doubling time may be obtained by linear regression extrapolation of 
absolute lymphocyte counts obtained at intervals of 2 weeks over an 
observation period of 2 to 3 months. In patients with initial blood 
lymphocyte counts of < 30x109/L (30,000/μL), lymphocyte-doubling 
time should not be used as a single parameter to define treatment 
indication. In addition, factors contributing to lymphocytosis or 
lymphadenopathy other than CLL/SLL (eg, infection, steroid 
administration) should be excluded.  
e. Constitutional symptoms, defined as any 1 or more of the following 
disease-related symptoms or signs:  
1. Unintentional weight loss of > 10% within the previous 6 months  
2. Significant fatigue (ie, inability to work or perform usual activities)   
3. Fevers > 100.5° F or 38°C for? 2 weeks without other evidence of 
infection  
4. Night sweats for > 1 month without evidence of infection  
3. ECOG performance status ≤ 2 

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4. Male or female ≥ 18 years of age 
5. Previous exposure to other PI3K inhibitors (except copanlisib) is 
acceptable provided there is no resistance (resistance defined as no 
response (response defined as PR or CR)) at any time during therapy, or 
PD after any response (PR/CR) or after stable disease within 6 months 
from the end of the therapy with a PI3K inhibitor. 
6. Willingness and ability to comply with study and follow-up procedures, 
and give written informed consent 
7. Female subjects of childbearing potential must be surgically sterile, be 
post-menopausal (per institutional guidelines), or must have a negative 
serum pregnancy test within 7 days prior to Cycle 1 Day 1 and agree to use 
medically acceptable contraception throughout the study period and for 4 
months after the last dose of either study drug. Men of reproductive 
potential may not participate unless they agree to use medically acceptable 
contraception throughout the study period and for 4 months after the last 
dose of either study drug.  
8. Patients must be expected to receive at least 2 cycles of therapy. 
9. Patients should have an expected survival if untreated of ≥90 days.  
10. Adequate baseline laboratory values collected no more than 7 days before 
starting study treatment: 
a) Total bilirubin ≤ 1.5 x ULN (< 3 x ULN for patients with Gilbert-
Meulengracht syndrome or for patients with cholestasis due to 
compressive adenopathies of the hepatic hilum). 
b) Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) 
≤ 2.5 x ULN (≤ 5 x ULN for patients with liver involvement by 
lymphoma). 
c) Lipase ≤ 1.5 x ULN. 
d) Glomerular filtration rate (GFR) ≥ 30 mL/min/1.73 m2 according to the 
Modification of Diet in Renal Disease (MDRD) abbreviated formula. If 
not on target, this evaluation may be repeated once after at least 24 
hours either according to the MDRD abbreviated formula or by 24 hour 
sampling. If the later result is within acceptable range, it may be used to 
fulfill the inclusion criteria instead. 
e) International normalized ratio (INR) ≤ 1.5 and partial thromboplastin 
time (PTT) ≤ 1.5 x ULN. PT can be used instead of INR if ≤ 1.5 x ULN 
f) Platelet count ≥ 75,000 /mm3. For patients with confirmed 
lymphomatous bone marrow infiltration, platelet count ≥ 50,000 /mm3.  
g) Hemoglobin (Hb) ≥ 8 g/dL. Packed red blood cell transfusion or 
erythropoietin should not be given less than 7 days before the exam 
collection. 
h) Absolute neutrophil count (ANC) ≥ 1,000/mm3. For patients with 
confirmed lymphomatous bone marrow infiltration, ANC count ≥ 
750/mm3. Myeloid growth factors should not be given less than 7 days 
before the exam collection  
5.2  
Exclusion Criteria 

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Patients who meet any of the following exclusion criteria are not to be enrolled 
to this study:  
1. Presence of chromosome 17p deletion, known p53 deletion, or known p53 
mutation that impairs normal function 
2. Prior treatment including systemic therapy or radiotherapy within 21 days 
of study initiation 
3. Prior treatment with bendamustine within 2 years 
4. Prior treatment with copanlisib 
5. Documented evidence of resistance to prior treatment with idelalisib or 
other PI3K inhibitors defined as: No response (response defined as partial 
response [PR] or complete response [CR]) at any time during therapy, or 
Progression (PD) after any response (PR/CR) or after stable disease within 
6 months from the end of the therapy with a PI3K inhibitor. 
6. Prior treatment including systemic therapy or radiotherapy within 21 days 
of study initiation 
7. Active autoimmune disease or prior autoimmune disease requiring 
systemic immunosuppression within the past 6 months. 
8. Poorly controlled diabetes mellitus defined as hemoglobin A1c > 8.5% 
9. Known lymphomatous involvement of the central nervous system. 
10. Known history of human immunodeficiency virus (HIV) infection. All 
patients must be screened for HIV up to 28 days prior to study drug start 
using a blood test for HIV according to local regulations. 
11. Hepatitis B (HBV) or C (HCV) infection. All patients must be screened for 
HBV and HCV up to 28 days prior to study drug start using the routine 
hepatitis virus laboratorial panel. Patients positive for hepatitis B surface 
antigen (HBsAg) or hepatitis B core antibody (HBcAb) will be eligible if 
they are negative for HBV-DNA, these patients should receive 
prophylactic antiviral therapy. Patients positive for anti-HCV antibody will 
be eligible if they are negative for HCV-RNA. 
12. Previous or concurrent history of malignancies within 3 years prior to 
study. Any exceptions beyond those listed below must be approved by the 
principal investigator: 
a. Cervical carcinoma in situ 
b. Non-melanoma skin cancer 
c. Superficial bladder cancer (Ta [non-invasive tumor], Tis [carcinoma in 
situ] and T1 [tumor invades lamina propria]) 
d. Localized prostate cancer 
13. Active, clinically serious infections (> CTCAE Grade 2). 
14. Known hypersensitivity to any of the study drugs, study drug classes, or 
excipients in the formulation. 
15. Proteinuria of ≥ CTCAE Grade 3 as assessed by a 24 h total urine protein 
quantification or estimated by urine protein : creatinine ratio > 3.5 on a 

 Protocol version 3.0 dated 16 October 2020 
 
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random urine sample. 
16. Unresolved toxicity from prior therapy higher than NCI-CTCAE grade 1 
attributed to any prior therapy/procedure excluding alopecia or sensory 
neuropathy. Concurrent diagnosis of pheochromocytoma. 
17. Pregnant or breast-feeding patients. Women of childbearing potential must 
have a pregnancy test performed a maximum of 7 days before start of 
treatment, and a negative result must be documented before start of 
treatment. 
18. Substance abuse, medical, psychological or social conditions that may 
interfere with the patient’s participation in the study or evaluation of the 
study result. 
19. Congestive heart failure > New York Heart Association (NYHA) class 2. 
20. Unstable angina (angina symptoms at rest), new-onset angina (begun 
within the last 3 months).  
21. Myocardial infarction less than 6 months before start of test drug. 
22. Uncontrolled arterial hypertension despite optimal medical management 
(per investigator’s assessment)  
23. Arterial or venous thrombotic or embolic events such as cerebrovascular 
accident (including transient ischemic attacks), deep vein thrombosis or 
pulmonary embolism within 3 months before the start of study treatment  
24. Non-healing wound, ulcer, or bone fracture. 
25. Patients with seizure disorder requiring medication. 
26. Patients with evidence or history of bleeding diathesis. Any hemorrhage or 
bleeding event ≥ CTCAE Grade 3 within 4 weeks prior to the start of study 
treatment. 
27. Any illness or medical conditions that are unstable or could jeopardize the 
safety of the patients and their compliance in the study. 
28. History of having received an allogeneic bone marrow or organ transplant.  
29. Anti-arrhythmic therapy (beta blockers or digoxin are permitted) 
30. Major surgical procedure or significant traumatic injury (as judged by the 
investigator) less than 28 days before start of treatment, open biopsy less 
than 7 days before start of treatment. 
31. Systemic continuous corticosteroid therapy at a daily dose higher than 15 
mg prednisone or equivalent is not allowed. Patients may be using topical 
or inhaled corticosteroids. Previous corticosteroid therapy must be stopped 
or reduced to the allowed dose at least 7 days performing the screening 
CT/MRI. If a patient is on chronic corticosteroid therapy, corticosteroids 
should be de-escalated to the maximum allowed dose before the screening. 
Patients may be using topical or inhaled corticosteroids. 
32. Use of CYP3A4 inhibitors and inducers (Appendix 4) . Copanlisib is 
primarily metabolized by CYP3A4. Therefore, concomitant use of strong 
inhibitors of CYP3A4 (e.g., ketoconazole, itraconazole, clarithromycin, 
ritonavir, indinavir, nelfinavir and saquinavir), and strong inducers of 

 Protocol version 3.0 dated 16 October 2020 
 
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CYP3A4 (e.g., rifampin, phenytoin, carbamazepine, phenobarbital, St. 
John's Wort) are not permitted from Day -14 of Cycle 1 until the end of 
treatment visit. 
6.0 
REGISTRATION 
 
6.1 
Subjects must be registered prior to the start of protocol therapy. All of the 
eligibility requirements must have been met. 
 
7.0 
TREATMENT PLAN 
 
7.1 
For treatment or dose modification related questions, please contact Dr. Lynch 
(MedCon may also be used to contact MDs at 206-543-5300). 
 
7.2 
Administration of therapeutic agents:  Each cycle of therapy is given every 28 
days. Copanlisib is given on days 1, 8 and 15 at a fixed dose of 60 mg IV per 
standard of care. Copanlisib will be administered in a normal saline solution, 
intravenously, over approximately 1 hour. No intravenous glucose preparations 
should be administered on the days of infusion. No dose should be given if blood 
pressure is ≥ 150/90 mmHg. See section 8.1.6 for details on management of 
blood pressure. Blood pressure should be measured before and after copanlisib 
infusion. See section 9.0 study calendar for details on treatment windows. 
Rituximab should be given on day 1 of each cycle that also includes 
bendamustine. Dosage of rituximab for cycle 1 will be 375 mg/m2 IV, and will 
increase to 500 mg/m2 IV for subsequent cycles per standard of care. 
Bendamustine will be given on days 1 and 2 of each cycle at 90 mg/m2. 
Infusional details should be as per institutional standard of care. The order of 
administration should be copanlisib, followed by rituximab (pre-medications for 
rituximab should be given after completion of copanlisib), followed by 
bendamustine.  Further recommendations are listed in section 8. Copanlisib 60 
mg IV will be defined as dose level 1, but may be decreased as outlined in table 
1, table 2, and section 8.  
 
Subjects should proceed with copanlisib dosing for cycles 7-12 at the same 
dose level that was administered during cycle 6 according to table 2. Dose 
level -1 and -2 are identical in the maintenance phase for cycle 7-12. If further 
decrease in copanlisib dosing is required based on toxicity beyond dose level -
1/-2, copanlisib should be permanently discontinued. 
 
Treatment with standard agent bendamustine will be prioritized for cycles 1-6. 
For example. If a subject on day 1 or 2 of cycles 2-6 requires a hold of 
copanlisib, but is but does not have bendamustine-related toxicity that would 
preclude treatment, the bendamustine (and rituximab) should be administered 
per the schedule and copanlisib dosing skipped without being replaced. 
Copanlisib can be resumed according the cycle schedule if/when the toxicity 
resolves to allow further dosing per Section 8. Patients must receive at least 4 

 Protocol version 3.0 dated 16 October 2020 
 
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cycles of bendamustine in order to proceed to cycle 5. Subjects with at least a 
partial response and MRD-positive disease after cycle 4 who require 
discontinuation of bendamustine due to toxicity may continue with the other 
study agents per protocol from cycle 5 onward 
 
Section 8.3 discusses bendamustine dose modifications which may include 
discontinuation of this drug while continuing other study agents. 
 
 
Drug 
Dose 
Route 
Days 
Dose level 
(Copanlisib 
only) 
Copanlisib 
60 mg 
IV 
Days 1, 8, 15 
1 
Copanlisib 
45 mg 
IV 
Days 1, 8, 15 
-1 
Copanlisib 
45 mg 
IV 
Days 1, 15 
-2 
 
 
 
 
 
Rituximab 
375 mg/m2 (500 
mg/m2 from 
cycle 2 onward) 
IV 
Day 1 
 
Bendamustine 
90 mg/m2 
IV 
Days 1, 2 
 
 
Table 1: Drugs and dosage schedule for proposed study with 28 day cycle length for 
cycles 1-6. * Copanlisib may be decreased to dose level -1 or dose level -2 as outlined 
in section 7.2 and section 8. 
 
Drug 
Dose 
Route 
Days 
Dose Level 
Copanlisib 
60 mg 
IV 
Days 1, 15 
1 
Copanlisib 
45 mg 
IV 
Days 1, 15 
-1 
Copanlisib 
45 mg 
IV 
Days 1, 15 
-2 
 
Table 2: Drugs and dosage schedule for proposed study with 28 day cycle length for 
cycles 7-12. *Copanlisib may be decreased to dose level -1 or dose level -2 as outlined 
in section 7.2 and section 8. Subjects should proceed with dosing for cycles 7-12 at the 
same dose level that was administered during cycle 6. Dose level -1 and -2 are 
identical in the maintenance phase for cycle 7-12. If further decrease in copanlisib 
dosing is required based on toxicity beyond dose level -1/-2, copanlisib should be 
permanently discontinued. 
 
7.2.1 Guidelines 
for 
administration 
of 
copanlisib, 
rituximab, 
and 
bendamustine 
 
• Method of Administration: Copanlisib, rituximab, and bendamustine will be 
administered intravenously on the schedule outlined above.  
• Potential Drug Interactions: Copanlisib is primarily metabolized by 
CYP3A4. Therefore, concomitant use of strong inhibitors of CYP3A4 (e.g., 

 Protocol version 3.0 dated 16 October 2020 
 
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ketoconazole, itraconazole, clarithromycin, ritonavir, indinavir, nelfinavir 
and saquinavir), and strong inducers of CYP3A4 (e.g., rifampin, phenytoin, 
carbamazepine, phenobarbital, St. John's Wort) are not permitted from Day 
-14 of Cycle 1 until the safety follow-up visit. Subjects who require one of 
these agents during the course of treatment should be removed from the 
protocol. 
• Prophylaxis: Patients are required to start prophylaxis treatment with 
Pneumocystis jiroveci pneumonia (PCP) and antiviral therapy prior to cycle 
1 day 1: 
o Anti-viral Prophylaxis: Valtrex 500 mg daily or Acyclovir 800 mg PO 
daily. 
o PCP Prophylaxis: Dapsone 100 mg daily or TMP-SMZ 160/800 mg PO 
daily 3 times per week, or twice daily 2 times per week. 
o NOTE:  If PCP or anti-viral therapy is not tolerated, alternate to a 
different PCP or anti-viral therapy, discontinue, or reduce dose/schedule 
as per investigator discretion. 
 
7.2.2 Laboratory criteria for treatment:  Laboratory criteria for cycle 1 day 1 
must meet inclusion criteria outlined in section 5.1. The below criteria 
must be met on day 1 from cycle 2 onward in order to proceed with 
treatment 
 
Laboratory test 
Criteria for day 1 dose (cycle 2 and higher) 
Glucose 
< 160 mg/dL (fasting) or < 200 mg/dL (non-
fasting) 
Hemoglobin 
≥ 8 g/dLa 
ANC 
≥ 1,000/mm3 or return to baseline 
Platelets 
≥ 75,000/mm3 e or return to baseline 
ALT 
< 2.5 x ULN b 
AST 
< 2.5 x ULN c 
Total bilirubin 
within normal limits d 
GFR (MDRD) 
≥ 40 mL/min/1.73 m2 
 
 
Table 3: Laboratory test criteria for day 1 dosing for cycle 2 and 
higher. Abbreviations: ALT = Alanine aminotransferase; ANC = 
Absolute neutrophil count; AST = Aspartate aminotransferase; GFR = 
Glomerular filtration rate; MDRD = Modification of Diet in Renal 
Disease; ULN = Upper limit of normal. 
 

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a: If hemoglobin is < 8 g/dL but ≥ 6 g/dL on the day of planned study drug 
administration it is permissible to give the study drug dose as scheduled and transfuse 
within 48 hours after the dose, if the subject is hemodynamically stable and in opinion 
of investigator benefits outweigh risks. Rationale and treatment should be recorded in 
source document. 
b: < 5 x ULN in subjects with documented liver involvement by lymphoma or with 
biliary obstruction due to lymphoma.  
c: < 5 x ULN in subjects with documented liver involvement by lymphoma or with 
biliary obstruction due to lymphoma.  
d: < 3 x ULN in subjects with Gilbert-Meulengracht syndrome, subjects with 
cholestasis due to compressive adenopathies of the hepatic hilum or documented liver 
involvement by lymphoma.  
e: For subjects with lymphomatous bone marrow infiltration at study entry (local 
assessment), platelet count ≥ 50,000/mm3. This value should be used throughout the 
study irrespective of bone marrow status changes. Platelet transfusion should not be 
given less than 7 days before the exam collection. 
 
 
7.2.3 Additional criteria for administration of copanlisib based on glucose level 
Period 
Fasting ≥ 8 hours 
required before first 
glucose measurements 
Pre-dose glucose 
levels (first glucose 
measurement) 
Fasting required 
before study drug 
infusion 
Day 1 of cycle 1 
Yes 
≤ 125 mg/dL (non-
diabetic subjects)  
< 160 mg/dL (diabetic 
subjects) 
Yes d 
Day 1 of 
subsequent cycles 
Conditional a, d, e 
< 160 mg/dL (fasting)  
< 200 mg/dL (non-
fasting) c 
Conditional a, d, e 
Days 8 and 15 of 
each cycle b 
No 
< 160 mg/dL (fasting)  
< 200 mg/dL (non-
fasting) 
Conditional a, d, e 
 
Table 4:  Fasting requirements and pre-dose glucose levels 
 
a: The decision regarding meal timing and fasting can be made by the investigator 
based on the glucose response patterns during prior treatment days. (see text below 
“Recommendations on meal timing on infusion days” for further details).  
b: Day 8 is not applicable during Cycles 7-12 
c: In case of non-compliance with the fasting requirement.  
d: Diabetic subjects who take insulin treatment at any cycle visit: Timing and content 
of caloric intake on infusion days will be managed and monitored by the investigator. 
Consultation with treating physician or diabetes specialist is advised.  
e: A low glycemic index meal may be taken at least 4 h before the start of the 
copanlisib infusion for subjects who have their infusions scheduled at a later hour, or 
due to their age or medical condition when fasting prior to infusion is not viable. 
 

 Protocol version 3.0 dated 16 October 2020 
 
Page 15 of 40 
 
 
7.3 
Growth factor support: will be at the discretion of the treating team. Growth 
factors should be avoided whenever possible within 10 days of FDG-PET 
imaging. Antibiotic and antiemetic prophylaxis will be per institutional standard 
of care however PJP and anti-viral prophylaxis is required per standard of care 
during treatment with copanlisib in combination with bendamustine (see Section 
7.2.1). Prophylaxis should continue for duration of copanlisib maintenance as 
well. 
 
7.4 
Criteria for removal from protocol treatment 
 
7.4.1 Documented progression of disease by IWCLL 2018 criteria (see 
appendix 3)1,26  
 
7.4.2 If at any time the constraints of this protocol are detrimental to the 
subject’s health and/or the subject no longer wishes to continue 
protocol therapy, protocol therapy shall be discontinued, the study chair 
shall be notified, and the reason for discontinuation shall be 
documented. 
 
7.4.3 Delay of treatment for more than 4 weeks due to related adverse events 
unless prophylactic measures can be taken for subsequent cycles.   
 
7.4.4 
The subject may withdraw from the treatment at any time for any 
reason. 
 
8.0 
DOSAGE MODIFICATIONS 
 
8.1 
Dose modification of copanlisib 
 
8.1.1 Hematological toxicity 
 
Neutropenia and febrile neutropenia are listed in the current version of IB as 
expected adverse events. If the guidelines given in table 5 are not followed, the 
rationale for other measures is to be documented in detail in the subject’s 
medical record. The use of myeloid growth factors in the therapeutic setting is 
allowed during study treatment at investigator’s discretion 
 
Hematological toxicity (any of the following) 
Study treatment action 

 Protocol version 3.0 dated 16 October 2020 
 
Page 16 of 40 
 
CTCAE Grade ≥ 3 thrombocytopenia 
Delay infusion until criteria in table 
displayed in table 3 are met.c,d  
Febrile neutropenia or ANC < 500/mm3 a 
INR or PTT CTCAE Grade ≥ 3 with bleeding b 
CTCAE Grade ≥ 3 anemiad 
 
Table 5: Dose modifications of copanlisib for hematological toxicity 
ANC = absolute neutrophil count; CTCAE = Common Terminology Criteria of 
Adverse Events, version 4.03; Hb = hemoglobin; INR = international normalized ratio; 
PTT = partial thromboplastin time; G-CSF = Granulocyte colony-stimulating factor  
a: These subjects should recover from neutropenia to ANC ≥ 500/mm3 without fever. 
G-CSF should be prescribed when ANC is < 1000/mm3 as per label.  
b: International normalized ratio (INR) and partial thromboplastin time (PTT) should 
have returned to ≤ 1.5 and ≤ 1.5 x ULN, respectively, with no signs of bleeding.  
c: After having fully recovered from toxicity and in the absence of any criteria for 
further dose reduction or study drug discontinuation, re-escalation is allowed at the 
investigator’s discretion.  
d: Treatment with transfusion is allowed at the investigator’s discretion 
 
8.1.2 Non- hematological toxicity 
Dose modification guidelines for non-hematologic toxicities attributable 
to copanlisib except for glucose increases, dermatologic toxicity, non-
infectious pneumonitis and blood pressure increases are outlined in table 
6.   
 
  
Study drug action 
Toxicity a 
Occurrence 
For current course of therapy 
For next course of therapy 
Grade 1-2 
Any appearance 
No change 
No change 
Grade 3 b 
1st appearance 
Interruption until grade ≤ 2 
No change 
  
2nd appearance 
Interruption until grade ≤ 2 
Decrease to dose level -1 
  
3rd appearance 
Interruption until grade ≤ 2 
Decrease to dose level -2 
  
4th appearance 
Permanent discontinuation 
- 
Grade 4 
Any appearance 
Permanent discontinuation 
- 
Toxicity requiring delay > 28 
days 
Permanent discontinuation 
- 
 
Table 6: Dose modification of copanlisib for non-hematological toxicity 
(except glucose increases, dermatologic toxicity, non-infectious 
pneumonitis and blood pressure increases) 
a: Toxicities according to CTCAE version 5.0  
b: Despite maximum supportive therapy 
 
8.1.3 Dermatologic toxicity 

 Protocol version 3.0 dated 16 October 2020 
 
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The guidelines for dose modifications in cases of dermatologic toxicity 
are outlined in table 7. If these guidelines are not followed, the rationale 
for other measures will be documented in detail in the subject’s medical 
record.  
 
 
Study drug action 
Toxicity a 
Occurrence 
For current course of therapy 
For next course of therapy 
Grade 1 
Any appearance 
No change 
No change 
Grade 2 b 
1st appearance 
Interruption until grade ≤ 2 
No change 
 
2nd appearance 
Interruption until grade ≤ 2 
Decrease to dose level -1 
 
3rd appearance 
Interruption until grade ≤ 2 
Decrease to dose level -2 
 
4th appearance 
Permanent discontinuation 
- 
Grade 3 
1st appearance 
Interruption until grade ≤ 2 
Decrease to dose level -1 
 
2nd appearance 
Interruption until grade ≤ 2 
Decrease to dose level -2 
 
3rd appearance 
Permanent discontinuation 
- 
Grade 4 
Any appearance 
Permanent discontinuation 
- 
Toxicity requiring delay > 28 
days 
Permanent discontinuation 
- 
 
 
 
 
Table 7: Dose modification of copanlisib for dermatologic toxicity 
 
 
 
a: Toxicities according to CTCAE version 5  
b: Despite maximum supportive therapy 
 
8.1.4 Non-infectious pneumonitis (NIP) 
 
In the event of suspected NIP, copanlisib treatment should be followed as Table 
8. Pneumonitis is to be reported as such only in the event of NIP 
 
Suspected or confirmed 
NIP per CTCAE 
Action taken 
Re-treatment dose 
after recovery 
Grade 1 
No change 
NA 
Grade 2 
Dose interruptions until recovery to grade 0-1 
Decrease to dose 
level -1 
Grade 2 second recurrence 
Permanent discontinuation 
NA 
Grade 3 
Permanent discontinuation 
NA 
Grade 4 
Permanent discontinuation 
NA 
 
Table 8: Dose adjustment in cases of NIP 
 
8.1.5 Glucose increases 
Patients who develop transient post-infusion glucose > 250 mg/dL after 
copanlisib administration may continue treatment. However, the next 

 Protocol version 3.0 dated 16 October 2020 
 
Page 18 of 40 
 
infusion must be delayed until the subject’s pre-infusion glucose levels 
return to < 160 mg/dL (fasting) or < 200 mg/dL (non-fasting). Guidelines 
for the management of glucose increases are given in section 8.1.7 
 
• Continuing occurrence of post-infusion blood glucose > 400 
mg/dL based on repeated laboratory analysis despite optimal 
glucose lowering therapy after 2 infusions of copanlisib will 
require dose reduction to next lowest dose level  
• Further dose reduction is allowed as long as discontinuation 
criteria was not met.  
• Dose re-escalation is allowed when a subject has achieved 
controlled glucose levels per investigator’s judgment.  
• Persistent occurrence of post-infusion blood glucose > 400 
mg/dL based on laboratory analysis which occurred at the lowest 
copanlisib dose level despite optimal glucose lowering therapy 
(after at least one cycle of treatment) with consultation of a 
diabetes specialist requires permanent discontinuation of the 
study treatment 
 
8.1.6 Arterial hypertension 
 
No dose should be given if blood pressure is ≥ 150/90 mmHg. 
Antihypertensive medication may be given to control the increased blood 
pressure. The phase I study of copanlisib suggested the benefit of 
dihydropyridine calcium channel blockers (amlodipine or felodipine). 
Dosing can proceed on the scheduled day if there are at least 2 
consecutive measurements < 150/90 mmHg. Otherwise dosing must be 
delayed. If drug-related arterial hypertension (post-dose blood pressure 
of CTCAE Grade 3 or ≥ 160/100 mmHg) is not manageable with optimal 
antihypertensive treatment, the dose for the subsequent copanlisib 
administrations may be reduced by 1 or 2 dose levels at the investigator’s 
discretion. Treatment of increased blood pressure should be personalized 
for each subject. For those with pre-existing hypertension, subjects 
should take their usual doses on the day of copanlisib infusion. Patients 
with a post-dose blood pressure that may have life-threatening 
consequences (e.g. malignant arterial hypertension, transient or 
permanent neurologic deficit, hypertensive crisis) must permanently 
discontinue the study drug. The guidelines for dose modifications of 
study treatment in case of arterial hypertension are given in table 9. 
Toxicity (CTCAE severity 
grade) 
Study drug action 
Recommendation 

 Protocol version 3.0 dated 16 October 2020 
 
Page 19 of 40 
 
Pre-dose measurements BP ≥ 
150/90 mmHg 
No dose should be given 
until recovery to < 150/90 
mmHg.  
Consider administering BP lowering 
medication. Dosing can proceed on 
the scheduled day if after at least 2 
consecutive measurements BP returns 
to < 150/90 mmHg. If BP doesn’t 
return to < 150/90 mmHg then delay 
dosing until next visit. 
During infusion: BP ≥ 160/100 
mmHg or CTCAE hypertension 
of grade 3 
Infusion can be 
interrupted or slowed 
down and administration 
of BP lowering therapy 
should be initiated. 
Infusion may be resumed immediately 
when BP has returned to < 150/90 
mmHg or otherwise skipped. 
Subsequent study drug administrations 
may be reduced by one dose level at 
the investigator’s discretionb. 
Post-dose: Drug related BP of ≥ 
160/100 mmHg a or CTCAE 
hypertension of grade 3 
- 
Administration of BP lowering 
therapy should be initiated according 
to local standard of care. Additional 
measurements to be performed as 
clinically indicated until recovery to < 
150/90 mmHg. Subsequent study drug 
administrations may be reduced by 
one dose level at the investigator’s 
discretionb. 
CTCAE hypertension of grade 4 
Permanent 
discontinuation 
- 
 
Table 9: Dose modification of study treatment for arterial hypertension 
BP = Blood pressure; CTCAE severity grade = Common Terminology Criteria for 
Adverse Events severity grade  
a: Not manageable despite optimal antihypertensive treatment.  
b: The lowest dose level is -2; if a subject is already on the lowest dose level and 
experiences post-dose hypertension of CTCAE Grade 3 or ≥160/100 mmHg, consider 
more intensive therapy than previously used. 
 
Blood pressure should also be monitored on infusion days as indicated 
below: 
 
• Blood pressure will be measured until there are two consecutive 
results < 150/90 mmHg. Provider should be notified for further 
instructions if two consecutive readings in range cannot be obtained 
after 4 measurements have been taken. The subject should rest for 
5-10 minutes before blood pressure is recorded. If blood pressure is 

 Protocol version 3.0 dated 16 October 2020 
 
Page 20 of 40 
 
≥ 150/90 mmHG, the investigator can consider a medical 
intervention or delaying the infusion of study drug. 
• On infusion days: blood pressure will be measured at pre-dose, 30 min 
(mid infusion), and 60 min (end of infusion). Note: a time window of 
±10 min is allowed for all BP measurements, except for the pre-dose 
measurement. Pre-dose measurement should be taken as close to the 
start of the drug infusion as possible – if there are delays in initiating 
copanlisib infusion of more than one hour since last reading, consider 
repeating blood pressure measurement. 
• In addition, blood pressure will be measured 30 minutes after the start 
of rituximab infusion and at the end of rituximab infusion (deviation of 
± 5 minutes is allowed) from Cycle 1 to Cycle 6. 
 
 
 
8.1.7 Management of transient post-infusion glucose increases that can occur 
with copanlisib 
 
Mild to moderate asymptomatic increases of blood glucose may occur 
with copanlisib infusion, and with larger increases potentially occurring 
post-prandially. The guidelines for management of transient post-
infusion glucose increases on infusion days are given in table 10. 
 
 

 Protocol version 3.0 dated 16 October 2020 
 
Page 21 of 40 
 
 
Criteria 
Recommendation 
Glucose increase of 
CTCAE Grade 1 
Continue study treatment 
Glucose increase of 
CTCAE Grade 2 
Hydration as clinically indicated. When planning next infusion 
prophylaxis with oral glucose lowering medication per standard of 
care. Consultation with endocrinologist for diabetic patients is 
recommended 
Glucose increases of 
Grade 3 or 4 
Hydration as clinically indicated (orally, IV). Insulin therapy per 
local standard of care. When planning next infusion consider 
prophylaxis with oral glucose lowering medication per local 
standard of care. Consultation with endocrinologist is recommended 
 
 
 
Table 10: Management of transient post-infusion glucose increases 
 
 
8.2 
Rituximab dose modification steps: Infusion related reactions and toxicities 
should be managed per prescriber information institutional standard of care. Pre-
medication prior to rituximab should also be administered per institutional 
standard of care. Recommendations include acetaminophen 650 mg PO and 
diphenhydramine 25 mg PO. Additional pre-medications may be given for 
subsequent cycles per institutional standard of care, including corticosteroids. If 
the investigator does not believe a rituximab infusion can be safely completed 
due to an infusion reaction, it may be omitted for that cycle and resumed for the 
subsequent cycle with adequate pre-medications. 
 
8.3 
Bendamustine dose modification steps: All subjects who meet inclusion criteria 
should start with standard dose of 90 mg/m2 on day 1 and 2. Toxicities should 
be managed per prescriber information and institutional standard of care.  Dose 
reduction to 60 mg/m2 is proposed as the first dose reduction, when needed. 
Patients who do not meet criteria listed in table 3 due to hematologic toxicity 
may have future doses of bendamustine reduced at investigator discretion. This 
may include discontinuation of bendamustine and continuation of the other 
study medications from cycle 5 onwards. 
 
8.4 
Concomitant therapy  
Medications used during the course of the study will be documented. 
 
8.4.1 
Prohibited Concomitant Therapy: The administration of concurrent 
medications intended to treat the primary cancer are not allowed during 

 Protocol version 3.0 dated 16 October 2020 
 
Page 22 of 40 
 
protocol therapy.  This includes any chemotherapy, investigational 
agent, biologic agent or other anti-tumor agents.  Radiation therapy is 
also prohibited. 
 
8.4.2 
Patients should be strongly discouraged from taking any “alternative” 
or “naturopathic” medications since these agents may interfere with 
metabolism of study medications. 
 

Protocol version 3.0 dated 16 October 2020 
 
Page 23 of 40 
 9.0 
STUDY CALENDAR  
 
  
  
  
Screening 
Treatment during combination therapy (C1-C6) 
  
 
  
  
Cycle 1 
Cycle 2 to Cycle 4 
Cycle 5 to Cycle 6 
  
 
Days 
D-42 to 
D-1 
D1 
D2 
D8 
D15 
D1 
D2 
D8 
D15 
D1 
D2 
D8 
D15 
Treatment window 
  
+/- 3 days 
  
+/- 2 days 
+/- 3 days 
  
+/- 2 days 
+/- 3 days 
  
+/- 2 days 
Patient informed consent 
X 
  
  
  
  
  
  
  
  
  
  
  
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Performance Status 
X 
X 
  
X 
X 
X 
  
  
  
X 
  
  
  
Clinic evaluation/physical exama 
X 
X 
  
X 
X 
X 
  
  
  
X 
  
  
  
Concomitant Medication Assessment 
X 
X 
  
X 
X 
X 
  
  
  
X 
  
  
  
Toxicity/AE assessment 
X 
X 
  
X 
X 
X 
  
  
  
X 
  
  
  
CT/tumor evaluationb 
X 
  
  
  
  
  
  
  
  
X 
  
  
  
Bone marrow biopsy and aspirateb 
X 
  
  
  
  
  
  
  
  
X  
  
  
  
Tumor chromosomal analysisc 
X 
  
  
  
  
  
  
  
  
  
  
  
  
12-lead EKG 
X 
  
  
  
  
  
  
  
  
  
  
  
  
Lab/monitoring 
  
Screening labsd 
X 
  
  
  
  
  
  
  
  
  
  
  
  
Complete blood count with 
differential 
X 
X 
  
  
  
X 
  
  
  
X 
  
  
  
Comprehensive metabolic panell 
X 
X 
X  
  
  
X 
  
  
  
X 
  
  
  
LDH, uric acid, phosphorus 
X 
X 
X 
 
 
 
 
 
 
 
 
 
 
Glucosee 
X 
X 
  
X 
X 
X 
  
X 
X 
X 
  
X 
X 
Blood pressuref 
X 
X 
  
X 
X 
X 
  
X 
X 
X 
  
X 
X 
Drug administration 
  
Rituximab 
  
X 
  
  
  
X 
  
  
  
X 
  
  
  
Bendamustine 
  
X 
X 
  
  
X 
X 
  
  
X 
X 
  
  
Copanlisib 
  
Xk 
  
Xk 
Xk 
Xk 
  
Xk 
Xk 
Xk 
  
Xk 
Xk 
 
 
 

 Protocol version 3.0 dated 16 October 2020 
 
Page 24 of 40 
 
 
  
  
  
Treatment 
EOT 
Survival 
FU 
  
 
  
Cycle 7-12 
Within 14 
days of 
cycle 12 
day 15 or 
within 7  
days after 
decision 
to stop 
treatment 
g 
Per 
institutional 
guidelinesh 
  
 
Days 
D1 
D15 
Treatment window 
+/- 3 days 
Patient informed consent 
  
  
  
  
Performance Status 
X 
 
X 
  
Clinic evaluation/physical exama 
X 
 
X 
  
Survival status 
  
  
  
X 
Concomitant Medication 
Assessment 
X 
 
X 
  
Toxicity/AE assessment 
X 
 
X 
  
CT/tumor evaluationb 
  
  
Xg 
 Xi 
Bone marrow biopsy and aspirate 
  
  
X 
  
Lab/monitoring 
  
Complete blood count with 
differential 
X 
  
X 
  
Comprehensive metabolic panell 
X 
  
X 
  
Glucosee 
X 
X 
X 
  
Blood pressuref 
X 
X 
X 
  
Drug administration 
  
Copanlisib 
X 
X 
  
  
 
Abbreviations: AE = Adverse event; C = Cycle; CMV = cytomegalovirus; CT = Computed tomography; D = Day; EKG = Electrocardiogram; EOT = End of treatment; FU = 
Follow up; HCV = Hepatitis C virus, HIV = Human immunodeficiency virus; MRD = minimal residual disease; PCR = polymerase chain reaction 
a: Patient may be seen on additional treatment days at provider discretion for evaluation/management of toxicity. 
b: Baseline bone marrow biopsy/aspirate and diagnostic CT of the neck, chest, abdomen, and pelvis should be performed at screening within 42 days of cycle 1 day 1. For interim 
response assessment, this may be performed any time after cycle 4 day 15 copanlisib infusion, and cycle 5 day 1. As part of this evaluation, a bone marrow biopsy/aspirate with 
MRD testing by flow cytometry and diagnostic CT neck (if involved), chest, abdomen, and pelvis is also required.   Patients will continue on treatment for cycle 5-12 if an MRD 

 Protocol version 3.0 dated 16 October 2020 
 
Page 25 of 40 
 
negative CR in the marrow is not achieved BUT has achieved at least a partial response to treatment. For those completing treatment through cycle 12, a repeat bone marrow 
biopsy/aspirate with marrow MRD testing by flow cytometry and diagnostic CT neck (if involved), chest, abdomen, and pelvis should be performed. Subjects with an MRD-
negative complete response in the marrow should discontinue further treatment. In these patients, an optional repeat bone marrow MRD assessment should be performed 1 year 
(+/- 14 days) after initial assessment. 
c: At a minimum this should include analysis for alterations in chromosome 17p. Previous testing is accepted as long as an original report is available. Additional abnormalities if 
analyzed will be recorded and presented, but are not mandatory 
d: Labs within screening window include: HBsAg, HBcAb, anti-HCV antibody, HIV test, serum pregnancy test (if female of child-bearing potential), GFR calculation (MDRD 
abbreviated formula, may be repeated one time if not within target range or verified with 24 hour urine collection), CMV PCR, hemoglobin A1c, PTT, PT/INR, lipase, quantitative 
immunoglobulins, complete blood count with differential, comprehensive metabolic panel, and random urine protein/creatinine ratio. If hepatitis B, C, or HIV testing screens 
positive, this may be confirmed by viral PCR. Patients with positive HBcAb should receive viral prophylaxis per institution standard of care. Repeat CMV PCR testing is not 
required unless clinically indicated.  
e: On day 1 of cycle 1-6, glucose will be measured at pre-dose (can use results from metabolic panel if performed the same day, and post dose of copanlisib administration. 
Glucose should also be checked after rituximab administration as well as bendamustine administration. On days where copanlisib alone is administered, pre-dose and post dose 
glucose testing should be performed. On day 2 of cycle 1-6, glucose will only need to be monitored if corticosteroid pre-medications are administered. See sections 8.1.5 and 8.1.7 
for more information. 
f: See section 8.1.6 for instructions on monitoring of blood pressure. 
g: A diagnostic CT should be performed to confirm progression prior to an end of treatment visit. However, it does not need to be within 7 days of an EOT visit. For those 
completing 12 cycles of treatment, a bone marrow biopsy/aspirate with MRD testing by flow cytometry and diagnostic CT neck (if involved), chest, abdomen, and pelvis should be 
performed for final response assessment. 
h: Patients will receive surveillance and clinical follow up per institutional standard of care. This may include having follow up care at a different oncology clinic. We will 
periodically assess for survival status (remotely if necessary) until up to 3 years after completion of the study treatment. 
i: For those who are MRD negative in the marrow after cycle 4, an optional repeat bone marrow MRD assessment should be performed 1 year (+/- 14 days) after initial assessment. 
j: This may be waived in cases of EOT for clear progression of disease either by laboratory testing or CT imaging. 
k: There must be at least 7 days between each consecutive infusion of copanlisib. 
l: Components of the comprehensive metabolic panel include sodium, potassium, chloride, bicarbonate/CO2, glucose, BUN, creatinine, calcium, AST, ALT, alkaline phosphatase, 
total bilirubin, total protein, and albumin. 
 

Protocol version 3.0 dated 16 October 2020 
 
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10.0 STUDY PROCEDURES 
 
10.1 Screening  
 
After signing consent, subjects should have laboratory testing (see section 9.0 for 
details, EKG, bone marrow biopsy/aspirate, and tumor evaluation. Additional detail is 
listed in section 9.0. Prophylaxis for tumor lysis syndrome with allopurinol or 
equivalent may be administered at the discretion of the investigator. 
 
10.2 Cycle 1, Day 1, 2 
 
On day 1, clinic evaluation/exam, performance status evaluation, concomitant 
medication assessment, laboratory testing, blood pressure, and toxicity AE assessment 
should be performed. Patients should fast prior to cycle 1 day 1, but fasting on 
subsequent days is at the discretion of the investigator based on any hyperglycemia seen 
after the first copanlisib infusion. Laboratory values should meet criteria listed in section 
5.1 and 7.2.3. See section 7.2 for additional details on administration of therapeutic 
agents. On day 1 the order of administration should be copanlisib, followed by rituximab 
(pre-medications for rituximab should be given after completion of copanlisib), 
followed by bendamustine.  Of note, rituximab dosing for cycle 1 is 375 mg/m2. Blood 
pressure should be monitored as outlined in section 8.1.6. Glucose will be measured at 
pre-dose of copanlisib (can use results from metabolic panel if performed the same day), 
and post dose of copanlisib administration. This can be done with point of care testing. 
On day 2, no clinic assessment is required per protocol prior to bendamustine 
administration, though laboratory monitoring for tumor lysis syndrome will be 
performed in cycle 1 only. Additional laboratory monitoring beyond what is mandated 
by the protocol may be ordered at the discretion of the investigator. 
 
10.3 Cycles 1 day 8, 15 
 
Subjects will have a clinic evaluation/exam, performance status evaluation, concomitant 
medication assessment, laboratory testing, blood pressure, and toxicity AE assessment. 
Fasting is conditional on previous episodes of hyperglycemia. Rituximab dosing 
increases to 500 mg/m2 from cycle 2 onwards. Blood pressure should be monitored as 
outlined in section 8.1.6. Glucose will be measured at pre-dose of copanlisib (can use 
results from metabolic panel if performed the same day), and post dose of copanlisib 
administration. Glucose should meet criteria listed in section 7.2.3 
 
10.4 Cycles 2-4 
 
Subjects will have a clinic evaluation/exam, performance status evaluation, concomitant 
medication assessment, laboratory testing, blood pressure, and toxicity AE assessment 
on day 1 of each cycle. Additional evaluations on other infusion days are at the 
discretion of the investigator. Laboratory values must be adequate as outlined in section 
7.2.2. Glucose should be monitored as on previous cycles/treatment days of copanlisib 
administration and treatment altered as outlined in section 7.2.3. After cycle 4 day 15, 

 Protocol version 3.0 dated 16 October 2020 
 
Page 27 of 40 
 
but prior to cycle 5 day 1, all subjects will undergo a bone marrow biopsy/aspirate with 
MRD evaluation, as well as a CT scan of the neck (if previously involved), chest, 
abdomen, and pelvis. Subjects with a complete response and MRD negativity (using  
10-4 as the threshold) will not receive further therapy and will undergo observation per 
institutional guidelines. Those who are MRD positive and with IWCLL response of 
stable disease or better may continue on study for cycles 5-12. Those with progressive 
disease should come off study to receive alternate therapy. Subjects with failed MRD 
testing or an indeterminate result should receive additional therapy on study at the 
discretion of the investigator after reviewing other response assessments including CT 
scans and complete blood counts with differential. Options include but are not limited 
to completing all 12 cycles of therapy, discontinuing therapy with copanlisib after 6 
cycles (so that a full course of standard therapy is administered), or coming off protocol 
to receive additional treatment at the discretion of the treating physician. 
 
10.5 Cycles 5-6  
 
Study procedures for cycles 5-6 should proceed identically to those in cycles 2-4 as 
outlined in section 9.0 and 10.4. Only patients with MRD-positive disease in the marrow 
and at least a partial response by IWCLL criteria should proceed with cycle 5 onwards. 
Subjects with stable disease or progressive disease should discontinue protocol therapy. 
Since the marrow is more sensitive for MRD, the MRD testing in the marrow will be 
used to adapt therapy27. We will use < 10-4 as our threshold for MRD-negativity28. No 
MRD assessment, CT evaluation, or response assessment is required at the completion 
of cycle 6. Bendamustine may be discontinued from cycle 5 onward due to toxicity at 
the discretion of the investigator. Subjects who require discontinuation of bendamustine 
prior to administration of at least 4 doses should be taken off protocol 
 
10.6 Cycle 7-12 
 
Starting with cycle 7, patients will no longer receive rituximab or bendamustine. 
Subjects will have a clinic evaluation/exam, performance status evaluation, concomitant 
medication assessment, laboratory testing, blood pressure, and toxicity AE assessment 
on day 1 of each cycle. Additional evaluations are optional. Copanlisib will be 
administered on days 1 and 15 with identical lab, glucose, and blood pressure 
requirements as outlined in sections 7.2.3, 8.1.6, and 9.0. 
 
10.7 EOT assessments/follow up 
 
Follow up after completion of study treatments should be performed per standard of 
care. Patients completing 12 cycles of treatment should have a repeat bone marrow 
MRD performed within 14 days of cycle 12 day 15. Survival data should be collected 
up to 3 years after completion of study. Subjects who are MRD-negative after 4 cycles 
should have an optional repeat bone marrow MRD assessment at 1 year (+/- 14 days) 
after completion of the previous assessment. Patients may follow with another 
oncologist if it is more convenient, with the study team periodically contacting them for 
updated information on survival and disease status. 

 Protocol version 3.0 dated 16 October 2020 
 
Page 28 of 40 
 
 
11. 0 CRITERIA FOR EVALUATION AND ENDPOINT DEFINITIONS 
 
Definitions of Disease, Criteria for Evaluation and Endpoint Definitions – response will 
be defined by standard IWCLL 2018 criteria1,26.   
 
12.0     STATISTICAL CONSIDERATIONS 
 
12.1 
This single-arm Phase II clinical trial will use a Simon optimal two-stage 
design to assess potential efficacy for the primary endpoint or marrow MRD-
negativity rate after 4 cycles of RB.  Previous data suggest an historical 
marrow MRD-negativity rate in the study population eligible for the current 
trial of 20%. We hypothesize that with BR-C the MRD-negative rate will be 
40%.  Using a Simon two-stage optimal design, up to 12 patients will be 
enrolled in the first stage.  If 2 or fewer responses among 12 (17% or less) 
patients are observed, consideration will be given the stopping the study due 
to a lack of efficacy.  On the other hand, if at least 3 responses are observed 
among the first 12 patients, an additional 13 will be enrolled.  After the 25th 
patient, if 8 or more responses are seen (32% or more), we shall conclude that 
BR-C is potentially efficacious and this would provide sufficient evidence 
that the true rate of marrow MRD-negativity is in excess of 20% and such a 
result would warrant a larger trial of MRD-directed BR-C.  This design has a 
one-sided significance level of .099 and a power of 81.5%.  The expected 
number of patients to be enrolled under the null hypothesis that the marrow 
MRD rate is 20% is 17.7, and the probability of stopping early under the null 
hypothesis is 0.56.   
Safety Stopping Rule 
 
Based on previous data with idelalisib11,29 and copanlisib30, we will define a 
threshold of > 13% of patients experiencing grade 3 or higher immune-related 
toxicity, or fatal toxicity, at least possibly related to study therapy as 
excessive.  
 
If this rate of toxicity is observed, the study will be suspended pending review 
by and ad hoc safety oversight committee.  This committee will analyze the 
data and make a recommendation to continue the study at the current starting 
dose, deescalate the starting study dose to dose level -1, terminate, or 
otherwise modify the study. These recommendations will consider the totality 
of the toxicity data, the patient mix, and efficacy data including frequency of 
response.  Sufficient evidence will be taken to be any observed ratio of 
toxicities-to-patients treated that has an associated lower one-sided 80% 
confidence limit that exceeds 13%. 
 

 Protocol version 3.0 dated 16 October 2020 
 
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Operationally, the following thresholds for grade 3 or higher immune-related 
toxicity or deaths related to study therapy will trigger study suspension and 
review:  2/2-6, 3/7-12, 4/13-18, 5/19, 6/20-24 
 
If the true probability of toxicity is 5%, the probability of an observed toxicity 
ratio that would trigger a suspension after 10 or 19 patients is approximately 
.03 and .04, respectively.  If the true probability of toxicity is 30%, the 
probability of an observed toxicity ratio that would trigger a suspension after 
10 or 19 patients is approximately .69 and .88, respectively.   
 
We will also suspend the study and refer to ad hoc safety committee if there 
are 2 deaths at any time that are possibly related to copanlisib. 
 
Given the complexity of the study and heterogeneity of possibilities for 
reaching the rules for study suspension, we have not pre-specified specific 
rules for de-escalating the starting dose. The recommendations of the 
committee will be followed, and the protocol will be modified or terminated 
accordingly.  
 
During a study suspension, accrual will be halted, but subjects who are 
already on study may continue treatment per protocol at the discretion of the 
investigator pending the result of the ad hoc safety oversight committee 
meeting. However, if the committee recommendation is to terminate the 
study, all subjects will discontinue study treatment and continue standard of 
care therapy at the discretion of the treating physician. 
 
 
 
12.2 
Anticipated accrual: We anticipate accrual of 25 subjects over 3 years.   
 
12.3 
Descriptive summary statistics for continuous variables will include sample 
size, mean, standard deviation (SD), median, minimum and maximum for both 
baseline and post-baseline measurements (if applicable).  Summary statistics for 
categorical variables will include sample size, frequency and percentages. 
 
 
13.0  STUDY MONITORING AND REPORTING PROCEDURES 
 
 
13.1 
Adverse Event Reporting  
 
Reporting of AEs and SAEs should commence after first administration of 
copanlisib and should continue until end of treatment visit. Complete and timely 
reporting of adverse events (AEs) is required to ensure the safety of subjects.  
Reporting requirements are determined by the characteristics of the adverse 
event including the grade (severity), the relationship to the study therapy 

 Protocol version 3.0 dated 16 October 2020 
 
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(attribution), and the prior experience (expectedness) of the adverse event.  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 v5.0 (CTCAE) will be used to classify and grade toxicities.  The 
CTC can be found on the Cancer Therapy Evaluation Program (CTEP) 
homepage at 
https://ctep.cancer.gov/protocolDevelopment/electronic_applications/docs/CTC
AE_v5_Quick_Reference_8.5x11.pdf 
 
13.2  Definitions and descriptions of terms used in adverse event reporting. 
 
Adverse Event (AE) 
An adverse event (AE) 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. The investigator 
should log AEs that are deemed to be clinically significant and assess their 
attribution to either or both of the study medications. 
 
Serious Adverse Event or Adverse Drug Reaction 
A Serious Adverse Event (SAE) or Adverse Drug Reaction (ADR) means any 
AE/ADR occurring at any dose that results in: 
 
• 
Death; 
• 
A life-threatening AE/ADR (i.e., the 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); 
• 
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 
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. 
 
Grade 
Grade is defined as the severity of the adverse event.  The CTCAE Version 5.0 
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 

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3 – Severe adverse event 
4 – Life-threatening or disabling adverse event 
5 – Fatal adverse event 
 
Attribution 
Attribution is defined as the determination of whether an adverse event is related 
to a medical treatment or procedure.  The investigator or authorized sub-
investigator will assess attribution according to the following categories 
 
• 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 
 
Unexpected Adverse Event 
An unexpected adverse event is any adverse event that is not listed in the current 
Investigator’s Brochure, package insert, protocol, or associated documents; or 
the specificity or severity of which is not consistent with these documents.   
 
13.3 
Routine Reporting 
 
Routine reporting at protocol-mandated clinic visits is required for all grade 
adverse events.  Routine reports include data after each cycle of therapy and 30 
days after the last dose of study drugs, or until the subject receives an alternative 
anti-cancer therapy, whichever date comes first.    
 
13.4  Expedited Reporting  
 
SAE Reporting to Bayer  
 
SAEs require expeditious handling and reporting to Bayer in order to comply 
with regulatory requirements.  All SAEs (regardless of causality assessment) 
occurring on study or within 30 days of last study treatment should be 
immediately reported to Bayer at 1-888-842-2937 or FDA at 1-800-FDA-1088 
or www.fda.gov/medwatch within 1 business day of the first knowledge of the 
event by the treating physician or research personnel on an SAE Form 
(MedWatch FORM FDA 3500 or equivalent) and followed until resolution (with 
autopsy report if applicable) 
 
SAE Reporting to Regulatory Agencies  
 
Sponsor-Investigator is responsible for reporting serious, unexpected, suspected 
adverse reactions (SUSARs) to the FDA in accordance with regulations under 
21 CFR 312.32.  Sponsor-Investigator is responsible for reporting unexpected 
fatal or life-threatening events associated with the use of the study drugs to the 

 Protocol version 3.0 dated 16 October 2020 
 
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FDA within 7 calendar days after being notified of the event.  Sponsor-
Investigator will report other SUSARs to the FDA by a written safety report 
within 15 calendar days of notification. Other SAEs will be reported to the FDA 
on an annual basis.  
 
The investigator must report SAEs and follow-up information to the responsible 
Institutional Review Board (IRB) according to the policies of the IRB.  
 
The following are events of special interest, and will need to be reported to Bayer 
within 2 business days of awareness by a member of the study team: 
 
Pregnancy 
 
During the course of the study, all female subjects of childbearing potential must 
contact the treating investigator immediately if they suspect that they may be 
pregnant (a missed or late menstrual period should be reported to the treating 
investigator).   
 
If an investigator suspects that a subject may be pregnant prior to administration 
of study drug(s), the study drug(s) must be withheld until the result of the 
pregnancy test is confirmed.  If a pregnancy is confirmed, the subject must not 
receive any study drug(s), and must be discontinued from the study.   
 
If an investigator suspects that a subject may be pregnant after the subject has 
been receiving study drug(s), the study drug(s) must immediately be withheld 
until the result of the pregnancy test is confirmed.  If a pregnancy is confirmed, 
the study drug(s) must be immediately and permanently stopped, the subject 
must be discontinued from the study, and the investigator must submit an SAE 
form to Bayer at 1-888-842-2937 or FDA at 1-800-FDA-1088 or 
www.fda.gov/medwatch within 1 business day of the first knowledge of the 
event by the treating physician or research personnel on an SAE Form 
(MedWatch FORM FDA 3500 or equivalent) and followed until resolution (with 
autopsy report if applicable).  Abortions (spontaneous, accidental, or 
therapeutic) must also be reported to Bayer at 1-888-842-2937 or FDA at 1-800-
FDA-1088 or www.fda.gov/medwatch within 1 business day of the first 
knowledge of the event by the treating physician or research personnel on an 
SAE Form (MedWatch FORM FDA 3500 or equivalent) and followed until 
resolution (with autopsy report if applicable). 
 
Study Drug Overdose 
 
Any accidental or intentional overdose with the study treatment that is 
symptomatic, even if not fulfilling a seriousness criterion is to be reported to 
Bayer 
at 
1-888-842-2937 
or 
FDA 
at 
1-800-FDA-1088 
or 
www.fda.gov/medwatch within 1 business day of the first knowledge of the 
event by the treating physician or research personnel on an SAE Form 

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(MedWatch FORM FDA 3500 or equivalent) and followed until resolution (with 
autopsy report if applicable). If a study drug overdose occurs, subjects should 
stop study drug dosing and be clinically monitored as appropriate, managing 
symptoms/side effects that may occur. 
 
Secondary / Second Malignancy 
 
Any secondary or second malignancy event must be reported to Bayer at 1-888-
842-2937 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch within 1 
business day of the first knowledge of the event by the treating physician or 
research personnel on an SAE Form (MedWatch FORM FDA 3500 or 
equivalent) and followed until resolution (with autopsy report if applicable). 
 
13.5 
Data Safety and Monitoring Plan  
 
Institutional support of trial monitoring will be in accordance with the 
FHCRC/University of Washington Cancer Consortium Institutional Data and 
Safety Monitoring Plan.  Under the provisions of this plan, FHCRC Clinical 
Research Support coordinates data and compliance monitoring conducted by 
consultants, contract research organizations, or FHCRC employees unaffiliated 
with the conduct of the study.  Independent monitoring visits occur at specified 
intervals determined by the assessed risk level of the study and the findings of 
previous visits per the institutional DSMP.  
 
In addition, protocols are reviewed at least annually and as needed by the 
Consortium Data and Safety Monitoring Committee (DSMC), Fred 
Hutchinson Cancer Research Center (FHCRC) Scientific Review Committee 
(SRC) and the FHCRC Institutional Review Board (IRB).  The review 
committees evaluate accrual, adverse events, stopping rules, and adherence to 
the applicable data and safety monitoring plan for studies actively enrolling or 
treating subjects.  The IRB reviews the study progress and safety information 
to assess continued acceptability of the risk-benefit ratio for human subjects.  
Approval of committees as applicable is necessary to continue the study. 
   
The trial will comply with the standard guidelines set forth by these regulatory 
committees and other institutional, state and federal guidelines. 
 
13.6 
Required Records and Materials 
13.6.1 Original signed informed consent form will be kept with the study 
coordinating office. A copy will be kept in the subject’s clinical chart.   
13.6.2 Data will be collected on subject characteristics, disease characteristics, 
protocol therapy, response to treatment, adverse events and follow-up for 
relapse and survival.  Source documentation may include the subject’s 
medical record from SCCA/UWMC and/or outside providers which 
would include history and physical exams, documentation of protocol 

 Protocol version 3.0 dated 16 October 2020 
 
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therapy, labs, scans, x-rays, hospitalizations, operative reports, 
pathology reports etc. 
 
 
 
 
 
14.0 
ELEMENTS OF INFORMED CONSENT 
 
All Institutional, NCI, State and Federal regulations concerning informed consent will 
be fulfilled.  Written consent will be obtained from all subjects entering the study. 
 
15.0  ADMINISTRATIVE AND REGULATORY CONSIDERATIONS 
 
15.1  Pre-Study Documentation 
 
The following documentation will be established in the Sponsor-Investigator’s files 
prior to initiation of the trial: FDA Form 1572 (if study is conducted under an IND); 
curricula vitae of the PI and all Sub-Investigators; copy of the correspondence from 
the IRB indicating approval of the protocol and Informed Consent Forms, signed by 
the IRB/EC chairperson or designee; copy of the Informed Consent Forms that were 
reviewed and approved by the IRB. 
 
15.2 Study Site Training 
 
Before initiation of the study, the PI, or its designated representatives will review and 
discuss the following items with the Investigator and clinic staff: the protocol, study 
procedures, record keeping and administrative requirements, drug accountability, AE 
reporting, Good Clinical Practice guidelines, and the ability of the site to satisfactorily 
complete the protocol.  
 
 
15.3 Ethical Considerations 
 
The investigators agree to conduct this study in accordance with applicable United 
States FDA clinical trial regulations and guidelines, applicable United States FDA 
clinical trial regulations and guidelines, the  International Council for Harmonisation 
of Technical Requirements for Pharmaceuticals for Human Use (ICH) (E6) GCP 
guidelines, the European Union Directive 2001/20/EC for clinical trials conducted in 
the European Union, the IRB/EC and local legal requirements and with the 
Declaration of Helsinki (1989). The Investigator will conduct all aspects of this study 
in accordance with all national, state, and local laws of the applicable regulatory 
agencies. 
 
15.4 Informed Consent 
 
The PI/subinvestigator assumes the responsibility of obtaining written Informed 
Consent for each subject or the subject’s legally authorized representative before any 
study-specific procedures are performed. 
 

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Subjects meeting the criteria set forth in the protocol will be offered the opportunity to 
participate in the study. To avoid introduction of bias, the Investigator must exercise 
no selectivity with regard to offering eligible subjects the opportunity to participate in 
the study. Subjects or parents/legal guardians of all candidate subjects will receive a 
comprehensive explanation of the proposed treatment, including the nature of the 
therapy, alternative therapies available, any known previously experienced adverse 
reactions, the investigational status of the study drug, and other factors that are part of 
obtaining a proper Informed Consent. Subjects will be given the opportunity to ask 
questions concerning the study, and adequate time to consider their decision to or not 
to participate. 
 
Informed Consent will be documented by the use of a written Consent Form that 
includes all the elements required by FDA regulations and ICH guidelines. A copy of 
the signed form will be given to the person who signed it, the original signed Consent 
Form will be filed with the subject’s medical records, and copy maintained with the 
subject’s study records. The date and time of time of the Informed Consent must be 
recorded in the source documents. 
 
If an amendment to the protocol changes the subject participation schedule in scope or 
activity, or increases the potential risk to the subject, the Informed Consent Form must 
be amended. Any amended Informed Consent must be reviewed by the Sponsor or 
designee and approved by the IRB/EC prior to use. The revised Informed Consent 
Form must be used to obtain re-consent from any subjects currently enrolled in the 
study if the subject is affected by the amendment, and must be used to document 
consent from any new subjects enrolled after the approval date of the amendment. 
 
15.5 Institutional Review Board/Ethics Committee 
 
The PI will assure that an appropriately constituted IRB/EC that complies with the 
requirements of 21 CFR Section 56 or written assurance of compliance with ICH (E6) 
guidelines will be responsible for the initial and continuing review and approval of the 
clinical study. Before initiation of the study, the PI or designee will forward copies of 
the protocol and Consent Form to be used for the study to the IRB/EC for its review 
and approval.  
 
The PI or designee will also assure that all changes in the research activity and all 
unanticipated problems involving risks to human subjects or others will be reported 
promptly to the IRB/EC, and that no changes will be made to the protocol without 
IRB/EC approval, except where necessary to eliminate apparent immediate hazards to 
human subjects. 
 
The Investigator or designee will be responsible for submitting periodic progress 
reports to the IRB/EC at intervals appropriate to the degree of subject risk involved in 
the study, but not less than once per year and at the completion or termination of the 
study. 
 

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15.6 Subject Privacy 
 
The investigators affirm and uphold the principle of the subject's right to privacy. The 
investigator shall comply with applicable national and local privacy laws. 
 
 
16.0 
REFERENCES:  
 
 
1. 
Hallek M, Cheson BD, Catovsky D, et al: iwCLL guidelines for diagnosis, 
indications for treatment, response assessment, and supportive management of CLL. Blood 
131:2745-2760, 2018 
 
2. 
Parikh SA, Rabe KG, Kay NE, et al: Chronic lymphocytic leukemia in young 
(</= 55 years) patients: a comprehensive analysis of prognostic factors and outcomes. 
Haematologica 99:140-7, 2014 
 
3. 
Eichhorst B, Fink AM, Bahlo J, et al: First-line chemoimmunotherapy with 
bendamustine and rituximab versus fludarabine, cyclophosphamide, and rituximab in patients 
with advanced chronic lymphocytic leukaemia (CLL10): an international, open-label, 
randomised, phase 3, non-inferiority trial. Lancet Oncol 17:928-942, 2016 
 
4. 
Goede V, Fischer K, Busch R, et al: Obinutuzumab plus chlorambucil in 
patients with CLL and coexisting conditions. N Engl J Med 370:1101-10, 2014 
 
5. 
Kwok M, Rawstron AC, Varghese A, et al: Minimal residual disease is an 
independent predictor for 10-year survival in CLL. Blood 128:2770-2773, 2016 
 
6. 
Fischer K, Cramer P, Busch R, et al: Bendamustine Combined With Rituximab 
in Patients With Relapsed and/or Refractory Chronic Lymphocytic Leukemia: A Multicenter 
Phase II Trial of the German Chronic Lymphocytic Leukemia Study Group. Journal of 
Clinical Oncology 29:3559-3566, 2011 
 
7. 
Seymour JF, Kipps TJ, Eichhorst BF, et al: Venetoclax Plus Rituximab Is 
Superior to Bendamustine Plus Rituximab in Patients with Relapsed/ Refractory Chronic 
Lymphocytic Leukemia - Results from Pre-Planned Interim Analysis of the Randomized 
Phase 3 Murano Study. Blood 130:LBA-2-LBA-2, 2017 
 
8. 
Fischer K, Cramer P, Busch R, et al: Bendamustine in Combination With 
Rituximab for Previously Untreated Patients With Chronic Lymphocytic Leukemia: A 
Multicenter Phase II Trial of the German Chronic Lymphocytic Leukemia Study Group. 
Journal of Clinical Oncology 30:3209-3216, 2012 
 
9. 
O'Brien S, Jones JA, Coutre SE, et al: Ibrutinib for patients with relapsed or 
refractory chronic lymphocytic leukaemia with 17p deletion (RESONATE-17): a phase 2, 
open-label, multicentre study. Lancet Oncol 17:1409-1418, 2016 
 
10. 
Roberts AW, Davids MS, Pagel JM, et al: Targeting BCL2 with Venetoclax in 
Relapsed Chronic Lymphocytic Leukemia. N Engl J Med 374:311-22, 2016 
 
11. 
Furman RR, Sharman JP, Coutre SE, et al: Idelalisib and rituximab in relapsed 
chronic lymphocytic leukemia. N Engl J Med 370:997-1007, 2014 
 
12. 
Lampson BL, Kasar SN, Matos TR, et al: Idelalisib given front-line for 
treatment of chronic lymphocytic leukemia causes frequent immune-mediated hepatotoxicity. 
Blood 128:195-203, 2016 
 
13. 
Zelenetz AD, Barrientos JC, Brown JR, et al: Idelalisib or placebo in 
combination with bendamustine and rituximab in patients with relapsed or refractory chronic 

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lymphocytic leukaemia: interim results from a phase 3, randomised, double-blind, placebo-
controlled trial. Lancet Oncol 18:297-311, 2017 
 
14. 
Flinn IW, Hillmen P, Montillo M, et al: Results from the Phase 3 
DUO<sup>TM</sup> Trial: A Randomized Comparison of Duvelisib Vs Ofatumumab in 
Patients with Relapsed/Refractory Chronic Lymphocytic Leukemia or Small Lymphocytic 
Lymphoma. Blood 130:493-493, 2017 
 
15. 
Mato AR, Cheson BD, Lamanna N, et al: KI Intolerance Study: A Phase 2 
Study to Assess the Safety and Efficacy of Umbralisib (TGR-1202) in Patients with Chronic 
Lymphocytic Leukemia (CLL) Who Are Intolerant to Prior BTK or PI3K-δ Inhibitor 
Therapy. Blood 130:4314-4314, 2017 
 
16. 
Patnaik A, Appleman LJ, Tolcher AW, et al: First-in-human phase I study of 
copanlisib (BAY 80-6946), an intravenous pan-class I phosphatidylinositol 3-kinase inhibitor, 
in patients with advanced solid tumors and non-Hodgkin's lymphomas. Ann Oncol 27:1928-
40, 2016 
 
17. 
Thorpe LM, Yuzugullu H, Zhao JJ: PI3K in cancer: divergent roles of 
isoforms, modes of activation and therapeutic targeting. Nat Rev Cancer 15:7-24, 2015 
 
18. 
Dreyling M, Morschhauser F, Bouabdallah K, et al: Phase II study of 
copanlisib, a PI3K inhibitor, in relapsed or refractory, indolent or aggressive lymphoma. Ann 
Oncol, 2017 
 
19. 
Dreyling M, Santoro A, Mollica L, et al: Phosphatidylinositol 3-Kinase 
Inhibition by Copanlisib in Relapsed or Refractory Indolent Lymphoma. J Clin 
Oncol:Jco2017754648, 2017 
 
20. 
Owens CN, Migliacci JC, Horwitz SM, et al: Dose-Adjusted EPOCH +/- 
Rituximab in Older Patients with High Grade Diffuse Large B-Cell Lymphoma, Burkitt and 
T-Cell Lymphoma: An Effective Regimen with Acceptable Toxicity Profile. Blood 124:4450-
4450, 2014 
 
21. 
Gerecitano J, Santoro A, Leppä S, et al: SAFETY RUN-IN OF COPANLISIB 
IN COMBINATION WITH RITUXIMAB PLUS BENDAMUSTINE IN PATIENTS WITH 
RELAPSED INDOLENT NON-HODGKIN'S LYMPHOMA. Hematological Oncology 
35:408-410, 2017 
 
22. 
Gafter-Gvili A, Polliack A: Bendamustine associated immune suppression and 
infections during therapy of hematological malignancies. Leuk Lymphoma 57:512-9, 2016 
 
23. 
Feugier P, Van Hoof A, Sebban C, et al: Long-term results of the R-CHOP 
study in the treatment of elderly patients with diffuse large B-cell lymphoma: a study by the 
Groupe d'Etude des Lymphomes de l'Adulte. J Clin Oncol 23:4117-26, 2005 
 
24. 
Rai KR, Sawitsky A, Cronkite EP, et al: Clinical staging of chronic 
lymphocytic leukemia. Blood 46:219-34, 1975 
 
25. 
Binet JL, Leporrier M, Dighiero G, et al: A clinical staging system for chronic 
lymphocytic leukemia: prognostic significance. Cancer 40:855-64, 1977 
 
26. 
Hallek M, Cheson BD, Catovsky D, et al: Guidelines for the diagnosis and 
treatment of chronic lymphocytic leukemia: a report from the International Workshop on 
Chronic Lymphocytic Leukemia updating the National Cancer Institute-Working Group 1996 
guidelines. Blood 111:5446-56, 2008 
 
27. 
Letestu R, Cartron G, Lepretre S, et al: Minimal Residual Disease (MRD) By 
8-Color Flow Cytometry (Flow-MRD) and IGH Clonospecific Quantitative PCR (ASO 

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RQPCR) Reached Similar Performances for Evaluation of CLL Treatment in a Phase II 
Clinical Trial: Cross Validation of the Methods. Blood 124:3307-3307, 2014 
 
28. 
Bottcher S, Ritgen M, Fischer K, et al: Minimal residual disease quantification 
is an independent predictor of progression-free and overall survival in chronic lymphocytic 
leukemia: a multivariate analysis from the randomized GCLLSG CLL8 trial. J Clin Oncol 
30:980-8, 2012 
 
29. 
Gopal AK, Kahl BS, de Vos S, et al: PI3Kdelta inhibition by idelalisib in 
patients with relapsed indolent lymphoma. N Engl J Med 370:1008-18, 2014 
 
30. 
Zinzani PL, Patnaik A, Morschhauser F, et al: Pooled Safety Analysis from 
Phase I and II Studies for Patients with Relapsed Indolent Non-Hodgkin's Lymphoma Treated 
with Intravenous Copanlisib. Blood 130:4042-4042, 2017 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
15.0 
Appendices 

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Appendix 1: ECOG Performance Status 
Grade 
Description 
0 
Normal activity. Fully active, able to carry on all pre-disease 
performance without restriction. 
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). 
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. 
3 
In bed >50% of the time. Capable of only limited self-care, confined 
to bed or chair more than 50% of waking hours. 
4 
100% bedridden. Completely disabled. Cannot carry on any self-care. 
Totally confined to bed or chair. 
5 
Dead. 
* As published in Am. J. Clin. Oncol.:  Oken, M.M., Creech, R.H., Tormey, D.C., Horton, J., Davis, T.E., 
McFadden, E.T., Carbone, P.P.: Toxicity And Response Criteria Of The Eastern Cooperative Oncology 
Group. Am J Clin Oncol 5:649-655, 1982. The Eastern Cooperative Oncology Group, Robert Comis 
M.D., Group Chair. 
Appendix 2: Common Terminology Criteria for Adverse Events V5.0 (CTCAE) 
The descriptions and grading scales found in the revised NCI Common Terminology Criteria 
for Adverse Events (CTCAE) version 5.0 will be utilized for adverse event reporting.  
Appendix 3:  Response Criteria: IWCLL 2018 
 
For a detailed description of the response parameters, see original reference1,27.  
*Sum of the products of 6 or fewer lymph nodes (as evaluated by CT scans and physical 
examination in clinical trials or by physical examination in general practice).  

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†Spleen size is considered normal if ,13 cm. There is not firmly established international 
consensus of the size of a normal liver; therefore, liver size should be evaluated by imaging and 
manual palpation in clinical trials and be recorded according to the definition used in a study 
protocol.  
CR, complete remission (all of the criteria have to be met); PD, progressive disease (at least 1 
of the criteria of group A or group B has to be met); PR, partial remission (for a PR, at least 2 
of the parameters of group A and 1 parameter of group B need to improve if previously 
abnormal; if only 1 parameter of both groups A and B is abnormal before therapy, only 1 needs 
to improve); SD, stable disease (all of the criteria have to be met; constitutional symptoms alone 
do not define PD).