Conditions: Mantle Cell Lymphoma (MCL)
Keywords: Copanlisib Ibrutinib 18-450
Allocation: NA | Intervention model: SEQUENTIAL
Enrollment: 8
Healthy volunteers: no

Brief summary:
The purpose of this study is to test the safety and any good and bad side effects of combining 2 study drugs, copanlisib and ibrutinib. This combination of drugs could shrink your Mantle Cell Lymphoma (MCL), but it could also cause side effects. Both these drugs have been given to people before, but this is the first time that they are being given together.

Detailed description:

Arms:
arm 1: Copanlisib is given intravenously on days 1, 8, and 15 of 28 day cycles. Ibrutinib is given orally every day on 28 days cycles. The maximum duration of treatment is 36 cycles not exceeding 36 months. In the phase II study, the cohort will expand and accrue patients at the recommended phase II dose of copanlisib and ibrutinib determined during phase I dose escalation. In a simon two stage mini-max design, an initial 18 patients will be enrolled, inclusive of 6 patients treated at MTD or RP2D from phase I study, in first stage.

Interventions: intervention 1: Copanlisib intervention 2: Ibrutinib
Intervention descriptions: intervention 1: Treatment will be with intravenous copanlisib on days 1, 8, 15 of 28 day cycles. intervention 2: Oral ibrutinib daily in 28 day cycles. A cycle is defined as 28 days of therapy.

Protocol document:
Prot_SAP_000.pdf: 
Memorial Sloan Kettering Cancer Center 
IRB Number: 18-450 A(10) 
Approval date: 08-Sep-2020 
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Phase I/II Clinical Trial of Copanlisib and Ibrutinib in Mantle Cell Lymphoma 
PROTOCOL FACE PAGE FOR 
MSK THERAPEUTIC/DIAGNOSTIC  PROTOCOL 
 
 
Principal 
Investigator/Department: 
Connie Batlevi, MD, PhD 
Medicine 
Co-Principal 
Investigator(s)/Department: 
Anita Kumar, MD 
Medicine 
Investigator(s)/Department: 
Gilles Salles, MD, PhD 
Philip Caron, MD 
Pamela Drullinsky, MD 
Audrey Hamilton, MD 
Paul Hamlin, MD 
Steven Horwitz, MD 
Andrew Intlekofer, MD, PhD 
Colette Owens, MD 
Matthew Matasar, MD 
Alison Moskowitz, MD Ariela 
Noy, MD 
Maria L. Palomba, MD 
David Straus, MD 
Santosha Vardhana, MD, PhD 
Andrew Zelenetz, MD, PhD 
Gottfried von Keudell, MD 
Ildefonso I. Rodriguez-Rivera, MD 
Erel Joffe, MD 
Lorenzo Falchi, MD 
Niloufer Khan, MD 
William Johnson, MD 
Venkatraman Seshan, PhD 
Ahmet Dogan, MD, PhD 
Jennifer Orozco, PharmD 
Kenneth Ng, MD 
Arlyn Apollo, MD 
Zoe Goldberg, MD 
Tiffany Troso-Sandoval, MD 
Hani Hassoun, MD 
Neha Korde, MD 
Avni Desai, MD 
Azadeh Namakydoust, MD 
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Marina Shcherba, DO 
Virginia Klimek, MD 
Oscar Lahoud, MD 
Ping Gu, MD 
Michael Mauro, MD 
Isabel Preeshagul, DO 
Rui Wang, MD, PhD 
Leslie Matthews, NP 
Melanie Albano, NP 
Diane Lee, NP 
Christine White, NP 
Joanna Mi, NP 
Jessica Chan, NP 
Julia Cook, NP 
Susan McCall, NP 
Raylene Langish, RN 
Sherie Mar-Chaim, RN 
Amy Pierre, APN 
Geri Arnell, RN 
Ofer Maimran, RN 
Nicole Heinz, RN 
Jessica Marchisotto, RN 
Sunyoung Ryu, RN 
Leslie Perez, RN 
Maureen Kennedy, RN 
Teresa Palumbo, PA 
Shelley Levi, PA 
Nadia DePaola, PA 
Jillian Schreiber, PA 
Michelle Wisniewski, PA 
Amy Lynes, PA 
Janet Cogswell, RN 
Gloria Wasilewski, RN 
Georgia Rose, NP 
Tara Duggan, NP 
Theresa Davey, PA 
Helen Hancock, NP 
Neena Mahajan,  NP 
Jeffrey Girshman, MD 
Lynn Brody, MD 
Ravinder Grewal, MD 
Honglei Zhang, MD 
Christopher Forlenza, MD 
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Consenting 
Connie Batlevi, MD, PhD 
Medicine 
Professional(s)/Department: 
Gilles Salles, MD, PhD 
Medicine 
Philip Caron, MD 
Medicine 
Pamela Drullinsky, MD 
Medicine 
Audrey Hamilton, MD 
Medicine 
Paul Hamlin, MD 
Medicine 
Steven Horwitz, MD 
Medicine 
Andrew Intlekofer, MD, PhD 
Medicine 
Anita Kumar, MD 
Medicine 
Colette Owens, MD 
Medicine 
Matthew Matasar, MD 
Medicine 
Alison Moskowitz, MD 
Medicine 
Ariela Noy, MD 
Medicine 
Maria L. Palomba, MD 
Medicine 
David Straus, MD 
Medicine 
Santosha Vardhana, MD, PhD 
Medicine 
Andrew Zelenetz, MD, PhD 
Medicine 
Gottfried von Keudell, MD 
Medicine 
Ildefonso I. Rodriguez-Rivera, MD 
Medicine 
Erel Joffe, MD 
Medicine 
Lorenzo Falchi, MD 
Medicine 
Niloufer Khan, MD 
Medicine 
William Johnson, MD 
Medicine 
Kenneth Ng, MD 
Medicine 
Arlyn Apollo, MD 
Medicine 
Zoe Goldberg, MD 
Medicine 
Tiffany Troso-Sandoval, MD 
Medicine 
Hani Hassoun, MD 
Medicine 
Neha Korde, MD 
Medicine 
Avni Desai, MD 
Medicine 
Azadeh Namakydoust, MD 
Medicine 
Virginia Klimek, MD 
Medicine 
Oscar Lahoud, MD 
Medicine 
Ping Gu, MD 
Medicine 
Michael Mauro, MD 
Medicine 
Rui Wang, MD, PhD 
Medicine 
Christopher Forlenza, MD 
Pediatrics 
Please Note: A Consenting Professional must have completed the mandatory Human 
Subjects Education and Certification Program. 
 
OneMSK  Sites 
Manhattan 
All Protocol Activities 
Basking Ridge 
All Protocol Activities 
Monmouth 
All Protocol Activities 
Westchester 
All Protocol Activities 
Commack 
All Protocol Activities 


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Nassau 
All Protocol Activities 
Memorial Sloan Kettering Cancer Center 
1275 York Avenue 
New York, New York 10065 


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Table of Contents 
1.0 
PROTOCOL SUMMARY AND/OR SCHEMA ....................................................................... 6 
2.0 
OBJECTIVES AND SCIENTIFIC AIMS ................................................................................ 6 
3.0 
BACKGROUND AND RATIONALE ..................................................................................... 7 
4.0 
OVERVIEW OF STUDY DESIGN/INTERVENTION ................................................................. 10 
4.1 
Design................................................................................................................................. 10 
4.2 
Intervention .............................................................................................................................. 11 
5.0 
THERAPEUTIC/DIAGNOSTIC AGENTS ........................................................................... 11 
6.0 
CRITERIA FOR SUBJECT ELIGIBILITY ............................................................................... 12 
6.1 
Subject Inclusion Criteria ..................................................................................................... 12 
6.2 
Subject Exclusion Criteria ................................................................................................... 13 
7.0 
RECRUITMENT PLAN .................................................................................................................... 15 
8.0 
PRETREATMENT EVALUATION ...................................................................................... 15 
9.0 
TREATMENT/INTERVENTION PLAN ................................................................................ 16 
10.0 
EVALUATION DURING TREATMENT/INTERVENTION .................................................... 43 
11.0 
TOXICITIES/SIDE EFFECTS .................................................................................................... 48 
12.0 
CRITERIA FOR THERAPEUTIC RESPONSE/OUTCOME ASSESSMENT ......................... 52 
13.0 
CRITERIA FOR REMOVAL FROM STUDY ....................................................................... 54 
14.0 
BIOSTATISTICS ............................................................................................................... 55 
15.0 
RESEARCH PARTICIPANT REGISTRATION AND RANDOMIZATION PROCEDURES 
58 
15.1 
Research Participant Registration ....................................................................................... 58 
15.2 
Randomization .................................................................................................................... 58 
16.0 
DAT A M ANAGEMENT ISSUES ........................................................................................ 58 
16.1 
Quality Assurance............................................................................................................... 59 
16.2 
Data and Safety Monitoring .................................................................................................... 59 
17.0 
PROTECTION OF HUMAN SUBJECTS ............................................................................ 60 
17.1 
Privacy ................................................................................................................................ 60 
17.2 
Serious Adverse Event (SAE) Reporting ............................................................................... 61 
17.2.1  ........................................................................................................................................  62 
18.0 
INFORMED CONSENT PROCEDURES................................................................................... 62 
19.0 
REFERENCES ....................................................................................................................... 63 
20.0 
APPENDICES ................................................................................................................... 65 


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1.0 
PROTOCOL SUMMARY AND/OR SCHEMA 
 
Title: Phase I/II Clinical Trial of Copanlisib and Ibrutinib in Mantle Cell Lymphoma 
 
Objectives: The objective of this trial is to determine toxicity, maximum tolerated dose and/or 
recommended phase II dose, and preliminary efficacy of the combination copanlisib and ibrutinib 
in patients with mantle cell lymphoma (MCL). 
Patient Population: Patients with relapsed or refractory MCL with at least 1 prior line of therapy 
are eligible. 
Study Design: This is a two stage protocol comprised of a single institution phase I dose 
escalation trial using standard 3+3 design and a phase II two stage Simon mini-max clinical trial. 
Treatment Plan: Following enrollment, patients will be assigned to receive therapy with ibrutinib 
given by mouth daily and copanlisib given by intravenous injection once per week on days 1, 8, 
15 of a 28 day cycle. 
The phase II cohort will accrue patients at the MTD dose of copanlisib and ibrutinib determined 
during phase I. Patients will accrue in a two stage design and monitored for safety of copanlisib 
and ibrutinib combination therapy, duration of response, best response within 1 year, progression 
free survival, event free survival, and correlative biomarkers. 
Time to Completion: In the phase I dose escalation portion of the study of 3 dose levels, a 
minimum of 4 patients and a maximum of 18 patients will be needed to complete this phase. The 
amount of time required to complete the dose escalation portion of this trial will depend on the 
number of dose levels studied and the number of patients accrued to each cohort. The phase II 
two stage Simon mini-max will enroll 18 patients in the first stage. If 5 or more patients have a 
complete response by 6 months, the trial will enroll to a total number of 33 patients. We anticipate 
enrolling 2-3 patients per month for an approximate accrual time of 2 years. 
 
 
2.0 
OBJECTIVES AND SCIENTIFIC AIMS 
 
2.1. PRIMARY OBJECTIVES 
 
• 
Phase I: Determine maximum tolerated dose and recommended phase II dose of copanlisib 
and ibrutinib combination 
• 
Phase II: Determine complete response rate based on best response by 6 months for 
combination of copanlisib and ibrutinib 
2.2. SECONDARY OBJECTIVE 
 
• 
Phase I Dose Escalation and Phase II Dose Expansion Stages 
o Assess the efficacy as defined by overall response rate (best response within 1 year). 
o Assess the disease control rate (best stable disease, partial responses and complete 
response within 1 year). 
o Assess the duration of response for this population 


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o Assess the event free survival for this population 
o Assess the progression free survival 
 
2. 3. EXPLORATORY ASSESSMENTS 
• 
Phase I Dose Escalation and Phase II Dose Expansion Stages 
o Determine the depth of response via targeted sequencing of peripheral blood 
circulating tumor DNA with combination targeted therapy 
o Correlate disease status, duration of response, PFS, and OS with sequentially 
measured ctDNA 
o Determine the pharmacokinetics of copanlisib and ibrutinib (phase I dose escalation 
only) 
 
 
3.0     BACKGROUND AND RATIONALE 
 
MCL is a unique subtype of NHL characteristic with the t(11;14) (q13;q32) balanced chromosomal 
translocation of the cyclin D1 gene (bcl-1) on chromosome 11 to the immunoglobulin heavy chain 
(IGH) enhancer region on chromosome 14, which results in Cyclin D1 over expression and 
increased cell proliferation of the tumor cells[1]. With a prevalence of 5% to 6% of all NHL, MCL 
accounts for up to 8000 newly diagnosed NHL cases in US and EU each year. 
With the exception of rare patients who enjoy long term disease-free survival after non- 
myeloablative allogeneic stem cell transplantation, patients with MCL are not considered cured of 
their disease. Most MCL patients are treated with rituximab in combination with different 
chemotherapy regimens. The initial treatment usually yields a high response rate, however, most 
patients relapse following initial therapy and their median survival after relapse is about 1-2 years 
[2]. For relapsed MCL, ibrutinib is an FDA approved agent. 
Ibrutinib in MCL has high response rates of 60-70%. However, the median duration of response is 
18 months [3]. We can potentially improve response rates and duration of responses with 
combination therapy. 
The BCR Pathway and ibrutinib 
 
Chronic activation of the B cell receptor (BCR) pathway is essential for survival and proliferation of 
malignant B cells. Strong survival, cell proliferation and cell homeostasis pathways including 
Bruton’s tyrosine kinase (BTK) mediated NF-ĸB activation and phosphatidylinositide 3-kinase 
(PI3K) triggered mTOR activation result from BCR engagement. Bruton's tyrosine kinase (BTK) 
functions as an intermediary between the BCR ligand activation and NF-ĸB activation in normal B 
cells. 
Ibrutinib forms an irreversible covalent bond at cysteine 481 in the BTK active site to quench BTK 
tyrosine phosphorylation. The drug is well tolerated and shows strong activity in many lymphomas 
including mantle cell lymphoma (MCL), follicular lymphoma (FL) and diffuse large B cell lymphoma 
(DLBCL) (Table 3-1). A phase I study of ibrutinib in various B cell malignancies showed that ibrutinib 
was well tolerated with an excellent safety profile and was associated with an objective response 
rate of 60%.[4] Across five dose levels (1.25, 2.5, 5.0, 8.3, and 12.5 mg/kg/day), there were only 2 
DLTs that occurred in 56 total patients (one grade 3 allergic  hypersensitivity in a patient with a 


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history of drug hypersensitivity and one dose interruption for more than 7 days due to transient 
grade 2 neutropenia). There was no consistent relationship between dose level and adverse events. 
An MTD was not reached. Therefore, for an average 70 kg person, doses ranging from 87.5 mg/day 
to 875 mg/day were found to be safe in the phase I study. For further study in B cell non-Hodgkin 
lymphoma, an optimal biologic dose of 560 mg/daily was established and associated with full BTK 
receptor occupancy. Recently published phase II studies of ibrutinib also demonstrated that the 
drug is well-tolerated at a dose of 560mg/daily in mantle cell lymphoma and 420 mg/daily in chronic 
lymphocytic leukemia [5, 6]. 
In R/R MCL, a phase II study of 111 patients showed an overall response rate of 68% while the 
majority of responses seen were partial responses (47%) [3]. The median duration of response was 
17.5 months with a PFS of 13.9 months [3]. In a small phase I study of FL, 16 patients treated with 
ibrutinib demonstrated an ORR of 55%, median PFS 13.4 months [7]. In DLBCL, the effectiveness 
of ibrutinib was seen primarily in non-GCB subtype. When analyzing both the non-GCB and GCB 
DLBCL responses, the ORR in DLBCL was 21.7% [8]. However, the non-GCB DLBCL subgroup 
showed an ORR of 40% with a median PFS of 5.5 months [8]. 
Clearly, ibrutinib has definitive clinical activity and improvements can be made to prolong overall 
response, duration of response (DOR) and progression free survival (PFS). Logically, ibrutinib is 
suitable for combination with other targeted therapies with broad single agent activity such as PI3K 
inhibitors (Table 3-1). 
 
Table 3-1. Overall response  rates of ibrutinib 
Drug 
Target 
Mantle Cell 
Lymphoma 
Follicular 
Lymphoma 
DLBCL 
ORR 
ORR 
ORR 
Ibrutinib 
BTK 
68%[3] 
55%[7] 
21.7%, 40% (non-GCB)  [8] 
 
 
The PI3K pathway and copanlisib 
 
The class I PI3K pathway includes four isoforms: PI3Kα, PI3Kβ, PI3Kδ, and PI3Kγ [9]. PI3Kδ and 
-γ expression is largely limited to leukocytes while PI3K-α and -β are ubiquitously expressed [10]. 
PI3Kα mutations and amplifications have been identified across multiple cancer subtypes and 
both overexpression of PI3Kα and gain of function PI3Kα mutations were found to be oncogenic 
[11-14]. PI3Kα  is also the primary isoform required for insulin signaling [15]. PI3Kβ isoform has 
roles in regulating formation and stability of integrin which is required for platelet activation [16]. 
PI3Kδ and -γ regulate leukocyte trafficking and cell proliferation [17-20]. Mice with functionally 
deficient PI3Kδ have impaired immune systems with abnormal antibody development and 
inflammatory bowel disease [20]. However, dissecting the individual function of class I PI3K 
isoforms have been complicated by the heterodimeric nature of the proteins as altering 
expression of one subunit affects the expression profile of others. 
Multiple PI3K inhibitors have been in development for B-cell non-Hodgkin lymphoma (NHL) (Table 
3-2). Idelalisib, a delta specific PI3K inhibitor, was the first and currently the only PI3K inhibitor  
with regulatory approval in relapsed/refractory chronic lymphocytic leukemia (CLL), small 
lymphocytic lymphoma (SLL) and follicular lymphoma (FL). Chronic administration of idelalisib is 
associated with low but clinically meaningful risk of transaminitis, pneumonitis, colitis, and 


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opportunistic infections [21]. Duvelisib, a PI3K δ and γ inhibitor, demonstrated approximately 50% 
overall response rate in indolent NHL with a 10 month median duration of response [22]. Dreyling 
et al. reported on the safety and efficacy of copanlisib, a pan PI3K inhibitor with primarily α and δ 
activity, in relapsed/refractory B-cell NHL. Clinical response rate is 59% in FL, and 64% in mantle 
cell lymphoma (MCL)[23, 24]. Most commonly observed adverse events were hyperglycemia 
(49%), hypertension (29%), fatigue (12%), and diarrhea (18%). The availability of a PI3Kα/δ 
inhibitor in the form of copanlisib allows us to dissect the relevance of specific PI3K isoforms in 
lymphoma. Potentially, the dual PI3K α/δ inhibition by copanlisib blocks compensatory resistance 
mechanisms to PI3K inhibitors. 
 
Table 3-2. Efficacy of PI3K inhibitors in lymphoma 
Drug 
Target 
Admin Disease CLL 
FL 
MZL 
SLL 
DLBCL 
/ Tx FL 
MCL 
Copanlisib 
[23, 24] 
Pan-PI3K 
Predominantly 
alpha, delta 
IV 
N 
13 
104 
23 
8 
67 
11 
CR/PR 
0/5 
15/46 
2/14 
0/6 
5/8 
2/5 
ORR 
38.5% 
58.7% 
69.9% 
75% 
19.4% 
63.6% 
DoR 
Indolent  – 12.8 mo 
Aggressive  – 5.46 mo 
Buparlisib 
[25] 
Pan-PI3K 
PO 
N 
26 
20 
CR/PR 
1/2 
1/4 
ORR 
11.5% 
25% 
DoR 
NA 
NA 
Idelalisib 
[26-29] 
Delta 
PO 
N 
88 
(+ 
Rituximab) 
72 
15 
28 
40 
CR/PR 
0/71 
6/33 
1/5 
0/15 
2/14 
ORR 
81% 
54% 
47% 
61% 
40% 
DoR 
Median 
NR 
Median 
NE 
NA 
11.9 mo 
2.7 mo 
Duvelisib 
(IPI-145) 
[22] 
Delta, Gamma PO 
N 
83 
18 
28 
10 
CR/PR 
1/35 
0/6 
0/19 
0/0 
ORR 
41 % 
33% 
68% 
0% 
DoR 
7.9 mo 
8.3 mo 
10.1 mo 
NA 
CR - complete response, PR – partial response, ORR – overall  response rate, DoR – duration of 
response, NR – not reached, NE – not evaluated,  NA – not available 
 
 
Various models support the importance of multiple PI3K isoforms in lymphomagenesis. In one 
model of resistance to PI3K inhibitors, primary mantle cell lymphoma patient samples 
demonstrated compensatory increase of PI3Kα in the relapsed setting [30]. In addition, while 
PI3Kδ inhibition reduced B-cell receptor induced PI3K activation, dual inhibition of PI3Kα and –δ 
was required for effective blockade of PI3K signaling[30].  Increased protein expression and copy 
number gains of PI3Kα have also been identified in various lymphomas indicating a role of PI3Kα 
in lymphomagenesis [31, 32]. Furthermore, two independent studies support the importance of 
dual PI3Kα and –δ inhibition. Using a PI3Kα shRNA knockdown model, DLBCL cell lines are 
more sensitive to dual inhibition of PI3Kα and –δ blockade [33]. Similar studies using PI3K 
isoform specific inhibitors demonstrate that combination of PI3Kα and –δ inhibition is required for 
suppression of phospho-AKT, and downstream NFkB and PI3K pathways [31, 33].  Resistance to 
PI3K δ inhibition may be overcome by concurrent PI3Kα inhibition [33]. 


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Synergy of PI3K and BTK inhibitors 
 
In vitro combinatorial screens identified PI3K inhibitors and BTK inhibitors as strongly synergistic 
[34]. A patient derived xenograft model demonstrate that combination of BTK and PI3K α/δ 
inhibition is more active compared to BTK inhibition alone [33]. An observed rebound activation of 
AKT and BTK associated with isolated PI3K or BTK inhibition provides a mechanistic rationale for 
synergy between PI3K and BTK inhibitors in diffuse large B cell lymphoma [31]. Thus, PI3K 
inhibitor such as copanlisib may be suitable for combination with BTK inhibitors such as ibrutinib. 
Two early phase studies using PI3K and BTK inhibitors demonstrate the feasibility of this 
approach [35, 36]. Both buparlisib, an oral pan-PI3K inhibitor, and umbralisib (TG-1202), an oral 
PI3K delta inhibitor have been combined with the BTK inhibitor ibrutinib with promising efficacy in 
CLL and MCL [35, 36]. The phase I/II study of buparlisib, a pan-PI3K inhibitor, and ibrutinib 
(protocol 16-009) at MSK showed high clinical activity in mantle cell lymphoma. Of 11 treated 
patients thus far, the overall response rate is 100% with 9 complete responses and 2 partial 
responses. Two independent preclinical studies investigating the combinations of copanlisib and 
ibrutinib and a PI3Kα/δ inhibitor and ibrutinib generated promising activity specifically in ABC- 
DLBCL [16, 33]. Therefore, a molecularly based evaluation of PI3Kα/δ and BTK inhibition is a 
promising approach for treatment of lymphoma. 
 
 
4.1 OVERVIEW OF STUDY DESIGN/INTERVENTION 
 
4.2 
Design 
 
This is a phase I/II, open label single institution trial. The phase I study is a standard 3 x 3 dose 
escalation trial to assess the safety of combination therapy with copanlisib and ibrutinib. We will 
enroll a dose escalation cohort treating patients with copanlisib and ibrutinib at escalating doses. 
Figure 3-1. IHC expression of PI3K isoforms in MCL.  A) Immunohistochemistry  of PI3Kα, 
PI3Kβ, and PI3Kδ at diagnosis, first relapse and beyond first relapse. B) 12 sequential cases 
of patients with paired biopsies showing increasing PI3Kα with disease progression.  C) 
Representative  IHC staining at 200x of sequential biopsies from  two patients showing 
significant increase in PI3Kα expression at relapse.  [30] 


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A maximum number of 18 patients will be enrolled in this stage. This will determine the maximum 
tolerated dose and the recommended phase II dose. 
In the phase II study, the cohort will expand and accrue patients at the recommended phase II dose 
of copanlisib and ibrutinib determined during phase I dose escalation. In a simon two stage mini- 
max design, an initial 18 patients will be enrolled, inclusive of 6 patients treated at MTD or RP2D 
from phase I study, in first stage. If 5 or more patients have a complete response by 6 months, then 
an additional 15 patients will be enrolled for a total accrual of 33 patients. 
4.3 
Intervention 
 
Treatment will be with intravenous copanlisib on days 1, 8, 15 of 28 day cycles and oral ibrutinib 
daily in 28 day cycles. A cycle is defined as 28 days of therapy. If patients are in a CR by RECIL 
criteria, copanlisib will be held after 2 cycles of combination past a CR or minimum of 6 cycles of 
therapy. Copanlisib will be restarted upon radiographic and pathologic progression of disease (see 
Section 9.9). Patients remain on continuous ibrutinib if copanlisib is held. It may then be restarted 
as clinically indicated. Therapy will continue until disease progression, intolerable toxicities or death 
with a maximum duration of treatment of 36 cycles not exceeding 36 months on therapy. 
 
 
5.0     THERAPEUTIC/DIAGNOSTIC AGENTS 
 
5.1. 
Copanlisib 
 
Copanlisib, also known as BAY 80-6946, is an intravenously-administered, small-moleculeinhibitor 
of PI3K manufactured by Bayer. The copanlisib IND will be cross referenced between MSKCC and 
Bayer. IND approval and activation is pending at MSKCC. 
Physical Description of Study Drug(s): Copanlisib lyophilisate 60 mg 1.5 mL for injection 001 is a 
single use container. 
Labeling: Study drug labels will contain information to meet the applicable regulatory requirements. 
The investigational products will be labeled as open-label material. 
Preparation, Handling, and Storage: 
 
Copanlisib is a lyophilized preparation filled in 6-mL injection vials. Due to the technically required 
overfill the total amount is 68.4 mg Copanlisib per vial. After reconstitution with 4.4 mL of 0.9 % 
NaCl solution a total volume of 4.55 mL is obtained. The resulting drug substance concentration is 
15 mg/mL Copanlisib. To obtain the target dose of copanlisib a volumes of 2.0 - 4.0 mL has to be 
withdrawn (Table 5-1). Withdraw the required amount of the reconstituted lyophilisate with an 
unused sterile syringe. Connect the syringe to the patient infusion bag with 100 mL 0.9 % NaCl 
solution. Transfer the required amount of the reconstituted lyophilisate into the bag. 
 
Table 5-1. Copanlisib dose based on reconstituted  copanlisib solution 
Copanlisib dose [mg] 
30 
45 
60 
Reconstituted Copanlisib  solution [mL] 
2 
3 
4 


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Chemical and physical in-use stability of reconstituted and diluted solution has been demonstrated 
for 24 hours at 2 °C to8 °C and room temperature. However, from a microbiological point of view, 
the solution product should be used immediately. If not used immediately, the time prior application 
should normally not be longer than 24 hours at 2 °C to 8 °C (refrigerated). It takes approximately 
60 minutes for the 100 mL dilution filled in bags to return to room temperature after refrigeration. 
Please refer to the pharmacy manual for detailed instructions for the reconstitution of the lyophilisate 
and dilution of the reconstituted solution. Please refer to the investigator’s brochure for copanlisib 
for more details regarding drug properties and formulation. 
5.2. 
Ibrutinib 
 
Ibrutinib is an orally-administered, small-molecule inhibitor of BTK manufactured by Janssen, and 
co-developed by Janssen and Pharmacyclics. The ibrutinib will be commercially available based 
on an approved FDA indication. 
Physical Description of Study Drug(s): Ibrutinib tablets are debossed with “ibr” on one side and the 
strength in milligrams on the other side (ie, “420”, “560”). Each 420mg tablet is a yellow green to 
green oblong tablet.  Each 560mg tablet is a yellow to orange oblong tablet. 
Packaging: Ibrutinib tablets will be packaged in a carton of one folded blister card containing two 
14-count blister strips for a total of 28 tablets with labels bearing the appropriate label text as 
required by governing regulatory agencies. 
Labeling: Study drug labels will contain information to meet the applicable regulatory requirements. 
Each carton of ibrutinib will contain a study specific label. 
Preparation, Handling, and Storage: Study drug will be stored at the study site in a secure area with 
restricted access until dispensed to the study subjects.  Tablets will be stored in the original packing 
at room temperature 20°C to 25°C (68°F to 77°F). Excursions are permitted between 15°C and 
30°C (59°F to 86°F). Retain in original package until dispensing. If a drug shipment arrives 
damaged, or if there are any other drug complaints, Janssen will replace the drug. Tablets are 
stable in their packaging until the indicated expiration date. The study drug may be destroyed at 
the study site per the local SOPs/policies. Refer to the USPI for additional information regarding 
storage and handling of ibrutinib. 
 
 
6.1 
CRITERIA FOR SUBJECT ELIGIBILITY 
 
6.2 
Subject Inclusion Criteria 
 
Patients eligible for inclusion in this study have to meet ALL of the following criteria: 
 
• 
Patient is ≥ 18 years of age at the time of signing Informed Consent 
• 
Patient is able and willing to adhere to the study visit schedule and other protocol 
requirements 
• 
Patient has histologically confirmed diagnosis of R/R mantle cell lymphoma who has 
received at least 1 line of therapy 


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o Autologous stem cell transplant recipients must have adequate bone marrow 
recovery and transfusion independent 
• 
Patients may have been previously treated with BTK or PI3K inhibitors: 
o If BTK/PI3K inhibitors were part of their last treatment, patients must have had a 
best response of stable disease or better. 
• 
Patient has at least one measurable lesion (≥ 2 cm) according to RECIL criteria[37] 
• 
Patient has an Eastern Cooperative Oncology Group (ECOG) performance status ≤ 2 
• 
Patient has adequate bone marrow and organ function by: 
o Absolute neutrophil count (ANC) ≥ 1 x 109/L , independent of growth factor support 
for 14 days unless there is bone marrow involvement.  For patients with bone 
marrow involvement, ANC ≥ 500/uL independent of growth factor support for 14 
days 
o Platelets ≥100 x 109/L, or ≥50 x 109/L if bone marrow involvement and independent 
of transfusion support for 14 days in either situation 
o Hemoglobin (Hgb) ≥ 9.0 g/dL (no RBC transfusion within past 14 days) 
o International Normalized Ratio (INR) ≤ 1.5 
o Serum Creatinine ≤ 1.5 x upper limit of normal (ULN) or creatinine clearance ≥ 25 
mL/min as determined by the Cockcroft-Gault equation or a 24 hour urine 
collection 
o Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) ≤ ULN (or 
≤ 3 x ULN if liver involved with disease 
o Total serum bilirubin ≤ ULN (or ≤ 1.5 x ULN if documented hepatic involvement; or 
total bilirubin ≤ 3 x ULN with direct bilirubin ≤ 1.5 x ULN in patients with 
documented Gilbert’s Syndrome. 
o Lipase ≤ 1.5x ULN 
o LVEF ≥ 50% 
o Hemoglobin A1c ≤ 8.5% 
 
 
6.3 
Subject Exclusion Criteria 
 
Patients eligible for this study must NOT MEET ANY of the following criteria: 
 
• 
Patient has a history of non-compliance to medical regimen or inability to grant consent 
• 
Patient is concurrently using other approved or investigational antineoplastic agent with 
the exception of BTK or PI3K inhibitors in patients who had these agents as the last line of 
treatment 
o Patients on BTK or PI3K inhibitors will be continued on therapy as they transition to 
protocol therapy 
• 
Patient has not recovered to Grade 1 or better (except alopecia) from related side effects 
of any prior antineoplastic therapy 
• 
Patient has had major surgery or a wound that has not fully healed within 4 weeks of 
starting study drugs. 


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• 
Patients who have had chemotherapy or radiotherapy within 2 weeks (6 weeks for 
nitrosoureas or mitomycin C) prior to entering the study or those who have not recovered 
from adverse events due to agents administered more than 2 weeks earlier. 
• 
Patients who have undergone an allogenic hematopoietic stem cell transplant 
• 
Patient has active or history of central nervous system (CNS) disease or meningeal 
involvement. 
• 
Patient has history of clinically significant interstitial lung disease and/or lung disease that 
severely impairs lung function (as judged by the investigator) 
• 
Patient has history of stroke or intracranial hemorrhage ≤ 6 months from starting study 
drugs. 
• 
Patient has impairment of gastrointestinal (GI) function or GI disease that may significantly 
alter the absorption of study drug (e.g., ulcerative diseases, uncontrolled nausea,  
vomiting, diarrhea, malabsorption syndrome, or small bowel resection) 
• 
Patient has 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, Left Ventricular 
Ejection Fraction (LVEF) <50% as determined by Multiple Gated acquisition (MUGA)  scan 
or echocardiogram (ECHO), unstable angina pectoris, symptomatic pericarditis, QTcF > 
480 msec on the screening ECG (using the QTcF formula) 
• 
Patient has a concurrent active malignancy. Malignancies treated with a curative intent 
with an expected life expectancy ≥ 5 years or a non-competing life expectancy risk are 
eligible (i.e. adequately treated basal or squamous cell carcinoma, non-melanomatous 
skin cancer, early stage breast cancer, treated prostate cancer or any other cancer from 
which the patient has been disease free for ≥ 3 years). 
• 
Patient with known history of human immunodeficiency virus (HIV), or any uncontrolled 
active systemic infection. 
• 
Patient has CMV viremia (peripheral blood CMV PCR positive), acute viral hepatitis 
(typically defined by elevated AST/ALT), or a history of chronic or active HBV or HCV 
infection. HBV infection is defined as having HBsAg and/or HBcAb positive test with 
concurrent detectable HBV DNA levels. HCV infection is defined as detectable HCV RNA 
levels. 
• 
Patient requires treatment with a strong or moderate cytochrome P450 (CYP) 3A4 
inhibitors, and inducers, and the treatment cannot be discontinued or switched to a 
different medication prior to starting study drug.  Moderate and strong CYP modulators 
(inducers and inhibitors) should have a washout period of at least 5-6 half-lives before 
initiating ibrutinib or copanlisib. 
• 
Patients with known bleeding diathesis (e.g. von Willebrand ‘s disease) or hemophilia 
• 
Patient is currently receiving warfarin or other Vitamin K antagonist. Therapy with heparin, 
low molecular weight heparin (LMWH), or fondaparinux is allowed. Refer to Section 9.5 for 
Concomitant medication 
• 
Patients with Child Pugh Class B or C hepatic cirrhosis 
• 
Patients with any life threatening illness, medical condition or organ system dysfunction 
that in the opinion of the investigator could compromise the subject’s safety, interfere with 
absorption of metabolism of study drugs or put the study outcomes at undue risk. 


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7.0       RECRUITMENT PLAN 
 
The study will be conducted at Memorial Sloan Kettering Cancer Center. Patients will be treated by 
the lymphoma service at MSKCC. Every effort will be made to include women and minorities in this 
research study. Patients will be recruited by the treating team of physicians and medical 
professionals. The consenting attending physician will inform patients of their diagnosis, current 
treatment options, including standard treatment, and the risks, benefits, and experimental nature of 
this treatment program. All patients will be required to sign a statement of informed consent that 
conforms to FDA and IRB guidelines. 
 
 
8.1 
PRETREATMENT EVALUATION 
 
Prior to initiating treatment: 
 
• 
Prior biopsy with pathologic confirmation of MCL. 
• 
Archival block 10-15 x 10 micron unstained slides and 1 H&E will be requested. A 
minimum of 40 micron material is requested. 
• 
If archival tissue is not available, patients will be asked to provide informed consent for an 
optional repeat biopsy. 
Within 4 weeks prior to initiating treatment: 
 
• 
Medical history and demographics 
• 
Complete history and physical exam (including weight, pulse, blood pressure, 
temperature, ECOG performance status) 
• 
Medication review 
• 
Hepatitis B surface antigen and Hepatitis B core antibody (HBV DNA PCR is only required 
if HBsAg is positive) 
• 
Hepatitis C antibody 
• 
HIV testing 
• 
Cytomegalovirus PCR testing 
• 
ECG 
• 
Echocardiogram or MUGA to evaluate cardiac function 
• 
PET scan 
• 
CT chest/abdomen/pelvis and neck CT if clinically indicated (MRI will be used for those 
who are unable to undergo CT scans). 
 
Within 1 week prior to initiating treatment: 
 
• 
Blood work: CBC with differential, PT/INR, electrolytes (Na, K, Cl, CO2), BUN, Cr, total 
bilirubin, total protein, albumin, AST, ALT, alkaline phosphatase, uric acid, LDH, 
magnesium, phosphorus, lipid panel, thyroid function tests, hemoglobin A1c, fructosamine, 
amylase, lipase, urinalysis, GFR 
• 
Serum beta-HCG (for WOCBP only) to assess for pregnancy 


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9.0       TREATMENT/INTERVENTION PLAN 
 
9.1. 
Study Treatment 
 
The investigational agents to be used in this study are copanlisib and ibrutinib. Copanlisib is given 
intravenously on days 1, 8, and 15 of 28 day cycles. Ibrutinib is given orally every day on 28 days 
cycles. The maximum duration of treatment is 36 cycles not exceeding 36 months. Dose changes 
or interruptions are allowed per below guidelines and must be recorded appropriately. 
Study personnel will maintain a log of all drugs supplied to the patient. Drug supplies for each 
patient will be inventoried and accounted for. Subjects will be given diary cards to complete for the 
ibrutinib taken at home. Subjects must bring the diary cards to the site on every visit so study site 
personnel can verify compliance. 
 
 
 
 
9.1.1 Copanlisib administration: 
 
Copanlisib is supplied as lyophilized preparation in a 6-mL injection vial. The total amount of 
copanlisib, BAY 80-6946, per vial is 60 mg. The solution for IV infusion is obtained after 
reconstitution of the lyophilisate with 0.9% sodium chloride solution. Please refer to the Pharmacy 
Instructions for detailed instructions for the reconstitution of the lyophilisate and for further dilution 
of the reconstituted solution. Study drug is administered in a normal saline solution, intravenously, 
over 1 h (or per MSK protocol). No intravenous glucose preparations should be administered on 
the days of infusion. Dosing is weekly for the first 3 weeks of a 28-day cycle (on Days 1, 8, and 15), 
followed by a 1-week break (i.e., no infusion on Day 22). Patients will be on 30 mg, 45 mg or 60 mg 
depending on their dose level. 
Laboratory blood tests on day 1 of copanlisib treatment must follow the below criteria: 
Figure 9-1. Trial schema of copanlisib and ibrutinib 


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Table 9-1: Laboratory test criteria for Day 1 dose of subsequent cycles 
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/dL a 
ANC 
≥ 1 x 109 
Platelets 
≥ 75 x 109b 
ANC = Absolute neutrophil  count; 
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 patient is hemodynamically  stable and in opinion of 
investigator  benefits outweigh risks. Rationale and treatment should be recorded in 
source document and eCRF. 
b: If Platelets is <75 x 109 but ≥ 50 x 109  on day of planned study drug administration, it 
is permissible to give  study drug if this is related to disease. 
 
Glucose Monitoring for copanlisib administration 
Treatment – Cycle 1 
Cycle 1, Day 1 
The following assessments should be performed on Cycle 1, Day 1 before receiving study 
treatment unless otherwise specified. 
• 
On Cycle 1 Day 1, patients should be fasting for at least 8 h prior to the pre-dose glucose 
measurement. Fasting glucose should be < 125 mg/dl for non-diabetic patients or <160 
mg/dl for diabetic patients. 
• 
Glucose will be measured at 0 h (pre-dose) and post dose 1 hour and 2 hours after the end 
of copanlisib infusion (deviation of  15 min is allowed). Additional measurements to be 
performed at the clinic as clinically indicated. 
NOTE: Patients should be educated on the signs and symptoms of hyperglycemia, suchas frequent 
urination, increased thirst, blurred vision, headaches and difficulty concentrating and must report 
these to the investigator or their physician immediately. If patient needs  to take a meal, then 
glucose test should be taken prior to meal intake. 
 
 
Cycle 1 Day 8, Cycle 1 Day 15, and all subsequent doses 
• 
Fasting is not required before first glucose measurement. 
o If patient is fasting, glucose should be <160 mg/dl prior to copanlisib infusion 
o If patient is non-fasting, glucose should be <200 mg/dL prior to copanlisib infusion 
• 
Glucose will be measured prior to and after the end of copanlisib study drug IV infusion 
(deviation of  10 min is allowed, except for the pre-dose measurement). Patients are not 
required to be fasting prior to pre-dose glucose measurement. 
 
Blood pressure measurement on treatment days 


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Blood pressure will be measured every 5 – 10 minutes prior to each copanlisib dose (no more than 
4 measurements) until there are two consecutive results < 150/90 mmHg. If blood pressure is ≥ 
150/90 mmHg, the investigator can consider a medical intervention or delaying the infusion of study 
drug. The patient should rest for 5-10 minutes before blood pressure is recorded. 
On infusion days, blood pressure will be measured at 0 h (pre-dose), 30 min (mid-infusion), 60 min 
(end of infusion), and 1 h and 2 hours after the end of infusion 
Note: a window of ±10 min is allowed for all BP measurements 
 
 
Ibrutinib administration: 
Ibrutinib will be administered once daily continuously until disease progression, intolerance, or 
completion of 36 cycles, not exceeding 36 cycles since start of therapy whichever comes first. 
Patients will be instructed to take 420 mg or 560 mg depending on the treating cohort. 
Ibrutinib should be administered at about the same time each day orally with 8 ounces or 
approximately 240 mL of water. The drug should be swallowed intact and subjects should not 
attempt to crush dissolve the tablets in water. If a dose is missed, the dose may be taken as soon 
as possible on the same day with a return to the normal schedule the following day. Extra tablets 
of ibrutinib should not be taken to make up for the missed dose. If a patient vomits the dose, the 
dose should not be retaken. On days when patients are receiving copanlisib and ibrutinib, patients 
should take their dose of ibrutinib in clinic just prior to the copanlisib infusion. 
 
 
9.2. Definitions of dose limiting toxicity, maximum  tolerated dose, and recommended phase 
II dose 
A dose limiting toxicity (DLT) is defined as any of the following adverse events occurring within cycle 
1 (28 days). A maximum tolerated dose (MTD) is defined as the highest dose studied for which the 
incidence of DLT is less than 33%. The recommended phase II dose (RP2D) is the dose with clinical 
efficacy without major toxicity. 
• 
Any AE resulting in a dose delay of >7 consecutive days within the DLT period based on 
dose modifications in Table 9-6 
• 
Non hematologic AE: 
o Hemorrhage 
requiring 
transfusion 
or 
procedural 
intervention, 
intracranial 
hemorrhage, intraocular hemorrhage of any grade 
o Grade 4 arterial hypertension 
o Any Grade ≥3 AE EXCEPT noted below 
▪ 
Grade ≥ 3 nausea, vomiting, constipation or diarrhea persisting for <48 hours 
▪ 
Grade ≥3 rash or skin hypersensitivity persisting for <7 days 
▪ 
<7 days of Grade ≥3 fatigue 
▪ 
<7 days of Grade ≥ 3 edema 
▪ 
<7 days of post infusion blood glucose >250mg/dL despite optimal glucose 
management or <2 days of blood glucose >500mg/dL despite optimal 
glucose management 


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• 
Grade 3 (or 4) isolated electrolyte abnormalities that resolve, with or without intervention, to 
Grade ≤ 2 in less than 72 hours Hematologic AE 
o Any Grade 4 neutropenia lasting more than 7 consecutive days 
o Febrile  neutropenia  ≥  Grade  3  (ANC  <1000/mm3 with a  single  temperature  of 
>38.3C or a sustained temperature of ≥ 38C for more than 1 hour 
o Grade 4 thrombocytopenia lasting more than 7 days or Grade 3 thrombocytopenia 
with evidence of ≥ Grade 2 bleeding 
• 
Any Grade 5 toxicity is considered a DLT. 
 
9.3. Phase I dose escalation phase 
 
Cohorts of 3-6 patients each will be treated with escalating doses of copanlisib and ibrutinib (Table 
9-2). If unforeseen toxicities are observed in 2 patients treated at dose level 1, the next cohort will 
be treated at dose level -1. 
 
Table 9-2. Dose  Escalation Levels 
No of pts 
Cohort  Level 
Copanlisib (mg/dose ) 
Ibrutinib  (mg/day) 
3-6 
-1 
45 
420 
3-6 
1 
45 
560 
3-6 
2 
60 
560 
 
 
• 
At least 2 patients will be treated at each dose level. All patients treated at the preceding 
dose level will be observed at minimum of 28 days (1 cycle) before dose escalation occurs. 
• 
Dose escalation will proceed as follows: 
o If none of the initial 3 patients in a cohort experiences dose limiting toxicity (DLT), 
then a new cohort of 3 patients will be treated at the next higher dose level. 
o If one of 3 patients in a cohort experiences DLT, then up to an additional 3 patients 
will be treated at the same dose level. Escalation will continue if only one of the 6 
patients experiences a DLT. 
o In the event that ≥2 of 3 patients, or ≥2 of 6 patients in the first cohort experiences a 
DLT related to study drugs, then the next cohort of patients will be treated at a lower 
dose level (dose level -1) and no further dose escalation will occur in this step. Three 
patients will be enrolled at this dose level, if 0 or 1 patients experiences a study drug 
related DLT, a further 3 patients will be enrolled at this dose level. If overall 0 or 1 
patient experiences a DLT at this dose level, this dose will be established as 
copanlisib/ ibrutinib maximum tolerated dose (MTD). 
o If ≥2 or more patients in the cohort experience DLT, then the maximum tolerated 
dose (MTD) will have been exceeded, and no further copanlisib and ibrutinib dose 
escalation will occur. The previous dose will be considered as the MTD. 
o If only 3 patients were treated at the dose level under consideration as the MTD, 
then up to an additional 3 patients will be accrued. If no more than 1 of 6 patients at 
that copanlisib and ibrutinib dose level experiences DLT, than that dose level will be 
confirmed as the MTD. If ≥2 or more patients in that cohort experience DLT, than 
the previous dose level will be studied in the same fashion. 


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The maximum tolerated dose (MTD) is the highest combination drug dosage not causing medically 
unacceptable DLT in ≥33% (i.e. 2/6 patients) in the first cycle of treatment. The recommended 
phase II dose (RP2D) is the dose balancing clinical efficacy and toxicity. 
9.4. Phase II dose expansion 
 
Patients will be enrolled at the MTD of copanlisib and ibrutinib combination. The safety events in 
the expansion cohorts will be reviewed on an ongoing basis by the primary investigator and several 
stopping rules are in place to protect patients from excessive toxicity (Section 14). Based on this 
review, we may adjust treating dose level to the RP2D. 
 
Table 9-3. Phase II Simon two stage mini-max dose expansion cohorts 
Disease 
1st stage 
Response  Needed 
2nd  stage 
Total Accrual 
Mantle cell 
lymphoma 
18 
(include 6 patients 
from phase I study 
at MTD/RP2D) 
If ≥5 patients with 
CR within 6 
months, proceed 
to 2nd stage 
15 
33 patients 
 
 
9.5. Pharmacokinetics 
 
Plasma concentrations of copanlisib, its metabolite M-1, and other metabolites if needed, and of 
ibrutinib will be measured at the following time points for pharmacokinetic (PK) assessment of 
patients in the phase I dose level 1 and 2 cohorts (see Table 9-4). 
 
Table 9-4. Pharmacokinetic assessments 
Cycle Day 
Planned time (h) 
after start of 
administration 
Acceptable 
time 
window 
Ibrutinib PK 
sampling 
Copanlisib 
PK sampling 
Ibrutinib 
dosing 
Copanlisib 
dosing 
1 
15 
0 (pre-dose) 
- 30 min 
X 
X 
X 
X 
1 (end of Infusion) a 
+ 5 min 
X 
X 
1.5 
± 15 min 
X 
X 
2.5 
± 30 min 
X 
X 
3.5 
± 30 min 
X 
X 
4.5 
± 30 min 
X 
X 
6 
± 30 min 
X 
X 
Cmax = Maximal plasma concentration; EoI = End of infusion; PK = Pharmacokinetic(s). 
a: The end of infusion sample for copanlisib and M-1 metabolite should be collected within 5 min after the end of 
infusion (EoI) of copanlisib for adequate characterization of Cmax. 
 
 
Samples should be collected at the planned time points as per Table 9-4, ideally within the allotted 
time windows. If samples are drawn outside the time window, it will not be considered a protocol 
deviation but the actual time of the blood draw should be noted. If clinically indicated, PK samples 
may be skipped without being considered a protocol deviation. For all samples, it is of importance 
that the actual date and time of blood sampling are documented in the eCRF because PK 
calculations will be based on the actual sampling times relative to dosing times. 
Details about the collection, processing, storage and shipment of samples are provided separately 
in the Laboratory Manual. 


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9.6. Concomitant Medications 
 
9.6.1 Permitted Concomitant Therapy 
 
• 
Standard therapies for concurrent medical conditions 
• 
Treatment with non-conventional therapies (for example herbs or acupuncture), and 
vitamin/mineral supplements is acceptable provided that they do not interfere with the study 
endpoints, in the opinion of the Investigator. St John’s Wort is not permitted. 
• 
Bisphosphonates 
• 
Close monitoring is recommended according to standard of care. If either of these values is 
above the therapeutic range, the doses should be modified and the assessments should be 
repeated weekly until it is stable. 
• 
Antiemetics: Prophylactic anti-emetics may be administered according to standard practice. 
The routine use of standard antiemetics, including steroids, 5-HT3 blockers, such as 
granisetron, ondansetron, or an equivalent agent, is allowed as needed. 
• 
Palliative and supportive care for the other disease-related symptoms and for toxicity 
associated with treatment will be offered to all patients in this trial. 
• 
Patients may receive palliative and supportive care for any underlying disease 
• 
Palliative irradiation shall be permitted provided that: 
o In the opinion of the investigator, the patient does not have progression of disease. 
o The radiation field does not encompass a target lesion 
o The  radiation  field  does  not  encompass  a  lung  field  (to  reduce  the  risk  for 
pneumonitis). 
• 
Low-dose aspirin (maximum 100 mg/day) and low-dose heparin are permitted. 
• 
Patients taking narrow therapeutic index medications should be monitored proactively, if 
these medications cannot be avoided. These medications may include quinidine, 
cyclosporine, and digoxin 
• 
Short term systemic corticosteroids will be allowed for the management of acute conditions 
• 
Use of neutrophil growth factors (filgrastim and pegfilgrastim) is not permitted in the dose 
escalation phase during cycle 1 unless a DLT has already been determined. Neutrophil 
growth factor support is allowed in the dose expansion portion of the study to treat 
neutropenia but not prophylactically. 
 
 
9.6.2 Prohibited Concomitant Therapy 
The following medications are prohibited during study treatment in the study (see Table 9-5 
below): 
This list is not comprehensive and is only meant to be used as a guide: 
 
• 
Strong inhibitors or inducers of CYP3A4/5 
• 
Other investigational and antineoplastic therapies 
• 
Anti-arrhythmic therapy other than beta blockers or digoxin 
• 
Ongoing immunosuppressive therapy 
• 
Concomitant radiotherapy (it is assumed that radiation would be indicated only in case of 
progression, when the patient would come off study medication anyway) 


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• 
Herbal medications include, but not limited to: St. John’s wort, Kava, ephedra (ma huang), 
gingko biloba, dehydroepiandrosterone (DHEA), yohimbe, saw palmetto, black cohosh and 
ginseng. Patients should stop using all herbal medications at least 7 days prior to first dose 
of study treatment. 
 
 
Table 9-5: List of prohibited medications during the study 
Category 
Drug name 
Strong CYP3A Inhibitors 
Voriconazole,  Boceprevir,  clarithromycin, cobicistat, 
conivaptan,  danoprevir/ritonavir,   eltegravir/ritonavi r, 
grapefruit  juice, indinavir/ritonavi r,  itraconazole, 
ketoconazole, lopinavir/ritonavi r,   mibefradil, 
nefazodone,  nelfinavir,  posaconazole,  ritonavir, 
saquinavir,  saquinavir/ritonavir,   telaprevir, 
telithromycin, tipranavir/ritonavir,   troleandomycin, 
Moderate  CYP3A Inhibitors 
Grapefruit,  grapefruit  hybrids, pummelos, star-fruit, 
and Seville oranges  (citrus paradisi fruit juice) 
Strong CYP3A Inducers 
Avasimibe,  carbamazepine,  mitotane, phenobarbital, 
phenytoin, rifabutin,  rifampin (rifampicin),  St. John's 
wort (hypericum  perforatum) 
Other Investigational  and 
Antineoplastic  Therapies 
Other investigational  therapies  must not be used 
while the patient is on the study. Anticancer therapy 
(chemotherapy,  biologic or radiation therapy, and 
surgery) other than the study treatments must not be 
given  to patients while the patient is on the study 
medication. If such agents are required for a patient 
then the patient must be discontinued from  the study. 
Herbal  Preparations/  Medications 
Herbal  preparations/medications   should be reviewed 
for appropriateness  and interactions  throughout  the 
study. These herbal  medications include, but are not 
limited to: St. John’s wort, Kava,  ephedra (ma 
huang),  gingko biloba, dehydroepiandrosterone 
(DHEA), yohimbe, saw palmetto, and ginseng. 
Patients should stop using these herbal  medications 
7 days prior to first dose of study drug 
Palliative  Radiotherapy 
No dose modification of study treatment is needed 
during  radiotherapy. 
 
 
9.6.3 Drug-drug Interactions 
 
Guideline for Use of CYP Inhibiting/Inducing  Drugs 
Both ibrutinib and copanlisib are metabolized primarily by CYP3A4. Plasma concentrations of 
ibrutinib and copanlisib may be increased from concomitant use of strong or moderate CYP3A4 
inhibitors. . Consequently, strong or moderate CYP3A4 inhibitor and inducers should be 
avoided. Ibrutinib and its major metabolite (dihydrodiol) have been shown, in vitro, to be weak 
inhibitors and inducers of CYP450 isoenzymes. Note that with the data available, it is not 
possible to confirm whether such interactions will occur in patients. Therefore, investigators, at 
their  discretion,  may  administer  concomitant  medications  known  to  be  metabolized  by 


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CYP3A4/5, CYP2C8, CYP2C9 and CYP2C19. The use of moderate and strong  CYP3A 
inducers and inhibitors is strictly prohibited during the DLT evaluation period. 
During phase II, strong inhibitors of CYP3A suchas ketoconazole, indinavir, nelfinavir, ritonavir, 
saquinavir, clarithromycin, telithromycin, itraconazole, and nefazodone, etc should be avoided. 
If strong CYP3A inhibitors cannot be avoided, consider holding ibrutinib and copanlisib while on 
CYP3A inhibitor if it will be used short-term. Re-initiate ibrutinib and copanlisib after 5 to 6 half- 
life washout period of the CYP3A inhibitor. If concurrent therapy with strong inhibitors cannot 
be avoided, reduce the copanlisib dose to 45 mg. If antifungal therapy is required, strong 
inhibitors of CYP3A4,  including ketoconazole,  itraconazole, posaconazole, and voriconazole 
should be avoided. Moderate inhibitors of CYP3A4, such as isavuconazonium sulfate, may be 
used. If used with a moderate CYP3A4 inhibitor, ibrutinib dosing should be reduced to 140 mg 
daily. No dose adjustment to copanlisib is needed. Avoid grapefruit and Seville oranges during 
ibrutinib treatment, as these contain moderate inhibitors of CYP3A (see Appendix 1). 
During phase II, strong inducers of CYP3A such as enzyme-inducing anti-epileptics 
(carbamazepine, phenytoin, etc), rifampin, and St. John’s Wort etc, should be avoided. Co- 
administration of ibrutinib with strong CYP3A inducers, rifampin, in healthy subjects decrease 
ibrutinib plasma concentrations by approximately 10-fold. Consider alternative agents with less 
CYP3A induction. If strong CYP3A inducers cannot be avoided, consider holding ibrutinib and 
copanlisib while on CYP3A inducer if it will be used short-term. Re-initiate ibrutinib and 
copanlisib after 5 to 6 half-life washout period of the CYP3A inducer.  Additionally, corticosteroid 
doses more than 4mg oral daily of dexamethasone-equivalent (>26mg prednisone) may induce 
CYP3A enzyme, so need to be discussed with investigators. 
A list of common, moderate to strong, CYP3A inhibitors or inducers is provided in the 
appendices; a comprehensive list of inhibitors, inducers, and substrates may be found at  
http://medicine.iupui.edu/clinpharm/ddis/main-table/. This website is continually revised and 
should be checked frequently for updates (Appendix 1). 
Sensitive substrates of CYP3A should be used with caution. A comprehensive list of sensitive 
substrates 
of 
CYP3A 
could 
be 
found 
on 
FDA 
website:  
https://www.fda.gov/drugs/developmentapprovalprocess/developmentresources/druginteractio  
nslabeling/ucm093664.htm#table3-1. 
 
Concomitant Use of Antiplatelet  Agents and Anticoagulants 
Ibrutinib may increase the risk of hemorrhage in patients receiving antiplatelet or anticoagulant 
therapies. The mechanism for this bleeding is not well understood. 
Warfarin or vitamin K antagonists should not be administered concomitantly with ibrutinib or 
copanlisib. Supplements such as fish oil and vitamin E preparations should be avoided. Use 
ibrutinib with caution in subjects requiring other anticoagulants or medications that  inhibit 
platelet function. 
Subjects receiving antiplatelet agents in conjunction with ibrutinib should be observed closely 
for any signs of bleeding or bruising and ibrutinib should be withheld in the event of any bleeding 
events. 


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Subjects requiring the initiation of anticoagulation therapy (other than warfarin or a vitamin K 
antagonist, which should be avoided) during the course of the study should have treatment with 
ibrutinib held, the PI should be contacted, and ibrutinib should not be restarted until the subject 
is clinically stable. Subjects should be observed closely for signs and symptoms of bleeding. 
Subjects were excluded from participation in ibrutinib Phase 2 and 3 studies if they required 
warfarin or other vitamin K antagonists. Therefore, ibrutinib should not be administered 
concomitantly with warfarin or other vitamin K antagonists. Ibrutinib should be used with caution 
in patients requiring other anticoagulants or medications that inhibit platelet function. Patients 
receiving antiplatelet agents in conjunction with ibrutinib should be observed closely for any 
signs of bleeding or bruising and ibrutinib should be withheld in the event of any bleeding events. 
Supplements such as fish oil and vitamin E preparations should be avoided. Patients with 
congenital bleeding diathesis have not been studied. 
9.7. Dose Continuation, Modification and Interruption 
 
Subjects will be evaluated for AEs at each visit with the NCI CTCAE v5.0 used as a guide for the 
grading of severity. Prior to completion of cycle 1 in both dose escalation or dose expansion phase, 
treatment with either ibrutinib, copanlisib or both may be interrupted for ≤ 7 days for any reason and 
then resumed at the same dose. If patients take less than 2 infusions of copanlisib or less than 14 
days of ibrutinib during the intended dose of cycle 1, they will be excluded from the DLT analysis 
and replaced. However if a patient takes less than 14 days of  the intended dose of cycle 1 due to 
a DLT, they will be included in the DLT analysis and not replaced. After completion of cycle 1, 
study drugs (either ibrutinib, copanlisib) may be interrupted for ≤ 28 days for any reason and then 
resumed at same or reduced dose. The investigator may remove any patient from study for any 
toxicity if the investigator believes it is in the best interest of the patient to discontinue study 
treatment. 
Intrapatient dose reduction will not be allowed during cycle 1 unless a DLT has occurred and been 
counted. This is in order to accurately determine the safe and tolerable dose of copanlisib when 
used in combination with ibrutinib. Dose reductions may be made to ibrutinib and/or copanlisib 
during cycles 2 and beyond. If a toxicity can be ascribed to a specific study drug, then that drug 
may be dose modified while the non-offending drug may be maintained. Whether to dose modify 
ibrutinib or copanlisib is at the discretion of the treating physician. 
If the patient experiences unacceptable toxicity that fails to resolve after a maximum dose delay of 
28 consecutive days, then the patient should be discontinued from the study treatments. In cases 
of treatment delays from reactivation of CMV, treatment delays can be extended for up to 2 months. 
In exceptional situations, if the patient is clearly benefiting from the study treatment (i.e. stable 
disease or better) and in the opinion of the investigator no safety concerns are present, the patient 
may remain on the study treatment. Patients who discontinue from study for a study related adverse 
event or an abnormal laboratory value must be followed as described in Section 10. 
Each patient is allowed a maximum of two dose reduction of each study drug. Dose reduction of 
copanlisib or ibrutinib indicates treatment at the next lower dose of copanlisib or ibrutinib based on 
Table 9-6. If after treatment interruption, resolution of toxicity, and treatment resumption at same 
dose, the subject presents with the same toxicity at the same severity, then the next treatment re- 


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initiation must resume at the next lower dose level irrespective of duration. A patient must 
discontinue therapy if after therapy is resumed at a lower dose, the same toxicity recurs with the 
same or worse severity. Copanlisib and ibrutinib dose modification guidelines for specific toxicities 
are outlined in Table 9-7. 
 
Table 9-6. Intrapatient dose reduction* 
Drug 
Maximum Dose 
Levels 
Reduction  Dose 
Level  1 
Reduction  Dose 
Level  2 
Copanlisib 
60 mg 
45 mg 
30 mg 
Ibrutinib 
560 mg daily 
420 mg daily 
280 mg daily 
*Dose reduction starts from the treating dose. 
 
Dose escalation is allowed after the DLT period for ibrutinib to the FDA approved dose levels of 560 
mg. However, patients will only be allowed to escalate to this dose once the DLT evaluation period 
for Dose Level 1 has passed and the dose will not exceed what has been deemed the MTD in other 
patients. There will be no intrapatient dose escalation of copanlisib. Once a dose reduction for 
copanlisib of a patient has occurred, the dose level may not be re-escalated during subsequent 
treatment cycles. 
The sections below describe dose reduction steps for patients enrolled in the expansion phase of 
the study. For patients in the dose expansion phase, the dose must be held per these guidelines 
and these dose reduction steps can be followed after cycle 1 and per discussionwith the PI. Inability 
to meet treatment criteria will result in holding the dose. If patients have been dose reduced to dose 
level -1 and continue to meet dose modification criteria to reduce the dose, they will be removed 
from study treatment. 


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Table 9-7. Dose modification guidelines 
Toxicity Category 
Severity (CTCAE 5.0 Grade) 
Dose Modifications for ibrutinib 
Dose Modifications for copanlisib 
HEMATOLOGIC 
 
Anemia 
Dose modify/hold copanlisib. May dose modify/hold ibrutinib as clinically indicated 
Grade ≥3 (Hgb <8 g/dL) 
Investigator discretion for ibrutinib dosing 
Delay copanlisib infusion until Hgb resolves to ≤ grade 3 
Dose reduction by 1dose level lower at the investigator’s 
discretion. If more dose reductions are required than 
allowed per protocol, discontinue copanlisib permanently. 
The lowest dose level is 30 mg. 
Neutropenia 
May dose modify/hold either ibrutinib, copanlisib or both as clinically indicated 
Grade 1 (ANC < LLN - 1.5 x 109/L) 
Grade 2 (ANC < 1.5 - 1.0 x 109/L) 
Maintain ibrutinib dose 
Maintain copanlisib dose 
Grade ≥3 (ANC < 1.0 x 109/L) 
Delay ibrutinib dose until resolves to ≤ Grade 1, then: 
If resolved ≤ 7 days, then maintain dose level 
If resolved > 7 days, then reduce 1 dose level 
Growth factor support is allowed after cycle 1. 
Delay copanlisib infusion until ANC resolves to < grade 3 
Dose reduction by 1dose level lower at the investigator’s 
discretion. If more dose reductions are required than 
allowed per protocol, discontinue copanlisib permanently. 
The lowest dose level is 30 mg. 
Growth factor support is allowed after cycle 1. 
Febrile neutropenia 
(ANC < 1.0 x 109/L, with a single 
temperature of ≥ 38.3 °C or a 
sustained temperature of ≥ 38 °C for 
more than one hour ) 
Delay ibrutinib dose until resolves to ≤ Grade 1, then 
reduce 1 dose level 
Growth factor support is allowed after cycle 1. 
Delay copanlisib until febrile neutropenia resolves 
Dose reduction by 1dose level lower at the investigator’s 
discretion. If more dose reductions are required than 
allowed per protocol, discontinue copanlisib permanently. 
The lowest dose level is 30 mg. 
Growth factor support is allowed after cycle 1. 
 
Thromb ocytopenia 
May dose modify/hold either ibrutinib, copanlisib or both as clinically indicated 
Grade 1 (PLT < LLN - 75 x 109/L) 
Grade 2 (PLT < 75 - 50 x 109/L) 
Maintain ibrutinib dose 
Maintain copanlisib dose 
Grade 3 (PLT < 50-25 x 109/L) 
Delay ibrutinib dose until resolves to ≤ Grade 1, then: 
If resolved ≤ 7 days, then maintain dose level 
If resolved > 7 days, then reduce 1 dose level 
Delay copanlisib infusion until platelet resolves to >75k 


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Grade 4 (PLT < 25 x 109/L) 
Delay ibrutinib dose until resolves to ≤ Grade 1, then 
reduce 1 dose level 
Dose reduction by 1dose level lower at the investigator’s 
discretion. If more dose reductions are required than 
allowed per protocol, discontinue copanlisib permanently. 
The lowest dose level is 30 mg. 
 
Bleeding 
Dose modify/hold Ibrutinib because of association with hemorrhagic event. May dose modify/hold copanlisib as clinically indicated 
Grade 1 (mild symptoms; no 
intervention indicated) 
Maintain ibrutinib dose 
Maintain copanlisib dose 
Grade 2 bleeding (medical 
intervention indicated/cauterization) 
Omit ibrutinib dose until resolves to ≤ Grade 1, then 
reduce 1 dose level ibrutinib 
Delay copanlisib infusion 
Dose reduction by 1dose level lower at the investigator’s 
discretion. If more dose reductions are required than 
allowed per protocol, discontinue copanlisib permanently. 
The lowest dose level is 30 mg. 
Grade ≥ 3 hemorrhage or 
hemorrhage resulting in intraocular 
bleeding causing loss of vision, 
transfusion of ≥ 2 units PRBCs, and 
any intracranial hemorrhage 
Discontinue ibrutinib 
Discontinue copanlisib 
RENAL 
May dose modify/hold either ibrutinib, copanlisib or both as clinically indicated 
 
Creatinine elevation 
Grade 1 (Cr <2 x ULN) 
Maintain ibrutinib dose 
Maintain copanlisib dose 
Grade 2 (Cr 2-3x ULN) 
Delay ibrutinib dose until resolves to ≤ Grade 1, then: 
If resolved ≤ 7 days, then maintain dose level 
If resolved > 7 days, then reduce 1 dose level 
Maintain copanlisib dose 
Grade ≥3 (Cr > 3-6 x ULN) 
Discontinue ibrutinib 
First occurrence: Delay copanlisib infusion until resolves to 
≤ Grade 2, no change to next dose 
Second and Third occurrence: Delay copanlisib infusion 
until resolves to ≤ Grade 2, decrease byone dose level 
Fourth occurrence: Discontinue copanlisib 
*Any grade 4 occurrence: discontinue copanlisib 
PULMONARY 
Dose modify/hold copanlisib because of association with pneumonitis. May dose modify/hold ibrutinib as clinically indicated 
 
Pneumonitis 
Grade 1 
Dose delaycopanlisib while treating infection. Resume at 
same dose once infection resolves 
Grade 2 
Dose delayuntil resolves to ≤ Grade 1. Decrease by one 
dose level. 
Second occurrence: Discontinue therapy 
If no symptom recovery ≤Grade 1 within 28 days 
CT scan with lung windows. Consider pulmonaryfunction 
testing includes: spirometry, DLCO, and room air O2 
saturation at rest. Repeat at least every 8 weeks (+/- 1 


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week), (or as per local practice) until return to within normal 
limits. Consider a bronchoscopywith biopsyand / or BAL. 
Grade ≥ 3 
Discontinue copanlisib 
GASTROINTESTINAL 
May dose modify/hold either ibrutinib, copanlisib or both as clinically indicated 
Bilirub in 
(*for patients with 
Gilbert Syndrome 
these dose 
modifications apply to 
changes in direct 
bilirubin only, Bilirubin 
will be fractionated if 
elevated) 
Grade 1 (> ULN - 1.5 x ULN) 
Maintain ibrutinib dose per investigator discretion 
Maintain copanlisib dose level with LFTs* monitored as per 
protocol 
Grade 2 (> 1.5 - 3.0 x ULN) with ALT 
or AST ≤ 3.0 x ULN 
Dose adjustments of ibrutinib per investigator 
discretion 
Omit dose until resolves to ≤ Grade 1, then: 
If resolved ≤ 7 days, then maintain dose level 
If resolved > 7 days, then reduce 1 dose level 
Grade 3 (> 3.0 - 10.0 x ULN) with 
ALT or 
AST ≤ 3.0 x ULN 
Omit dose until resolves to ≤ Grade 1, then: 
If resolved ≤ 7 days, then maintain dose level 
If resolved > 7 days, then discontinue 
Grade 4 (> 10.0 x ULN) 
Discontinue ibrutinib 
Discontinue copanlisib 
AST/ALT Elevation 
Note: confounding 
factors and/or 
alternative causes for 
increased 
transaminases like 
concomitant 
medications, infection, 
hepato-biliary disorder, 
ob struction, liver 
metastasis, etc. should 
be excluded before 
dose 
interruption/reduction 
Grade 1 (> ULN – 3.0 x ULN) 
Maintain ibrutinib dose per investigator discretion 
Maintain dose level with LFTs monitored as per protocol 
Grade 2 (> 3.0 - 5.0 x ULN) without 
total bilirubin elevation to > 2.0 x 
ULN 
Dose adjustments of ibrutinib per investigator 
discretion 
Maintain dose at reduce 1 dose level of copanlisib. 
Grade 3 (> 5.0 - 20.0 x ULN) without 
total bilirubin elevation to > 2.0 x 
ULN 
Omit dose until resolves to ≤ Grade 1, then reduce 1 dose 
level. 
If no recovery in ≤28 days discontinue copanlisib, patient 
off study 
Grade 4 (> 20.0 x ULN) without 
bilirubin elevation to > 2.0 x ULN 
Discontinue ibrutinib 
Discontinue copanlisib 
AST or ALT Elevation 
and concurrent bilirubin 
elevation 
AST or ALT > 3.0 x ULN and total 
bilirubin > 2.0 x ULN 
Discontinue ibrutinib 
*** All patients with ALT or AST >3.0x ULN and total 
bilirubin > 2.0x ULN in the absence of cholestasis ULN 
must immediatelybe withdrawn from copanlisib and 
every attempt should be made to carry out the liver 
event follow-up assessments 
Discontinue copanlisib 
Pancreatitis 
Grade 2 (enzyme elevation or 
radiographic findings) 
Dose adjustments of ibrutinib per investigator 
discretion 
Dose adjustments of copanlisib per investigator discretion 
Grade 3 (medical intervention 
indicated) 
Discontinue ibrutinib 
Discontinue copanlisib 


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*** Hepatic toxicity monitoring (*for patients with Gilbert Syndrome: total and direct bilirubin must be monitored, intensified monitoring applies to changes in direct bilirubin only; the 
monitoring includes the following LFTs: albumin, ALT, AST, total bilirubin (fractionated if total bilirubin > 2.0 x ULN), alkaline phosphatase (fractionated if alkal ine phosphatase is 
grade 2 or higher) and GGT): 
In case of any occurrence of ALT/AST, or bilirubin* increase ≥ grade 2 the liver function tests must be monitored weeklyor more frequentlyif clinicallyindicated until resolved to ≤ 
grade 1 
In case of any occurrence of ALT/ AST, or bilirubin* increase ≥ grade 3 the liver function tests must be monitored weeklyor more frequently if clinicallyindicated until resolved to ≤ 
grade 1; hereafter the monitoring should be continued every other week or more frequently if clinicallyindicated until the e nd of treatment with study medication 
Patients who discontinued studytreatment should be monitored weekly, including LFTs* or more frequentlyif clinicallyindicated until resolved to ≤ grade 1 or stabilization (no 
CTCAE grade change over 4 weeks). 
ENDOCRINE 
 
Hyperglycemia 
Dose modify/hold copanlisib because of association with hyperglycemia. May dose modify/hold ibrutinib as clinically indicated 
Level 1: Fasting glucose > 125 – 
160 mg/dL 
Maintain ibrutinib dose per investigator discretion 
Maintain copanlisib dose level 
Level 2:  Fasting glucose > 160 – 
250 mg/dL 
Maintain copanlisib dose level. 
●If signs or symptoms of hyperglycemia (for example, 
mental status changes, excessive thirst, polyuria), manage 
as for Level 3 hyperglycemia (see below) 
●If asymptomatic, maintain dose and re-check FPG within 
24 hours. If level worsens or improves then follow specific 
level recommendations. If FPG remains at Level 2: 
○Maintain dose level and monitor FPG at least weekly 
until FPG resolves to ≤ Level 1 
○Initiate or intensifymedication with appropriate anti- 
diabetic treatment such as metformin; consider adding a 
second oral agent if not improvement after several days. 
○Instruct patient to follow dietary guidelines according to 
local and/or institutional standards for management of 
diabetes mellitus (such as those provided by the American 
Diabetes Association) during the study 
○If FPG does not resolve to ≤ Level 1 within 14 days 
after institution of appropriate anti-diabetic treatment 
reduce copanlisib by1 dose level 
●Consider referral to endocrinologist for diabetic 
management 
Level 3: > 250 - 500 mg/dL (> 13.9 
- 27.8 mmol/L) 
Immediatelyomit copanlisib, initiate or intensify medication 
with appropriate anti-diabetic treatment, re-check FPG 
within 24 hours. If level worsens or improves then follow 
specific level recommendations. 
If FPG remains at Level 3: 


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●Administer intravenous hydration and intervention for 
electrolyte/ ketoacidosis/hyperosmolar disturbances as 
clinicallyappropriate 
●Continue to omit copanlisib 
●Monitor FPG at least twice weekly until FPG resolves to ≤ 
Level 1 
If FPG resolves to < Level 1 in 7 days or less, then re-start 
copanlisib and reduce by1 dose dose level 
If FPG remains greater than Level 1 severity for more than 
7 days, then discontinue patient from copanlisib 
●Initiate or continue anti-diabetic treatment as appropriate 
○instruct patient to follow dietary guidelines according to 
local and/or institutional standards for management of 
diabetes mellitus (such as those provided by the American 
Diabetes Association) during the study 
○consider use of oral anti-hyperglycemic therapy such as 
metformin 
●Consider referral to endocrinologist for diabetic 
management 
 
Level 4: > 500 mg/dL (≥ 27.8 
mmol/L) 
Dose adjustments of ibrutinib per investigator 
discretion 
Immediatelyomit copanlisib, initiate or intensify medication 
with appropriate anti-diabetic treatment, re-check within 24 
hours. If level improves then follow specific level 
recommendations. 
If FPG is confirmed at Level 4: 
●Administer intravenous hydration and intervention for 
electrolyte/ ketoacidosis/hyperosmolar disturbances as 
clinicallyappropriate 
●Discontinue patient from study 
●Instruct patient to follow dietary guidelines according to 
local and/or institutional standards for management of 
diabetes mellitus (such as those provided by the American 
Diabetes Association) during the study 
●Consider use of oral anti-hyperglycemic therapy such as 
metformin 
●Consider referral to endocrinologist for diabetic 
management 
For non-fasting plasma glucose >500 mg/dL (> 27.8 
mmol/L) accom panied bysigns/symptoms of 
hyperglycemia (for example, mental status changes, 
excessive thirst, polyuria), or presence of blood or urine 


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ketones, discontinue copanlisib and following guidance for 
management of Level 4 fasting plasma glucose (FPG). 
CARDIAC 
 
Arterial hypertension 
Dose modify/hold copanlisib because of association with arterial hypertension. May dose modify/hold ibrutinib as clinically indicated 
Pre-dose measurements 
BP ≥ 150/90 mmHg 
Maintain ibrutinib dose per investigator discretion 
Delay copanlisib until recoveryto <150/90 mmHg 
Consider BP lowering medication. Dosing can proceed on 
the scheduled dayif after at least 2 consecutive 
measurements BP returns to < 150/90 mmHg. If BP doesn’t 
return to < 150/90 mmHg, delay dosing until next visit. 
During infusion: 
Grade 3 
(≥ 160/100 mmHg) 
Dose adjustments of ibrutinib per investigator 
discretion 
Infusion can be interrupted or slowed down and 
administration of BP lowering therapyshould be initiated. 
Infusion maybe resumed when BP has returned to < 150/90 
mmHg at the investigator’s discretion or skipped. 
Subsequent studydrug administrations maybe reduced by 
1 dose level at the investigator’s discretion. 
Post-dose: 
Drug-related Grade 3 
(≥ 160/100 mmHg despite optimal 
anti-hypertensive treatment) 
Dose adjustments of ibrutinib per investigator 
discretion 
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 studydrug administrations maybe reduced by 
1 dose level at the investigator’s discretion. 
Grade 4 (Malignant hypertension, 
transient/permanent neurologic 
deficits, hypertensive crisis) 
Discontinue therapy 
Discontinue therapy 
Left ventricular systolic 
dysfunction 
*Event is considered 
resolved when the 
patient is asymptomatic, 
has a resting ejection 
fraction ≥ 40% and 
≤20% decrease from 
baseline. 
Dose modify/hold copanlisib because of association with cardiac dysfunc tion. May dose modify/hold ibrutinib as clinically indicated 
Asymptomatic, resting ejection 
fraction 40-50%; or 10-20% drop 
from baseline 
Maintain ibrutinib dose per investigator discretion 
Maintain copanlisib dose level, and continue with caution 
Repeat LVEF within 4 weeks or as clinicallyappropriate 
Symptomatic, responsive to 
intervention, ejection fraction 20- 
39% 
or > 20% drop from baseline 
Dose adjustments of ibrutinib per investigator 
discretion 
- Omit copanlisib dose until resolved* (as defined to left), 
then reduce 1 dose level copanlisib 
- LVEF measurement to be repeated, if not resolved* within 
28 days, permanentlydiscontinue patient from copanlisib 
treatment 
Refractory or poorly controlled, 
ejection fraction < 20% 
Discontinue therapy 
Discontinue therapy 
QTc prolongation 
Dose modify/hold copanlisib because of association with QTc prolongation. May dose modify/hold ibrutinib as clinically indicated 
QTc > 500 ms (≥ Grade 3) 
or > 60 ms change from baselineon 
at least two separate ECGs 
Dose adjustments of ibrutinib per investigator 
discretion 
First Occurrence: 
- Omit copanlisib dose 


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- Perform a repeat ECG within one hour of the first QTc of 
> 500 ms or >60 ms from baseline. Repeat as clinically 
indicated until QTcF returns to < 480 ms 
- Seek cardiologyinput; address electrolytes, correct with 
supplements as clinicallyindicated ; review concomitant 
medication 
- Once QTc prolongation has resolved, restarted at one 
lower dose level 
Second Occurrence: 
- Off study 
Atrial fib rillation or atrial 
flutter 
Dose modify/hold ibrutinib because of association with atrial fibrillation. May dose modify/hold copanlisib as clinically indicated 
Grade 1 or 2 
Maintain ibrutinib dose level 
Maintain copanlisib dose level 
Grade 3 (Symptomatic and 
incompletelycontrolled with 
medications or device) 
Omit ibrutinib dose until resolves to ≤ Grade 1, then 
resume at reduce 1 dose level 
Third recurrence: off study 
Dose adjustments of copanlisib per investigator discretion 
Grade 4 
Discontinue ibrutinib 
Discontinue copanlisib 
OTHER CARDIAC 
DISORDERS 
May dose modify/hold copanlisib, ibrutinib or both as clinically indicated 
Grade 1 or 2 
Omit dose until resolved to ≤ Grade 1, then reduce 1 dose level 
Grade ≥ 3 
Off study 
SKIN 
May dose modify/hold copanlisib, ibrutinib, or both based on association with rash 
 
Rash 
Grade 1 
(<10% body surface area BSA; no 
associated erythema or pruritus) 
Maintain ibrutinib dose level 
Consider to initiate appropriate skin toxicitytherapy, e.g. 
with topical corticosteroids B.I.D. and oral antihistamines 
Maintain copanlisib dose level 
Grade 2 
(10 to 30% BSA and associated 
with erythema or pruritus; limited 
instrumental activities of dailyliving 
(ADL)) 
Tolerable Grade 2: 
•Initiate/intensifyappropriate skin toxicitytherapy, e.g. 
with topical steroids B.I.D. and oral antihistamines. 
•Maintain ibrutinib level. 
Intolerable Grade 2 (if considered associated with 
ib rutinib): 
•Omit ibrutinib dose and initiate/intensifyappropriate skin 
toxicity therapy, e.g. with topical steroids B.I.D., oral 
antihistamines and oral steroids. 
First occurrence: 
•If resolved to grade ≤ 1 in ≤ 2 weeks, maintaindose 
level. 
•If resolved grade≤ 1 in more than 2 weeks, ↓ 1 dose 
level. 
Tolerable Grade 2: 
•Initiate/intensifyappropriate skin toxicitytherapy, e.g. with 
topical steroids B.I.D. and oral antihistamines. 
•Maintain copanlisib level. 
Intolerable Grade 2 (if considered associated with copanlisib): 
•First occurrence: Delay infusion until resolves to ≤ Grade 
1, maintain dose level 
•Second and Third occurrence: Delay infusion until 
resolves to ≤ Grade 1, decrease by one dose level 
•Fourth occurrence: Discontinue 
•Start skin directed therapy 


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•Consider continuingskintoxicitytherapyup to 2 weeks 
after re-introduction of ibrutinib. In case of flare after 
cessation of skin toxicitytherapy, consider prompt re- 
implementation. 
Second occurrence: Omit ibrutinib dose andfollow 
treatment guidance above. 
•Once resolved to grade ≤ 1, reduce ibrutinib 1 dose 
level 
According to the investigators discretion, a paired skin 
biopsycould be obtained (from both an affected and an 
unaffected skin area for local histopathology 
assessment) if clinical appropriate. 
 
Grade 3 
(Non-macular, papular rash 
covering >30%BSA with or without 
symptoms) 
•Initiate/intensifyappropriate skin toxicitytherapy, e.g. 
with topical steroids B.I.D., oral antihistamines and oral 
steroids. 
•May continue ibrutinib with short term follow up of rash 
to monitor for improvement 
•If rash does not improve after 5 days on intensified 
approach, then consider stopping ibrutinib. Once 
resolved to grade ≤ 1, consider reducing ibrutinib 1 
dose level. 
•Consider continuing skin toxicitytherapy up to 2 weeks 
after re-introduction of ibrutinib. In case of flare after 
cessation of skin toxicity therapy, consider prompt re- 
implementation. 
•Initiate/intensify appropriate skin toxicity therapy, e.g. with 
topical steroids B.I.D., oral antihistamines and oral steroids. 
•May proceed with copanlisib infusion with short term follow 
up of rash to monitor for improvement 
•If  rash does  not  improve  after  5  days  on  intensified 
approach, then delay infusion of copanlisib. 
•Consider continuing skin toxicity therapy up to 2 weeks 
after re-introduction of ibrutinib. In case of flare after 
cessation of skin toxicity therapy, consider prompt re- 
implementation. 
•First occurrence: Delay infusion until resolves to ≤ Grade 
1, decrease by one dose level 
•Second occurrence: Delay infusion until resolves to ≤ 
Grade 1, decrease by one dose level 
•Third occurrence: Discontinue 
 
Grade 3 
(Macules or papules covering 
>30%BSA with or without 
symptoms) 
•Omit ibrutinib dose and initiate/intensifyappropriate 
skin toxicity therapy, e.g. with topical steroids B.I.D., 
oral antihistamines and oral steroids. 
•Once resolved to grade ≤ 1, reduce ibrutinib 1 dose 
level. 
•Consider continuing skin toxicitytherapy up to 2 weeks 
after re-introduction of ibrutinib. In case of flare after 
cessation of skin toxicity therapy, consider prompt re- 
implementation. 
First occurrence: Delay infusion until resolves to ≤ Grade 1, 
decrease by one dose level 
Second occurrence: Delay infusion until resolves to ≤ 
Grade 1, decrease by one dose level 
Third occurrence: Discontinue 


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According to the investigators discretion, a paired skin 
biopsycould be obtained (from both an affected and 
an unaffected skin area for local histopathology 
assessment) if clinical appropriate. 
Grade 4 
(including other skin toxicity than 
maculo-papular rash) 
Discontinue ibrutinib 
According to the investigators discretion, a paired skin 
biopsycould be obtained (from both an affected and 
an unaffected skin area for local histopathology 
assessment) if clinical appropriate. 
Discontinue copanlisib 
GENERAL 
May dose modify/hold copanlisib, ibrutinib or both as clinically indicated 
Fatigue 
Grade 1 or 2 
Maintain dose level 
Grade 3 
Omit dose until resolves to ≤ Grade 1, then: 
If resolved ≤ 7 days, then maintain dose level 
If resolved > 7 days, then reduce 1 dose level 
Grade 4 
Discontinue therapy 
 
OTHER NON- 
HEMATOLOGIC 
EVENTS 
May dose modify/hold copanlisib, ibrutinib or both as clinically indicated 
Grade 1 or 2 
Maintain dose level 
Grade 3 
Omit dose 
If resolved ≤ 7 days, then maintain dose level 
If resolved > 7 days, then reduce 1 dose level 
Grade 4 
Discontinue therapy 
Note: The investigator mayremove any patient from the study for any toxicity, if investigator believes that it is in the best inte rest of the patient. 
Note: The investigator maydose reduce either ibrutinib or copanlisib. In situations where toxicities are associate with one drug, the investigator must hold and reduce drug associated 
with toxicity. The second drug maybe continued or modified at the investigator’s discretion. 
Note: If any one drug is permanentlydiscontinued, the patient will be taken off study unless in exceptional situations i.e. if the patient is clearlybenefiting from the studytreatment (i.e. 
stable disease or better) and in the opinion of the investigator no safetyconcerns are present, the patient mayremain on the studytreatment. 


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9.8. Management of Toxicities or Procedures 
Reproductive Toxicity 
Copanlisib may cause embryo-fetal harm. Female patients of childbearing potential are advised to 
use highly effective contraception (contraception with a failure rate <1% per year) during and up to 
1 month after treatment with copanlisib. Advise male patients with female partners of childbearing 
potential to use highly effective contraception in addition to a barrier method of contraception during 
and up to 1 month after treatment with copanlisib. 
Based on findings in animals, ibrutinib can cause fetal harm when administered to a pregnant 
woman. Administration of ibrutinib to pregnant rats and rabbits during the period of organogenesis 
caused embryofetal toxicity including malformations at exposures that were 2-20 times higher than 
those reported in patients with hematologic malignancies. Advise women to avoid becoming 
pregnant while taking ibrutinib and for 1 month after cessation of therapy. If this drug is used during 
pregnancy or if the patient becomes pregnant while taking this drug, the patient should be apprised 
of the potential hazard to a fetus. 
Women of child-bearing potential who are sexually active must use highly effective contraception 
during the study and for 1 month after the last dose of ibrutinib or copanlisib. Men who are sexually 
active must use highly effective contraception during the study and for 1 month after the last dose 
of ibrutinib or copanlisib. Subjects should promptly notify the investigator if they, or their partner, 
become pregnant during this period. If a female subject becomes pregnant during the treatment 
period, she must discontinue ibrutinib and copanlisib immediately. Pregnancy in a female subject 
or a male subject’s partner must be reported in the samemanner as a SAE. Womenare considered 
post-menopausal and not of child-bearing potential if they have had 12 months of natural 
(spontaneous) amenorrhea with an appropriate clinical profile (e.g. age appropriate, history of 
vasomotor symptoms) or have had surgical bilateral oophorectomy (with or without hysterectomy) 
at least six weeks ago. For women with therapy-induced amenorrhea, oophorectomy or serial 
measurements of FSH and/or estradiol are needed to ensure postmenopausal status. 
Guidelines for Ibrutinib and Copanlisib Management with Surgeries or Procedures 
Ibrutinib may increase risk of bleeding with invasive procedures or surgery (including excisional 
lymph node biopsies). The following guidance should be applied to the use of ibrutinib in the 
perioperative period for patients who require surgical intervention or an invasive procedure while 
receiving ibrutinib: 
Minor Surgical Procedures 
For 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. 


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For bone marrow biopsies that are performed while the subject is on ibrutinib or copanlisib, it is not 
necessary to hold ibrutinib or copanlisib for these procedures. 
Major Surgical Procedures 
 
For any 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. 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 the discretion of the investigator. 
Copanlisib may be interrupted at the discretion of the treating physician with surgical procedures. 
 
Guidelines for Second Primary Malignancies 
 
Other malignancies (range, 5 to 14%) including non-skin carcinomas (range, 1 to 3%) have 
occurred in patients treated with ibrutinib. The most frequent second primary malignancy was non- 
melanoma skin cancer (range, 4 to 11 %). All new malignant tumors including solid tumors, skin 
malignancies and hematologic malignancies will be reported for the duration of study treatment and 
collected for 30 days post study treatment. 
Management of lymphocytosis  and leukostasis associated with ibrutinib: 
 
Similar to other agents targeting B-cell receptor signaling, transient lymphocytosis is a 
pharmacodynamic effect of ibrutinib, in which the inhibition of BTK-mediated cellular homing and 
adhesion results in a mobilization of tumor cells to the peripheral blood.12 
Upon initiation of ibrutinib, a temporary increase in lymphocyte counts (i.e., ≥ 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. High number of circulating malignant cells 
(>400,000/mcL) may confer increased risk; these patients should be closely monitored. 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. Administer supportive care such as hydration and/or leukapheresis 
as indicated. This observed transient lymphocytosis is usually not associated with an adverse event 
and should not be considered progressive disease in the absence of other clinical findings. 
Management of hematologic toxicity associated with copanlisib 
 
Neutropenia and febrile neutropenia are listed in the current version of investigator’s brochure for 
copanlisib as expected adverse events. Please refer to Table 9-7 for dose modifications based on 
hematologic toxicity. If the guidelines are not followed, the rationale for other measures is to be 
documented in detail in the patient’s medical record. 
Management of Pneumonitis in patients receiving copanlisib 


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Non-infectious pneumonitis has been associated with PI3K inhibitors. The investigator is requested 
to differentiate between non-infectious pneumonitis, and infectious pneumonitis (viral, bacterial, 
fungal), aspiration pneumonitis, or other pneumonitis clearly not due to a potential hypersensitivity 
reaction to the copanlisib infusion; and provide the basis for his/her assessment that it is infectious 
or other, as appropriate. The investigator is requested to report with the most specific clinical terms 
to describe the condition, not simple “pneumonitis”. 
In the event of suspected non-infectious pneumonitis, modify copanlisib treatment as per guidelines 
in Table 9-7 and Table 9-8. If the guidelines are not followed, the rationale for other measures is to 
be documented in detail in the patient’s medical record. 
 
Table 9-8. Management of Pneumonitis 
Worst 
Grade 
Recommended  Investigations 
Recommended 
Management 
Action with 
Copanlisib 
Retreatment 
Dose after 
Recovery 
Grade 1 
CT scans with lung windows.  Repeat  at 
least every  8 weeks (+/- 1 week), (or as 
per local practice) until return to within 
normal limits. 
No specific therapy 
is required 
No change 
NA 
Grade 2 
CT scan with lung windows. Consider 
pulmonary  function testing includes: 
spirometry, DLCO, and room air O2 
saturation at rest. Repeat at least every 
8 weeks (+/- 1 week), (or as per local 
practice) until return to within normal 
limits. Consider a bronchoscopy  with 
biopsy and / or BAL. 
Symptomatic  only. 
Consider 
corticosteroids  if 
symptoms are 
troublesome. 
Dose 
interruption 
until 
recovery  to 
≤ grade 1 
Decrease 
dose to the 
next lowest 
dose level, 
minimum 
dose is 
30mg 
copanlisiba 
Grade 3 
CT scan with lung windows  and 
pulmonary  function testing includes: 
spirometry, DLCO, and room air O2 
saturation at rest. Repeat at least every 
8 weeks (+/- 1 week), (or as per local 
practice) until return to within normal 
limits. Bronchoscopy with biopsy and / 
or BAL is recommended. 
Consider 
corticosteroids  if 
infective  origin is 
ruled out. Taper  as 
medically indicated. 
Discontinue 
copanlisib 
NA 
Grade 4 
CT scan with lung windows  and 
required pulmonary function testing, if 
possible, includes: spirometry, DLCO, 
and room air O2 saturation at rest. 
Repeat at least every 8 weeks (+/- 1 
week), (or as per local practice) until 
return to within normal  limits. 
Bronchoscopy with biopsy and / or BAL 
is recommended  if possible. 
Consider 
corticosteroids  if 
infective  origin is 
ruled out. Taper  as 
medically indicated. 
Discontinue 
copanlisib 
NA 
 
 
Guidelines for the treatment of copanlisib induced 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. Dosing can proceed on the scheduled day if there 
are at least 2 consecutive measurements <150/90 mmHg. Otherwise dosing must be delayed. 


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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. 
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. Please see table 9-7. 
Treatment of blood pressure increases associated with copanlisib 
 
It is important that patients with pre-existing arterial hypertension adhere to their regular medication 
schedule and take their usual doses on the days of study drug infusion. 
The management of acute blood pressure increases following copanlisib will need to be 
individualized for each patient, but experience in Phase I has suggested the benefit of 
dihydropyridine calcium channel blockers (i.e. amlodipine, felodipine). Topical nitrates should also 
be considered. Verapamil and diltiazem(non-dihydropyridine calcium channel blockers and 
moderate inhibitors of CYP3A4) should be used with caution due to a potential CYP3A4 interaction. 
In general, it is advisable for sites to be prepared, so that antihypertensive medication is readily 
available in case of need. 
In the event of the occurrence of arterial hypertension ≥ 150/90 mmHg during infusion of copanlisib 
at any cycle, antihypertensive treatment is suggested as indicated in Table 9-7. In the event of the 
occurrence of CTCAE Grade 3 arterial hypertension (≥ 160/100 mmHg) during infusion of 
copanlisib, the infusion should be interrupted and antihypertensive treatment as suggested above 
is administered. Infusion can be resumed when blood pressure has returned to <150/90 mmHg. 
Guidelines for the monitoring and treatment of copanlisib induced hyperglycemia 
 
Hyperglycemia is a common side effect of PI3K and also mTOR inhibitors. Hyperglycemia is often 
infusion-related and is dose-dependent. Transient increase of glucose levels have been observed 
in somepatients. Regular monitoring of FPG to identify early hyperglycemia and prevent acute/sub- 
acute complications is important. Caution is warranted for patients with history of DM, or taking 
corticosteroids, or with other severe medical conditions (e.g. infections), or patients who show 
potential acute signs suchas poly-nocturia, polydipsia, confusion, etc. Hyperglycemia management 
guidance includes patient education and dietetic measures/life-style changes as well as appropriate 
anti-diabetic medications as per investigator’s decision and/or local guidelines. 
Oral anti-diabetics such as metformin should be considered for sustained and more severe 
hyperglycemia (other drugs as appropriate). Provided hyperglycemia is asymptomatic and there 
are no acute complications, sufficient time should be given to install optimal management (e.g. up 
titrate metformin, addition of a second oral anti-diabetic agent to be considered as needed, etc.). 
Patients with history of DM, management should take prior anti-DM treatments into account. Note 
that some oral anti-diabetic are CYP3A inducers or inhibitors and may be prohibited (see Appendix 
1 for more details). Patients who develop Grade 3 or 4 or symptomatic hyperglycemia should be 
managed urgently as per standard clinical practice, with the goal of stabilizing glycemic control 
within 24 hours. More guidance on dose reductions and interruptions is provided in Table 9-7. 


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Recommendations on me al timing on infusion days 
Caloric intake and timing recommendations for diabetic patients who require insulin treatment prior 
to the infusion at any cycle visit should be managed by the investigator based on consultation with 
treating physician or diabetes/endocrinologist physician. 
Cycle 1 Day 1 
Fasting is required before the first glucose measurement on date of infusion. 
 
Subsequent dosing beyond Cycle 1 Day 1: 
Fasting is not required before the first glucose measurement. 
 
Management of transient post-infusion glucose increases that can occur with copanlisib 
study treatment 
Mild to moderate asymptomatic increases of blood glucose may occur with copanlisib infusion, and 
with larger increases potentially occurring post-prandially. 
 
Table 9-9. Hyperglycemic management during copanlisib infusion 
Criteria 
Recommendation 
Suggested  Treatment 
Asymptomatic  glucose 
increases ≤ 250mg/dL 
Does not generally  require 
treatment with glucose lowering 
medication. 
None 
Asymptomatic  glucose 
increase > 250 mg/dl 
• Should have  repeated 
laboratory  glucose determination. 
• If the repeated  glucose value 
is decreasing,  the glucose may 
be followed without glucose 
lowering medication  treatment if 
hydration status is normal  as 
clinically assessed. 
• Consultation with an 
endocrinologist  is recommended 
• 
Hydration  if appropriate 
• 
When planning next 
infusion  consider prophylaxis 
with oral glucose  lowering 
medication 
Symptomatic or  persisting 
glucose  increases > 250mg/dL 
• Hydration status should be 
clinically assessed. 
• If clinical assessment is 
consistent with dehydration, 
fluids should be given  as 
clinically appropriate  (orally or 
IV). 
• Laboratory  test confirming 
increase should be repeated.  If 
the repeated  glucose value  is 
persistent and/or patient is 
symptomatic and/or the hydration 
status indicates the need for 
hydration, glucose lowering 
medication should be 
administered. 
• Prompt input from  a diabetes 
specialist should be obtained. 
• 
Hydration  if appropriate 
• 
Rapid/ short acting insulin 
may be given  for glucose 
persisting at > 250 mg/dL, or if 
the patient is symptomatic during 
the infusion day. 
• 
Rapid/short  acting insulin 
according  to the institution sliding 
scale coverage  of glucose 
persisting at > 250 mg/dL is 
recommended,  with oral or IV 
hydration  as clinically 
appropriate 
• 
When planning next 
infusion  consider prophylaxis 
with oral glucose  lowering 
medication 


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Table 9-10.  Hyperglycemic management in between copanlisib infusion 
Criteria 
Recommendation 
Suggested  Treatment 
Max post infusion glucose > 
200 mg/dL noted on 
subsequent  days 
• Oral Glucose Lowering 
Medication  Recommended 
at physicians’ discretion on 
subsequent  days 
• Consultation with 
endocrinologist is 
recommended. 
• The use of 
sulphonylurea/metaglinides, 
insulin  secretagogues 
medications to manage 
increased glucose levels  post 
drug infusions  is not 
recommended. 
• Treatment  with glucose 
lowering  medication 
suggested according the local 
standards of practice. 
• Based on mechanisms of 
action 
and decreased risk of 
hypoglycemia,  metformin, 
SGLT-2-inhibitor   or DPP4- 
inhibitor might be useful 
treatment  options 
• DPP4 = Dipeptidyl peptidase-4;  IV = intravenous;  SGLT-2 = Sodium/glucose co-transporter  2 
 
Guidelines for the Management of Ibrutinib and Copanlisib induced stomatitis/oral mucositis 
 
General guidance and management include patient awareness and early intervention. 
Evaluation for herpes virus or fungal infection should be considered. 
Patients should be informed about the possibility of developing mouth ulcers/ oral mucositis and 
instructed to report promptly any signs or symptoms to their physician, Patients should be educated 
about good oral hygiene, instructed to avoid spicy/acidic/salty foods, and should follow the following 
guidelines: 
• 
For mild toxicity (grade 1), use conservative measures such as non-alcoholic mouth wash 
or salt water (0.9%) mouth wash several times a day until resolution. 
• 
For more severe toxicity (grade 2 in which case patients have pain but are able to maintain 
adequate oral alimentation, or grade 3 in whichcase patients cannot maintain adequate oral 
alimentation), the suggested treatments are topical analgesic mouth treatments (i.e., local 
anesthetics such as benzocaine, butyl aminobenzoate, tetracaine hydrochloride, menthol, 
or phenol) with or without topical corticosteroids, such as triamcinolone oral paste 0.1% 
(Kenalog in Orabase®), or as per local practice. 
• 
Agents containing alcohol, hydrogen peroxide, iodine, and thyme derivatives may tend to 
worsen mouth ulcers. It is preferable to avoid these agents. 
Antifungal agents should be avoided unless a fungal infection is diagnosed as they may interfere 
with copanlisib metabolism. 
Guidelines for management of hyperlipidemia 


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Total cholesterol, LDL and triglycerides will be tested only at with fasting labs on Cycle 1 Day 1 and 
non-fasting labs on Day 1 of every even cycle starting from Cycle 2, and at the EOT visit. If lipids 
are abnormal with non-fasting labs, a repeat fasting lipid panel is recommended. As lipids are 
monitored for the duration of this study it is recommended to treat significant deviations from normal 
range with standard interventions and therapy in standard doses according to local  medical 
practice. Goals of therapy are to keep fasting triglycerides < 300 mg/dL and low-density lipoproteins 
(LDL) < 190 mg/dL (lower LDL depending on cardiovascular risk) in patients with a life expectancy 
>1 year. The goals for fasting triglycerides can be raised to < 500 mg/dL for patients with life 
expectancy <1 year. Although there is a paucity of data on the effects of hyperlipidemia and cancer 
outcomes, these goals have been chosen to decrease risk of established complications of 
hypertriglyceridemia (pancreatitis) and hypercholesterolemia (cardiovascular events). 
Guidelines for the treatment of copanlisib or ibrutinib induced diarrhea 
 
The investigator should consider/investigate potential concomitant medication, food or comorbidity 
driven causes of diarrhea (including infectious causes) and remedy these causes if possible (e.g. 
discontinuation of concomitant medication, dietary modification, treatment of comorbidity). 
The patient should be monitored for signs of dehydration and instructed to take preventive 
measures against dehydration as soon as diarrhea occurs. Concomitant medication for the 
treatment of diarrhea should be considered, as per local practice and best investigator’s judgment 
and may consist for example, as per “the recommended guidelines for the treatment of cancer 
treatment-induced diarrhea”[38], of loperamide given at a standard dose (e.g. initial administration 
of 4mg, then 2mg every 4 hours, maximum of 16 mg/day), along with oral hydration and dietetic 
measures could be considered for Grade 1-2 diarrhea. More severe diarrhea should be treated 
appropriately according to investigator discretion, including for example IV fluids. 
Dose modification of copanlisib or ibrutinib in case of treatment related diarrhea should follow the 
guidelines presented above for other non-hematological adverse events. 
 
 
Guidelines for the treatment of ibrutinib or copanlisib induced skin toxicity 
 
Skin toxicity is a class-effect observed with both ibrutinib and PI3Ki/mTORi agents. Close 
monitoring of potential skin reactions will be performed at each planned visit and will be reported 
as adverse event. The most frequent skin adverse events reported are: maculopapular rash (only 
a minority present acneiform rash); pruritus and dry skin. The onset is typically within the first 2 
months of treatment start and is reversible with adequate co-medication and treatment interruption 
if needed. Photographs of a skin rash event as well as skin biopsy are recommended, if possible. 
According to the investigators discretion, a paired skin biopsy could be obtained (from both an 
affected and an unaffected skin area for local histopathology assessment) to further assess rash if 
clinically appropriate. 
 
Recommended therapies for skin toxicity events: 


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• 
Topical steroids of moderate potency (face and folds): triamcinolone 0.025%; clometasone 
0.05% (< 8 weeks continuously), for mild and moderate rashes. 
• 
Topical steroids of high potency (trunk/extremities): fluocinonide 0.05%; clobetasol 0.05% 
cream or spray (< 8 weeks continuously), for mild and moderate rashes. 
• 
Oral antihistamines (sedating, evening): diphenhydramine 25 to 50mg t.i.d; hydroxizine 
25mg tid or q.i.d; 
• 
Oral antihistamines (non-sedating, day time): fexofenadine 180mg q.d. or 60mg tid (monitor 
the use of this class of drugs since skin toxicity has also been reported) 
• 
Oral corticosteroids: prednisone 0.5mg/kg or equivalent up to 2 weeks of treatment 
• 
In caseof mild acneiform rashes topical antibiotics: clindamycin 1% to 2%; erythromycin 1% 
to 2% (gel or solution formulation can be used, ointments cannot be used); metronidazole 
1%; silver sulphadiazine. 
• 
For more severe acneiform rashes oral antibiotics: doxycycline 100mg B.I.D.; minocycline 
100mg B.I.D.; oxytetracycline 500mg B.I.D. for 6 weeks can be considered. If infection 
suspected (yellow crusts, purulent discharge, painful skin/nares), then switch to broad 
spectrum/gram negative antibiotics; consider skin swab for bacterial culture. 
• 
Topical antipruritics (pramoxine 1%, doxepin 5% cream) applied twice daily 
• 
For severe pruritus GABA Agonists: Gabapentin 300mg every 8 hours, or pregabalin 50 to 
75 mg every 8 hours (to adjust of renal impairment) can be considered. Dose should be 
adjusted depending on patient’s clinical condition beware of potential and common side 
effects observed with GABA agonists such as: somnolence, dizziness (both drugs) and 
peripheral edema (Gabapentin) among others AEs. 
 
 
Dry skin has been reported, it is recommended that patients with dry skin use mild and fragrance 
free soaps and detergents. According to the severity and BSA extension patients may apply mild 
moisturizers, ammonium lactate cream 12% or salicylic acid cream 6% B.I.D. 
Patients should be advised to take measures to protect themselves from direct exposure to sunlight, 
including regular use of sunscreen (factor 20 at least), wearing of sunglasses, using of hats, and 
protective clothes when outdoors. 
Guidelines for the management of ibrutinib induced hemorrhage 
 
Fatal bleeding events have occurred in patients treated with ibrutinib. Bleeding events (subdural 
hematoma, gastrointestinal bleeding,  hematuria and post procedural hemorrhage) have occurred 
in up to 6% of patients. Bleeding events of any grade, including bruising and petechiae, occurred 
in approximately half of patients treated with ibrutinib. 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 post- surgery depending upon the type of surgery and the risk of bleeding. If bleeding 
diathesis occurs, consider platelet transfusions to reverse the inhibition of platelet adhesion and 
collagen induced platelet aggregation from ibrutinib[39]. 
Guidelines for the infectious prophylaxis 


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Cytomegalovirus (CMV) reactivation and Pneumocystis pneumonia (PCP) have been observed in 
patients treated with other PI3K inhibitors suchas idelalisib. Patients will undergo CMV PCR testing 
every cycle. Patients should be placed on prophylaxis for PCP pneumonia unless there is a medical 
contraindication. 
9.9. Criteria to Resume Treatment after Complete Response: 
 
For subjects who stop copanlisib after achieving a complete response, copanlisib may be restarted 
upon radiographic and pathologic progression of disease. Subjects may resume treatment if any 
drug-related AE(s) resolve to Grade ≤1 or baseline value, with the following exceptions: 
• 
Subjects may resume treatment in the presence of Grade 2 fatigue 
• 
Subjects who have  not experienced a Grade  3 or 4 drug-related  skin AE  may resume 
treatment in the presence of Grade 2 skin toxicity 
• 
Drug-related pulmonary toxicity, diarrhea, or colitis, must have resolved to baseline before 
treatment is resumed. 
• 
Drug-related  endocrinopathies   adequately   controlled  with  only   physiologic   hormone 
replacement may resume treatment 
 
Patients must also meet the following criteria: 
 
• 
Investigator  assessed clinical benefit 
• 
Tolerance of study treatment 
• 
Stable performance status 
• 
Repeat treatment with copanlisib and ibrutinib will not delay an imminent intervention  to 
prevent serious complications of disease progression (eg CNS metastasis) 
• 
Participant provides written informed consent prior to receiving additional copanlisib and 
ibrutinib. 
 
A radiographic assessment with FDG-PET/CT or PET-MRI should be performed within 6-10 weeks 
of re-initiating treatment to assess response. 
 
 
10.0   EVALUATION DURING TREATMENT/INTERVENTION 
 
10.1. General requirements 
 
Evaluations during this period are per Table 10-1. 
 
10.2. Treatment period 
 
Patients will receive study treatments copanlisib and ibrutinib until disease progression, 
unacceptable toxicity or until other discontinuation criteria are met, whichever come first. Maximum 
duration of treatment is 36 cycles not exceeding 36 months. 


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Patients will follow the visit schedule as per Table 10-1. Permitted visit windows for assessments 
within the treatment period and at efficacy follow-up visits are included in the table. If copanlisib is 
held based on achievement of a complete response, patient visits will be every 2 cycles during C1- 
C6, every 3 cycles during C7-C12, every 4 cycles during C13-36. 
Information on drug exposure will be collected on the Dosage Administration Record eCRF. 
Concomitant medications/significant non-drug therapies prior to start (≤ 28 days) and after start of 
study treatment will be recorded on the appropriate eCRFs. 
Compliance will be assessed by the investigator and/or study personnel at each visit using box 
counts and information provided by the caregiver. 
10.3. 
End of treatment visit including premature withdrawal and study safety followup 
 
Patients will continue study treatment until disease progression, until any of the study’s 
discontinuation criteria are met, or a maximum treatment period of 36 cycles, not exceeding 36 
months (Section 13). Patients who discontinue study treatment or at completion therapy should be 
scheduled for an End-of-Treatment visit within 7 days from treatment discontinuation or as early as 
possible per patient’s convenience at which time all of the assessments listed for the EOT visit will 
be performed. For details of assessments, refer to Table 10-1. An End of Treatment eCRF page 
should be completed, giving the date and reason for discontinuation of study treatment. Patients 
will have an additional follow up 1 month after last dose. 
If a patient withdrawal occurs, or if the patient fails to return for visits, the investigator must 
determine the primary reason for a patient’s premature withdrawal from the study and record this 
information on the End of Treatment eCRF page. 
Patients will be assessed for any adverse events 30 days, +/- 7 days, from the last dose of either 
study drug or until new therapy is initiated, whichever comes first. 
10.4. 
Correlative studies 
 
Patients consented on this trial will have tumor samples analyzed for genomic alterations via next 
generation targeted sequencing. Optional post treatment biopsy will be obtained to compare the 
differences in genomic alterations prior to treatment and post treatment. In addition, circulating 
tumor DNA and circulating tumor RNA samples will be collected throughout treatment to serially 
assess the genomic profile of treated patients. 
Gene sequencing will be performed in the CLIA certified Molecular Diagnostics Service laboratory, 
a division of the MSKCC Pathology Department, using IMPACT-Heme (Integrated Mutation 
Profiling for Actionable Cancer Targets Hematology Panel) with paired tumor and normal tissue 
samples, or a custom panel of genes depending on baseline IMPACT-Heme results. IMPACT 
provides full exon coverage of 410 cancer related genes including CARD11, MYD88, PIK3CA, BTK, 
and can be used to detect base substitutions, small indels, copy number alterations and select gene 
re-arrangements. In some cases, the Molecular Diagnostic Service will utilize an additional assay, 
such as Sanger Sequencing, B cell clonality, or fluorescence in situ hybridization (FISH), to confirm 
specific results from these multiplexed assays. We will assess for the following: 


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1) Determine variations on circulating tumor RNA throughout treatment 
2) Correlate spectrum of genomic mutations in tumor tissue versus circulating tumor DNA 
3) Assess tumor variant allele frequency in circulating tumor DNA 
4) Correlate circulating tumor DNA to radiographic response 


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Table 10-1. Schedule of Evaluation 
Timepoint 
Screening 
C1D1 
C1D8 
C1D15 
CxD1 
CXD8 
CXD15 
EOT 
30 day FU after 
last doseH 
Window 
-28 
-7 
+/- 3 days 
+/- 3 days 
+/-3 days 
+/-3 days 
+/-3 days 
+/- 7 days 
+/- 7 days 
Treatment 
Copanlisib 
X 
X 
X 
XA 
XA 
XA 
Ibrutinib 
Daily 
Evaluation 
Obtain Informed Consent 
X 
Demography 
X 
Inclusion/Exclusion criteria 
X 
Medical/Diagnosis/Treatment history 
X 
Prior/Concomitant medications 
X 
X 
X 
X 
X 
XK 
Physical Examination 
X 
X 
X 
X 
X 
X 
X 
ECOG and Vitals (Weight, Blood 
pressure, Pulse, Resp, Temp) 
X 
X 
X 
X 
X 
X 
Hematology: CBC with Diff 
X 
X 
X 
X 
X 
X 
Chemistry(BMP, TBili, AST, ALT, TP, 
Alb, AP, UA, LDH, amylase, lipase, 
GFR, Mag, Phos) 
X 
X 
Fasting 
X 
X 
X 
X 
X 
X 
Lipid panel 
Urinalysis, Urine protein 
X 
Day 1 
Cycle 3, 5, 7, 10, 13, 
17, 21, 25, 29, 33 
X 
T3, T4, TSH 
X 
As clinicallyindicated 
X 
Fructosamine 
X 
X 
X 
X 
Hemoglobin A1c 
X 
X 
X 
Coagulation (PT/PTT) 
X 
X 
B cell Clonalityby NGS 
X 
Day 1 
Cycle 3, 5, 7, 10, 13, 
17, 21, 25, 29, 33 
X 
Hepatitis B/CB 
X 
Hepatotoxicity testing/procedures as clinicallyindicatedC 
HIV 
X 
Cytomegalovirus PCR 
X 
X 
X 
Serum/Urine beta-HCG for women of 
childbearing age 
X 
Post Infusion Glucose EvaluationD 
XD 
Fasting 
XD 
XD 
XD 
XD 
XD 
Post Infusion Blood PressureE 
XE 
XE 
XE 
XE 
XE 
XE 
Radiographic assessmentF 
X 
Before Day 1 
Cycle 3, 5, 7 (first 6 months), 
10, 13, (1 year), 
17, 21, 25, 31 (year 2-3) 
X (if not 
within 4 
weeks) 
ECHO or MUGA 
X 
X 
ECG 
X 
X 


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PCP pneumonia prophylaxis 
Continuous (unless clinicallycontraindicated) 
Pill Diary 
X 
X 
X 
Tumor biopsy(archived/fresh biopsy)G 
XG 
OptionalG 
Research Blood Tests: ctDNA, ctRNA 
X 
X 
X 
Cycle 2: D1, D8, D15 
Cycle 3-7: D1 
X 
Research Blood Tests: 
Pharmacokineticsj 
X 
 
A: Copanlisib Dosing: If copanlisib is held based on achievement of a complete response, patient visits will be every 2 cycles during C1 -C6, every 3 cycles during C7-C12, 
every 4 cycles during C13-36. 
B: Hepatitis Evaluation: HbsAg, HBcAb, anti-HCV Ab, Hep B/C PCR if positive 
C: Additional viral hepatitis workup as clinicallywarranted: HAAb, HBsAg, HBsAb, HBcAb, HCV RNA or HDV RNA (where needed), H EAb, CMVAb, EBcAb, CMV IgM Ab, 
EBV IgM Ab, HSV, AP, CPK, LDH,Carriers of hepatitis B should be closelymonitored for clinical and laboratorysigns of active HBV infection, signs of hepatitis during and 
for several months following ibrutinib/copalisib treatment. Carriers of hepatitis B (positive HBsAg and/or HBcAg but negative HBV-DNA is required to be on prophylactic 
antiviral therapy. If viral load becomes positive, patients should be withdrawn from study. Hep C carriers (anti -HCV Ab positive, negative HCV-RNA PCR must be tested 
monthlyfor HCV reactivation. If HCV-RNA PCR becomes positive, patients should be withdrawn from study. 
D: Post Infusion Glucose Evaluation: C1D1 – fasting glucose prior to copablisib (0h), 60 min (end of infusion) and 2 hours ; all subsequent doses – non-fasting glucose prior 
to copanlisib (0h), post infusion. 
E: Post Infusion Blood Pressure Evaluation: Blood pressure (5-10min, +/- 10 min) prior to copanlisib must be <150/90mmHg for two consecutive measurements. If blood 
pressure prior to infusion is ≥150/90 mmHg, medical intervention or dose delayshould be considered. Blood pressure post infusion should b e measured at 30 min (mid- 
infusion), 60 min (end of infusion), 1 hour and 2 hour post infusion (+/- 10 min). 
F: Radiographic assessment via PET and CT chest/abdomen/pelvis and neck CT if clinicallyindicated (MRI will be used for those who are unable to undergo CT scans). 
G: Pretreatment archived biopsymaterial (10-15 x 10 microns) or an optional pretreatment core biopsy (2-3 cores). Post treatment optional core biopsy(2-3 cores). 
H: Maximum 36 cycles, not exceeding 36 months of treatment 
J: Exact schedule for PK testing is in Table 9-4. 
K: Not required to collect if patient has begun new anti-cancer therapywithin 30 days after last dose of either study dru g on protocol. 


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11.0   TOXICITIES/SIDE EFFECTS 
 
11.1. 
Adverse Event 
 
11.1.1. Definitions and reporting 
 
An adverse event is defined as the appearance of (or worsening of any pre-existing) undesirable 
sign(s), symptom(s), or medical condition(s) that occur after patient’s signed informed consent has 
been obtained. Abnormal laboratory values or test results occurring after informed consent constitute 
adverse events only if they induce clinical signs or symptoms, are considered clinically significant, 
require therapy (e.g. hematologic abnormality that requires transfusion or hematological stem cell 
support), or require changes in study medication(s). 
Adverse events that begin or worsen after informed consent should be recorded in Medidata. 
Conditions that were already present at the time of informed consent should be recorded in the Medical 
History in Medidata. Adverse event monitoring should be continued for at least 30 days following the 
last dose of study treatment or until initiation of new therapy, whichever comes first. Adverse events 
(including lab abnormalities that constitute AEs) should be described using a diagnosis whenever 
possible, rather than individual underlying signs and symptoms. When a clear diagnosis cannot be 
identified, each sign or symptom should be reported as a separate Adverse Event. 
Adverse events will be assessed according to the Common Terminology Criteria for Adverse Events 
(CTCAE) version 5.0. If CTCAE grading does not exist for an adverse event, the severity of mild, 
moderate, severe, and life-threatening, corresponding to Grades 1 - 4, will be used. CTCAE Grade 5 
(death) will not be used in this study; rather, information about deaths will be collected though a Death 
form. 
The occurrence of adverse events should be sought by non-directive questioning of the patient 
(subject) during the screening process after signing informed consent and at each visit during the 
study. Adverse events also may be detected when they are volunteered by the patient (subject) during 
the screening process or between visits, or through physical examination, laboratory test, or other 
assessments. As far as possible, each adverse event should be evaluated to determine: 
• 
The severity grade (CTCAE Grade 1-4) 
• 
Its duration (Start and end dates) 
• 
Its relationship to the study treatment (Reasonable possibility that AE is related: No, Yes) or 
its relationship to the study treatment (Reasonable possibility that AE is related: No, Yes, 
investigational treatment, Yes, the study treatment (non-investigational), Yes, both and/or 
indistinguishable) 
• 
Action  taken  with  respect  to  study  or  investigational  treatment  (none,  dose  adjusted, 
temporarily interrupted, permanently discontinued, unknown, not applicable) 
• 
Whether  medication   or   therapy   taken   (no   concomitant  medication/non-drug   therapy, 
concomitant medication/non-drug therapy) 
• 
Outcome 
(not 
recovered/not 
resolved, 
recovered/resolved, 
recovering/resolving, 
recovered/resolved with sequelae, fatal, unknown) 
• 
Whether it is serious, where a serious adverse event (SAE) is defined as in Section 11.2.1 


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• 
All adverse events should be treated appropriately. If a concomitant medication or non-drug 
therapy is given, this action should be recorded in Medidata. 
• 
Once an adverse event is detected, it should be followed until its resolution or until it is judged 
to be permanent, and assessment should be made at each visit (or more frequently, if 
necessary) of any changes in severity, the suspected relationship to the study treatment, the 
interventions required to treat it, and the outcome. 
• 
Progression of malignancy (including fatal outcomes), if documented by use of appropriate 
method (Cheson criteria), should not be reported as a serious adverse event. 
• 
Adverse events separate from the progression of malignancy (example, deep vein thrombosis 
at the time of progression or hemoptysis concurrent with finding of disease progression) will 
be reported as per usual guidelines used for such events with proper attribution regarding 
relatedness to the drug. 
 
 
11.1.2. Laboratory test abnormalities 
 
Laboratory abnormalities that constitute an Adverse event in their own right (are considered clinically 
significant, induce clinical signs or symptoms, require concomitant therapy or require changes in study 
treatment), should be recorded in Medidata. Whenever possible, a diagnosis, rather than a symptom 
should be provided (e.g. anemia instead of low hemoglobin). Laboratory abnormalities that meet the 
criteria for Adverse Events should be followed until they have returned to normal or an adequate 
explanation of the abnormality is found. When an abnormal laboratory or test result corresponds to a 
sign/symptom of an already reported adverse event, it is not necessary to separately record the 
lab/test result as an additional event. 
Laboratory abnormalities, that do not meet the definition of an adverse event, should not be reported 
as adverse events. A Grade 3 or 4 event (severe) as per CTCAE does not automatically indicate a 
SAE unless it meets the definition of serious as defined below and/or as per investigator’s discretion. 
A dose hold or medication for the lab abnormality may be required by the protocol in which case the 
lab abnormality would still, by definition, be an adverse event and must be reported as such. 
11.2. 
Serious Adverse Event 
 
A serious adverse event is one that is fatal or life-threatening (see below), is temporarily or 
permanently disabling, requires inpatient hospitalization (initial or prolonged), or is associated with a 
congenital anomaly, a new cancer or a drug overdose (either accidental or intentional). In addition, 
any event suggesting a significant hazard, contraindication, side effect or precaution should also be 
considered serious. 
11.3. 
Life-threatening event 
 
The event is an immediate risk of death from the reaction as it occurred. Life-threatening does not 
include a reaction that, had it occurred in a more serious form, might have causeddeath. For example, 
drug-induced hepatitis that resolved without evidence of hepatic failure would not be considered life- 
threatening even though drug-induced hepatitis can be fatal. 
11.4. 
Reporting procedures for adverse events 


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All adverse events occurring during the study, observed by the investigator or reported by the subject, 
will be reported to the IRB either in memorandum form or on the Medidatatoxicity form. The following 
attributes must be assigned: description; dates of onset and resolution; severity; assessment of 
relatedness to study drug, other suspect drug, or device; and action taken. The investigator may be 
asked to provide follow-up information. 
11.5. 
Ibrutinib anticipated toxicities 
 
Ibrutinib is an FDA approved drug for mantle cell lymphoma. 
 
Likely (>20%): Diarrhea, nausea, constipation, abdominal pain, vomiting, upper respiratory tract 
infection, fatigue, peripheral edema, bruising, rash, musculoskeletal pain, dyspnea, decreased 
appetite, platelets decreased, neutrophils decreased, hemoglobin decreased 
Less Likely (4-20%): stomatitis, dyspepsia, urinary tract infection, pneumonia, skim infections, 
sinusitis, pyrexia, asthenia, petechiae, muscle spams, arthralgia, cough, epistaxis, dehydration, 
dizziness, headache, hyperuricemia, hemorrhage (gastrointestinal bleeding, hematuria and post 
procedural hemorrhage), hypertension, second primary malignancies- most common non-melanoma 
skin cancer 
Rarely (<3%): intracranial and subdural hematoma, cardiac arrhythmias, lymphocytosis, tumor lysis 
syndrome, progressive multifocal leukoencephalopathy 
Most side effects listed above have been mild to moderate in severity; however severe side effects 
have occurred. Some side effects have been severe enough to lead to study drug discontinuation, 
dose modification or reduction, hospitalization, disability and sometimes death. 
11.6. 
Ibrutinib adverse events of special interest 
 
Hemorrhagic Adverse Events 
 
Fatal bleeding events have occurred in patients treated with ibrutinib Grade 3 or higher bleeding 
events (subdural hematoma, gastrointestinal bleeding, hematuria and post procedural hemorrhage) 
have occurred in up to 6% of patients. Bleeding events of any grade, including bruising and petechiae, 
occurred in approximately half of patients treated with ibrutinib. The mechanism for the bleeding 
events is not well understood. Ibrutinib may increase the risk of hemorrhage in patients receiving 
antiplatelet or anticoagulant therapies. 
Subjects in the current study will be monitored closely for hemorrhagic adverse events. Ibrutinib should 
be held at least 3 to7 days pre and post-surgery depending upon the type of surgery and the risk of 
bleeding (please refer to Section 9.7 for further details). 
 
Infection 
 
Fatal and non-fatal infections have occurred with ibrutinib therapy. Grade 3 or greater infections 
occurred in 14% to 29% of patients. Cases of progressive multifocal leukoencephalopathy (PML) have 
occurred in patients treated with ibrutinib. Monitor patients for fever and infections and evaluate 
promptly. 
 
Cytopenias 


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Treatment-emergent Grade 3 or 4 cytopenias including neutropenia (range, 19 to 29%), 
thrombocytopenia (range, 5 to 17%), and anemia (range, 0 to 9%) occurred in patients treated with 
ibrutinib. Monitor complete blood counts monthly. 
Atrial Fibrillation 
 
Atrial fibrillation and atrial flutter (range, 6 to 9%) have occurred in patients treated with ibrutinib, 
particularly in patients with cardiac risk factors, acute infections, and a previous history of atrial 
fibrillation. Periodically monitor patients clinically for atrial fibrillation. Patients who develop arrhythmic 
symptoms (e.g., palpitations, lightheadedness) or new onset dyspnea should have an ECG performed. 
If atrial fibrillation persists, consider the risks and benefits of ibrutinib treatment and dose modification 
based on recommendations in Section 9. 
 
Hypertension 
 
Hypertension (range, 6 to 17%) has occurred in patients treated with ibrutinib with a median time to 
onset of 4.6 months (range, 0.03 to 22 months). Monitor patients for new onset hypertension or 
hypertension that is not adequately controlled after starting ibrutinib. Adjust existing anti-hypertensive 
medications and/or initiate anti-hypertensive treatment as appropriate. 
 
Secondary Primary Malignancies 
 
Other malignancies (range, 5 to 16%) including non-skin carcinomas (range, 1 to 4%) have occurred 
in patients treated with ibrutinib. The most frequent second primary malignancy was non-melanoma 
skin cancer (range, 4 to 13%). 
 
Tumor Lysis Syndrome 
 
Tumor lysis syndrome has been reported with ibrutinib therapy. Assess the baseline risk (e.g. high 
tumor burden) and take appropriate precautions. Monitor patients closely and treat as appropriate. 
Embryo-Fetal Toxicity 
 
Based on findings in animals, ibrutinib can cause fetal harm when administered to a pregnant woman. 
Administration of ibrutinib to pregnant rats and rabbits during the period of organogenesis caused 
embryofetal toxicity including malformations at exposures that were 2-20 times higher than those 
reported in patients with MCL, CLL/SLL or WM. Advise women to avoid becoming pregnant while 
taking ibrutinib and for 1 month after cessation of therapy. If this drug is used during pregnancy or if 
the patient becomes pregnant while taking this drug, the patient should be apprised of the potential 
hazard to a fetus. 
11.7. 
Copanlisib anticipated toxicities 
 
The side effects listed below have been reported by patients who have received copanlisib in clinical 
trials 
Likely (>20%): Anemia, hyperglycemia, hypertension, fatigue, nausea, diarrhea, neutropenia 
(including febrile neutropenia), infections, rash (including macular, maculopapular, pruritic, pustular, 
erythematous, generalized, exfoliative rash, pruritus/Pruritus generalized, dermatitis acneiform, 
dermatitis allergic and dermatitis exfoliative) 


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Less Likely (4-20%): Dysgeusia, leukopenia, lymphopenia, elevated amylase and lipase increased, 
hypomagnesemia, 
hyponatremia, 
paraesthesia, 
pneumonitis, 
interstitial 
lung 
disease, 
thrombocytopenia, vomiting, chills, mucosal inflammation (including stomatitis and mouth ulceration), 
dry mouth, muscle spasms 
Rarely (<3%): alopecia, hyperinsulinemia, infusion related reaction, hypersensitivity, gastritis, colitis, 
aphthous ulcer, eosinophilia,  Pancreatitis, Stevens-Johnson syndrome 
Most side effects listed above have been mild to moderate in severity; however severe side effects 
have occurred. Some side effects have been severe enough to lead to study drug discontinuation, 
dose modification or reduction, hospitalization, disability and sometimes death. 
11.8. 
Copanlisib adverse events of special interest 
 
Non-Infectious  Pneumonitis 
 
Non-infectious pneumonitis is an adverse event of special interest. In general, non-infectious 
pneumonitis was symptomatic, with fever, cough, and dyspnea but asymptomatic in some patients. 
Therefore CT scans may be used to assess for radiographic indications of non-infectious pneumonitis. 
The CT findings in case of non-infectious pneumonitis were diffuse ground-glass opacities. A 
bronchoscopy may not show any findings. Non-infectious pneumonitis resolved in all 9 patients, 
usually within 2 to 4 weeks. No patient died due to non-infectious pneumonitis. In all 9 patients, study 
drug was interrupted and in 3 patients permanently discontinued due to non-infectious pneumonitis. 
Interruption of study drug alone improved non-infectious pneumonitis in 1 patient, 1 patient received 
steroids only, 2 patients received antibiotics only, and 6 patients received antibiotics and steroids. Re- 
treatment with study drugs was performed in 2 patients, resulting in re-occurrence of non-infectious 
pneumonitis in 1 of them. 
 
Hyperglycemia 
 
The PI3K/AKT pathway plays a significant role in regulating glucose metabolism. Hyperglycemia is 
considered as an “on target” effect of copanlisib, and has been commonlyobserved in patients treated 
with copanlisib with an incidence approximately 50-70%. 
 
Hypertension 
 
Approximately 42% of patients have post infusion drug related Grade 3 hypertension. There were no 
cases of Grade 4 hypertension. There was a CTC Grade 3 SAE hypertension. Hypertension was 
reported in the medical  history of 22 out of 76 patients; 16 of them were already receiving 
antihypertensive treatment at study start. Antihypertensive treatment was administered in 8 treatment 
naive patients as a consequence of post infusion hypertension, and in 7 patients due to a worsening 
of already therapy controlled baseline hypertension. Six of the eight naive patients received treatment 
only on the day of infusion, and 2 naive patients started chronic antihypertensive treatment. 
12.0   CRITERIA FOR THERAPEUTIC RESPONSE/OUTCOME ASSESSMENT 
 
Response and progression of disease will be evaluated in this study using the RECIL criteria[37]. 
Clinical evaluation and tumor assessments will be performed periodically, as is indicated in Table 10- 
1, based on physical examination, radiological evaluation and core bone marrow biopsy (in patients 


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with pre-existing bone marrow involvement). Clinical suspicion of disease progression at any time will 
require a physical examination and radiological confirmation to be performed promptly, rather than 
waiting for the next scheduled tumor assessment. In case of an unscheduled or delayed tumor 
assessment for any reason, subsequent tumor assessments must be performed according to the 
originally planned schedule from baseline. 
Measurability of lesion for objective response and measurement of target lesions: Measurable 
disease: lesions that can be accurately measured in two dimensions by CT, MRI, plain x-ray of other 
conventional technique and have a greatest transverse diameter of 1.5 cm or greater. Non- 
measurable disease: All other lesions including uni dimensional lesions, lesions too small to be 
considered measurable, pleural or pericardial effusions, ascites, bone disease, leptomeningeal 
disease, lymphangitis, pulmonitis, abdominal masses not confirmed by CT, or disease documented 
only by indirect evidence (e.g. lab values). 
Assessment of tumor burden in lymphoma clinical trials can use the sum of longest diameters (SLD). 
In patients with disseminated disease, a maximum of three target lesions should be selected and used 
to estimate tumor response. Target lesions should be selected from those with the largest size that 
can be reproducibly measured and preferably representing multiple sites and/organs. In most cases, 
lymph nodes can be considered target lesions if the lymph node longest diameter measures ≥15 mm. 
Similar to RECIST 1.1, a lymph node measuring between 10 and 14 mm is considered abnormal but 
should not be selected as a target lesion. Lymph nodes measuring <10mm in diameter are considered 
normal. In certain anatomical sites (inguinal, axillary, and portocaval), normal lymph nodes may exist 
in a narrow, elongated form, and such nodes should not be selected as target lesions if alternatives 
are available. Extranodal lesions are selected as target lesions if they have soft tissue component, 
based on their size, and the ease of reproducibility of repeated measurements, with a minimum 
measurement of the longest diameter of ≥ 15 mm. All other lesions should be identified as nontarget 
lesions and should be recorded at baseline, without the need to measure them. Nontarget lesions 
should be followed and reported as present, absent, or clear progression. 
Objective disease response assessment: Objective status is to be recorded at each evaluation 
according to the RECIL criteria 


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13.0 
CRITERIAFOR REMOVAL FROM STUDY 
 
Patients may voluntarily withdraw from the study or be removed from the study at the discretion of the 
investigator at any time. Patients may be withdrawn from the study if any of the following occur: 
• 
Disease progression. However, if progression develops after CR while patient is on ibrutinib 
alone, patients could restart treatment upon radiographic and pathologic expression of 
disease. 
• 
Ineligibility  (at the pretreatment evaluation) of the patient as defined in the inclusion/ exclusion 
criteria 
• 
Treatment will be discontinued at the request of the patient, refusal of therapy, non-compliance, 
or upon the development of an intercurrent significant medical illness. 
• 
Significant protocol violation 
• 
Unacceptable toxicity 
o Grade 4 arterial hypertension 
o Grade 4 dermatologic toxicity 
o  Non-infectious pneumonitis 
o Drug induced clinically relevant pancreatitis 
o Grade ≥3 hypersensitivity reaction 
• 
Decision by the investigator that termination is in the patient’s best medical interest. 
• 
Loss to follow-up 
Table 12-1. Criteria for RECIL Response  Assessment  of Non-Hodgkin  Lymphoma 


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• 
Development of active HBV or HCV infection, hepatitis, or HIV infection 
• 
Pregnancy or a positive pregnancy test 
• 
Death of the patient 
 
 
In addition to the general study treatment withdrawal criteria, the following study specific criteria will 
also require premature study treatment discontinuation: 
• 
Use of prohibited medication 
• 
Start of any other anti-neoplastic therapy 
 
 
If a study treatment withdrawal occurs, or if the patient fails to return for visits, the investigator must 
determine the primary reason for a patient’s premature withdrawal from study treatment and record 
this information on the End of Treatment CRF page. 
 
 
14.0     BIOSTATISTICS 
 
14.1. Phase I 
 
In the Phase I part the standard 3+3 dose escalation scheme will be used. If none of the initial cohort 
of 3 has a DLT (defined in Section 9.2) the dose level will be escalated. If one has a DLT that dose 
level will be expanded with 3 more patients. Dose escalation will stop if 2 or more DLTs are seen at a 
dose level within the treatment and observation periods as described in Section 9.2. The MTD is 
defined as the highest dose level at which at most 1 of the 6 patients treated at that level has a DLT. 
Two dose levels plus a “-1” dose level are planned for this study. The maximum sample size is 18 
patients. Toxicity seen after 4 weeks that are likely or definitely related to treatment with study drugs 
will be collected and evaluated by the investigators. 
All patients that stop protocol therapy or have dose reductions due to a DLT will be included in the 
DLT analysis. If a patient stopped therapy for other reasons and has taken ≤75% of planned doses (2 
of 3 copanlisib doses and 21 of 28 doses of ibrutinib) in the first cycle then they will be excluded from 
DLT analysis. In the event that a patient withdraws from the trial due to a reason unrelated to a DLT 
before completing cycle one, they will be replaced. We expect that less than 10% of patients will be 
replaced due to insufficient time of treatment. The probability of dose escalation based on various 
underlying DLT rates (Table 2). 
 
 
Table 14-1. DLT probability table 
True DLT rate 
5% 
10% 
15% 
20% 
25% 
30% 
40% 
50% 
Probability of 
escalation 
0.97 
0.91 
0.81 
0.71 
0.60 
0.49 
0.31 
0.17 
 
 
It is expected that 2-3 patients will be enrolled per month and so the phase I portion of the trial will be 
completed in approximately 6 months. 
14.2. Phase II 


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The primary objective for this phase II cohort is to assess the complete response rate based on best 
response by 6 months of ibrutinib and copanlisib and the secondary objective is to measure the 
disease control rate (stable disease, partial response, and complete response), overall response rate 
(partial and complete response), duration of response, progression and event free survival. A Simon 
mini-max two stage design will be used with the goal to increase by complete response rate based on 
best response by 6 months from 20% to 40%. In first stage, if 5 or more of 18 patients have responses, 
then the trial will proceed to stage 2. In stage 2, additional patients are enrolled to make the total 
sample size 33. If 11 or more responses are observed, then the combination is deemed promising. 
Accrual will not be held while the initial 18 patients in the first stage are evaluated for the 6-month 
response endpoint. The one sided type I error rate is 0.05 and the power is 0.80. A total of 33 patients 
will be enrolled, though patients treated at MTD/RP2D from phase I portion of the study will be included 
in the phase II analysis. Expected accrual is 2-3 patients per month and so the phase II portion will 
be completed within a year. 
For other secondary objectives, the event free survival and progression free survival rates will be 
assessed by the Kaplan-Meier estimation. Event free survival is defined from the date of first dose to 
progression, or death, and any events including treatment discontinuation for adverse events or 
severe adverse events whichever came first. Progression free survival is defined from the date of first 
dose to progression or death, whichever came first. The duration of response will also be assessed 
by Kaplan-Meier method but on a sub-cohort of patients who showed any response. 
To protect patients from excessive toxicity of the treatment during the entire treatment period, several 
stopping rules are implemented during the study based on the maximum total number of treated 
patients in both phase I and II (45).Treatment related Grade ≥3 Pneumonitis or Colitis: 10% 
unacceptable rate, 2.5% acceptable rate. Trial to hold enrollment if ≥4 deaths related to treatment at 
any point during the study. Otherwise, hold enrollment based on number of treated patients. 
 
Number of treated patients 
1 
14 
33 
45 
Number of Gr≥3 Pneumonitis/Colitis 
to stop the trial 
1 
2 
3 
4 
 
 
 
 
Operating characteristics of the early stopping rule for grade ≥3 treatment related pneumonitis/colitis: 
 
True tox rate 
0.025 
0.04 
0.055 
0.07 
0.085 
0.1 
Probability of claiming treatment too toxic 
0.092 
0.224 
0.377 
0.528 
0.661 
0.767 
 
 
Treatment related death: 10% unacceptable rate, 2.5% acceptable rate. Trial to hold enrollment if 
≥4 deaths related to treatment at any point during the study. Otherwise, hold enrollment based on 
number of treated patients. 
 
Number of treated patients 
1 
14 
33 
45 
Number of death to stop the trial 
1 
2 
3 
4 
Operating characteristics of the early stopping rule for treatment related death: 


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True tox rate 
0.025 
0.04 
0.055 
0.07 
0.085 
0.1 
Probability of claiming treatment too toxic 
0.092 
0.201 
0.323 
0.444 
0.555 
0.652 
 
 
Any one Grade ≥3 Treatment non-hematologic Related Toxicity: 60% unacceptable rate, 40% 
acceptable rate. Trial to hold enrollment if ≥25 single toxicity event related to treatment at any point 
during the study. Otherwise, hold enrollment based on number of treated patients. 
 
Number of 
treated patients 
Number of Gr>=3 non-hematologic 
toxicity events to stop the trial 
1 
1 
2 
2 
4 
4 
5 
5 
7 
6 
9 
7 
10 
8 
12 
9 
14 
10 
16 
11 
18 
12 
20 
13 
22 
14 
24 
15 
26 
16 
28 
17 
30 
18 
32 
19 
34 
20 
36 
21 
39 
22 
41 
23 
43 
24 
45 
25 
 
 
Operating characteristics of the early stopping rule for grade ≥3 treatment non-hematologic related 
toxicity: 
 
True tox rate 
0.40 
0.44 
0.48 
0.52 
0.56 
0.60 
Probability of claiming treatment too toxic 
0.099 
0.194 
0.339 
0.522 
0.707 
0.854 
 
 
14.3 Treatment re-initiation 
 
Patients who discontinue copanlisib may restart if they meet requirements set out in Section 9.9 and 
after discussion with study PI. Patients who have a complete response, then restart copanlisib for 
progression will be counted as a progression.  Future responses will be censored. 
14.4 Exploratory assessments 


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Baseline targeted sequencing of patient tumor samples will be analyzed by Fisher’s exact test for 
correlation with response/resistance and log rank test for correlation with duration of response. The 
proportion of patients with detectable ctDNA will be estimated along with a 95% CI as well as a mean 
(variance) of ctDNA. I plan to plot the variant allele frequency of each mutation over time for each 
patient. ctDNA levels will be correlated with response or duration of response to treatment. A 
multivariate logistic regression model will be fit with best response to treatment as the outcome 
variable and ctDNA and patient-related factors as covariates. To test the relation between ctDNA and 
disease status, defined as no evidence of radiographic disease (CR) vs radiographic disease 
(combined PR, SD, POD), all serial measurements will be used in a logit model with generalized 
estimating equations to correct for within-patient correlations. Logistic regression will be used to 
assess the correlations between the markers and tumor status. Overall survival (OS) and progression- 
free survival (PFS) will be assessed by Kaplan-Meier methods. The effect of ctDNA on OS will be 
analyzed as a time-dependent covariate using a Cox proportional hazards model. Similar evaluations 
will be performed on ctRNA. The statistical analysis will be primarily descriptive and the data will 
provide initial information regarding the kinetics of response and sensitivity of the assay itself. 
Pharmacokinetic assessments will be based on patients in the phase I dose escalation level 1 and 2 
cohorts. A non-compartmental analysis (NCA) will be performed in this study and pharmacokinetic 
parameters will be calculated using WinNonlin, in the latest version. Based on the plasma 
concentration–time data, the following pharmacokinetic parameters will be calculated. 
 
Copanlisib 
Ibrutinib 
Main PK parameters 
Cycle 1 Day 15 
Cmax, AUC(0–24) 
Cycle 1 Day 15 
Cmax, AUC(0–tlast),  AUC(0–24) 
and AUC 
Additional  PK parameters 
M-1, if applicable 
Cmax, AUC(0–tlast) 
tmax, tlast, t1/2 
CL and Vd if possible 
 
 
15.1 
RESEARCH PARTICIPANT REGISTRATION AND RANDOMIZATION PROCEDURES 
 
15.2 
Research Participant Registration 
 
Confirm eligibility as defined in the section entitled Inclusion/Exclusion Criteria. Obtain informed 
consent, by following procedures defined in section entitled Informed Consent Procedures. During 
the registration process registering individuals will be required to complete a protocol specific 
Eligibility Checklist. The individual signing the Eligibility Checklist is confirming whether or not the 
participant is eligible to enroll in the study. Study staff are responsible for ensuring that all 
institutional requirements necessary to enroll a participant to the study have been completed. See 
related Clinical Research Policy and Procedure #401 (Protocol Participant Registration). 
15.3 
Randomization 
 
NA 
 
16.1 
DATA MANAGEMENT ISSUES 
 
A Research Study Assistant (RSA) will be assigned to the study. The responsibilities of the RSA 
include  project  compliance,  data  collection,  abstraction  and  entry,  data  reporting,  regulatory 


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monitoring, problem resolution and prioritization, and coordinate the activities of the protocol study 
team. 
The data collected for this study will be entered into a secure database (Medidata) at Memorial Sloan 
Kettering Cancer Center. Source documentation will be available to support the computerized patient 
record. 
16.2 
Quality Assurance 
 
Registration reports will be generated on an ongoing basis to monitor patient accruals and 
completeness of registration data. Routine data quality reports will be generated to assess 
missing data and inconsistencies. Accrual rates and extent and accuracy of evaluations and 
follow-up will be monitored periodically throughout the study period and potential problems will 
be brought to the attention of the study team for discussion and action. 
Random-sample data quality and protocol compliance audits will be conducted by the study 
team, at a minimum of two times per year, more frequently if indicated. 
16.3 
Data and Safety Monitoring 
 
The Data and Safety Monitoring (DSM) Plans at Memorial Sloan-Kettering Cancer Center were 
approved by the National Cancer Institute in September 2001. The plans address the new 
policies set forth by the NCI in the document entitled “Policy of the National Cancer Institute 
for Data and Safety Monitoring of Clinical Trials” which can be found at: 
 
http://cancertrials.nci.nih.gov/researchers/dsm/index.html. 
 
The DSM Plans at MSKCC were established and are monitored by the Office of Clinical 
Research. The MSKCC Data and Safety Monitoring Plans can be found on the MSKCC 
Intranet 
at: 
https://one.mskcc.org/sites/pub/clinresearch/Documents/MSKCC%20Data%20and%20Safet 
y%20Monitoring%20Plans.pdf 
 
There are several different mechanisms by which clinical trials are monitored for data, safety 
and quality. There are institutional processes in place for quality assurance (e.g., protocol 
monitoring, compliance and data verification audits, therapeutic response, and staff education 
on clinical research QA) and departmental procedures for quality control, plus there are two 
institutional committees that are responsible for monitoring the activities of our clinical trials 
programs. The committees: Data and Safety Monitoring Committee (DSMC) for Phase I and II 
clinical trials, and the Data and Safety Monitoring Board (DSMB) for Phase III clinical trials, 
report to the Center’s Research Council and Institutional  Review Board. 
During the protocol development and review process, each protocol will be assessed for its 
level of risk and degree of monitoring required. Every type of protocol (e.g., NIH sponsored, 
in-house sponsored, industrial sponsored, NCI cooperative group, etc.) Will be addressed and 
the monitoring procedures will be established at the time of protocol activation. 


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17.1 
PROTECTION OF HUMAN SUBJECTS 
 
Potential risks to human subjects include drug related toxicity; pain and discomfort associated with 
therapy; treatment side effects; phlebotomy; and possible psychologic discomfort from the stresses 
associated with obtaining imaging studies (e.g., CT scan, PET scan). 
The side effects and potential toxicities of all agents are listed in sections 5.0 and 11.0. All efforts will 
be made to avoid any complication by completely reviewing patients’ symptoms, providing appropriate 
management, and monitoring blood tests. 
If an adverse medical event occurs, the patient will first contact the primary oncologist or the principal 
investigator. At nights and weekends, there is an oncology physician on call at all times. Patients may 
either call or come directly to the Urgent Care Center at Memorial Hospital (or to their local emergency 
room) to be seen. 
Costs to the patient (third party insurer) will include the cost of blood tests and diagnostic studies, 
office visits, and those admissions which may be required as a consequence of treatment-related 
complications. 
All serious adverse events incurred while a patient is on study will be reported to the IRB at Memorial 
Hospital, and Bayer. All serious adverse experiences and relevant laboratory findings will be reported 
to the principal investigator immediately. An adverse experience is considered serious if death occurs, 
the condition is life threatening, hospitalization is required, or there is permanent disability or 
incapacity. All information regarding serious adverse experiences must be recorded on the form 
provided. Patients suffering serious adverse reactions must be carefully followed and all follow-up 
information also recorded. 
All life threatening and lethal known, unknown, or suspected reactions (toxicities) must be reported to 
the principal investigator. An SAE report will be submitted to Bayer within 24 hours of the principal 
investigator’s knowledge of the event, and the IRB within 5 days. Any death, regardless of cause, must 
be reported to the principal investigator by telephone or fax and in writing. It is the treating physician’s 
responsibility to investigate and report the date and cause of death of any patient entered on this trial. 
17.2 
Privacy 
 
MSK’s Privacy Office may allow the use and disclosure of protected health information 
pursuant to a completed and signed Research Authorization form. The use and disclosure of 
protected health information will be limited to the individuals described in the Research 
Authorization form. A Research Authorization form must be completed by the Principal 
Investigator and approved by the IRB and Privacy Board (IRB/PB). 
The consent indicates that individualized  de identified information collected for the purposes 
of this study may be shared with other qualified researchers. Only researchers who have 
received approval from MSK will be allowed to access this information which will not include 
protected health information, such as the participant’s name, except for dates. It is also 
stated in the Research Authorization that their research data may be shared with other 
qualified  researchers. 


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17.3 
Serious Adverse Event (SAE) Reporting 
 
An adverse event is considered serious if it results in ANY of the following outcomes: 
• 
Death 
• 
A life-threatening adverse event 
• 
Development of a new malignancy 
• 
Pregnancy 
• 
An adverse event that results in inpatient hospitalization or prolongation of existing 
hospitalization 
• 
A persistent or significant incapacity or substantial disruption of the ability to conduct 
normal life functions 
• 
A congenital anomaly/birth defect 
• 
Important Medical Events (IME) that may not result in death, be life threatening, or 
require hospitalization may be considered serious when, based upon medical judgment, 
they may jeopardize the patient or subject and may require medical or surgical 
intervention to prevent one of the outcomes listed in this definition 
Note: Hospital admission for a planned procedure/disease treatment is not considered an 
SAE. 
 
SAE reporting is required as soon as the participant starts investigational 
treatment/intervention. SAE reporting is required for 30-days after the participant’s last 
investigational treatment/intervention. Any event that occur after the 30-day period that is 
unexpected and at least possibly related to protocol treatment must be reported. 
 
Please note: Any SAE that occurs prior to the start of investigational treatment/intervention 
and is related to a screening tet or procedure (i.e., a screening biopsy) must be reported. 
 
All SAEs must be submitted in PIMS. If an SAE requires submission to the HRPP office per 
IRB SOP RR-408 ‘Reporting of Serious Adverse Events’, the SAE report must be submitted 
within 5 calendar days of the event. All other SAEs must be submitted within 30 calendar 
days of the event. 
 
The report should contain the following information: 
• 
The date the adverse event occurred 
• 
The adverse event 
• 
The grade of the event 
• 
Relationship of the adverse event to the treatment(s) 
• 
If the AE was expected 
• 
Detailed text that includes the following 
o An explanation of how the AE was handled 
o A description of the participant’s condition 
o Indication if the participant remains on the study 
• 
If an amendment will need to be made to the protocol and/or consent form • If the 
SAE is an Unanticipated Problem 


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For IND/IDE protocols: 
The SAE report should be completed as per above instructions. If appropriate, the report will 
be forwarded to the FDA by the IND Office 
 
17.2.1 
 
Bayer specific SAE reporting: 
 
Research team shall immediately, within 24 hours at the latest, report to Bayer by e-mail to  
drugsafety.gpv.us@bayer.com  : 
• 
All Serious Adverse Events occurring after start of administration of BAYER product, 
independent of their causal relationship to study drugs 
• 
Any other relevant safety information including but not limited to: 
o Reports of drug exposure via mother / father with and without adverse events 
(exposure during conception, pregnancy, childbirth and breastfeeding) 
including their outcome; 
o If linked to a serious adverse event, reports of misuse, abuse, overdose, 
medication error and other uses outside what is foreseen in the protocol, drug 
dependency, occupational exposure suspected transmission of an infectious 
agent, withdrawal syndrome, drug interactions with respect to study drugs 
o Any communication concerning safety related information to regulatory 
authorities or ethics committees including but not limited to: 
▪ 
Development Safety Update Reports / relevant parts of IND reports for 
the study drugs 
▪ 
Any other safety related reports, issues and queries that are either 
raised by or communicated to regulatory authorities or ethics 
committees (e.g., reportable non-serious cases) 
 
 
18.1 
INFORMED CONSENT PROCEDURES 
 
Before protocol-specified procedures are carried out, consenting professionals will explain full 
details of the protocol and study procedures as well as the risks involved to participants prior 
to their inclusion in the study. Participants will also be informed that they are free to withdraw 
from the study at any time. All participants must sign an IRB/PB-approved consent form 
indicating their consent to participate. This consent form meets the requirements of the Code 
of Federal Regulations and the Institutional Review Board/Privacy Board of this Center. The 
consent form will include the following: 
1. The nature and objectives, potential risks and benefits of the intended study. 
2. The length of study and the likely follow-up required. 
3. Alternatives to the proposed study. (This will include available standard and 
investigational therapies. In addition, patients will be offered an option of supportive 
care for therapeutic studies.) 
4. The name of the investigator(s) responsible for the protocol. 


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5. The right of the participant to accept or refuse study interventions/interactions and to 
withdraw from participation at any time. 
Before any protocol-specific procedures can be carried out, the consenting professional will 
fully explain the aspects of patient privacy concerning research specific information.  In addition 
to signing the IRB Informed Consent, all patients must agree to the Research Authorization 
component of the informed consent form. 
Each participant and consenting professional will sign the consent form. The participant must 
receive a copy of the signed informed consent form. 
 
 
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IRB Number: 18-450 A(10) 
Approval date: 08-Sep-2020 
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IRB PROTOCOL 
 
 
 
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20.0 
APPENDICES 
 
APPENDIX 1: A list of CYP3A4 inhibitors and inducers 
 
A list of strong inhibitors and inducers of CYP3A4 is shown below: 
 
Strong CYP3A4 
inhibitors 
Boceprevir,  clarithromycin, conivaptan,  grapefruit  juice, indinavir, 
itraconazole, ketoconazole, lopinavir/ritonavir,   mibefradil,  nefazodone, 
nelfinavir,  posaconazole,  ritonavir,  saquinavir,  telaprevir,  telithromycin, 
voriconazole,  atazanavir,  tipranavir,  troleoandomycin,  elvitegravir, 
danoprevir,  conivaptan,  boceprevir,  suboxone and cobicistat 
Strong CYP3A4 
inducers 
Avasimibe,  carbamazepine,  mitotane, phenobarbital,  phenytoin,  rifabutin, 
rifampin (rifampicin),  St. John's wort (hypericum  perforatum)  and 
enzalutamide 
CYP3A4 = Cytochrome  P450 isoenzyme 3A4 
• 
A strong inhibitor for a specific CYP is defined as an inhibitor that increases the AUC of a 
substrate for that CYP by equal or more than 5-fold 
• 
Strong Inducer for a specific CYP is defined  as an inducer that decreases  the AUC of a 
substrate  for that CYP by  ≥ 80% 
Source: 1-4 
1. 
Food and Drug Administration (FDA), Guidance for Industry, Drug Interaction Studies  – 
Study Design, Data Analysis, Implications for Dosing, and Labeling Recommendations  Center for 
Drug Evaluation  and Research (CDER),  Draft  Guidance (2012).  Available  online: 
http://www.fda.gov/downl  oads/drugs/guidancecompliance 
regulatoryinformation/guidances/ucm292362.pdf. 
2. 
FDA Drug Development  and Drug Interactions: Table of Substrates, Inhibitors  and 
Inducers.  Available  online:  http://www.fda.gov/drugs/developmentapprovalprocess/ 
developmentresources/drugi  nteractionslabeling/ucm093664.htm. 
3. 
Metabolism and Transport  Drug Interaction Database,  University  of Washington, 
Department  of Pharmaceutics (2008) Last update:  July, 2014. Available  online: 
www.druginteractioninfo.org. 
4. 
Flockhart DA. Drug Interactions: Cytochrome P450 Drug Interaction Table. Indiana 
University  School of Medicine (2007) Last update: July 2013. Available online: 
http://medicine.iupui.edu/flockhart/table.htm