MATCH Treatment Subprotocol Z1F: Phase II Study of Copanlisib in Patients With Tumors With PIK3CA Mutations (PTEN Loss Allowed)
Phase: PHASE2
Conditions: Advanced Lymphoma, Advanced Malignant Solid Neoplasm, Hematopoietic and Lymphatic System Neoplasm, Refractory Lymphoma, Refractory Malignant Solid Neoplasm, Refractory Multiple Myeloma
Sponsor: National Cancer Institute (NCI)

i
28 State Street, Suite 1100, Boston, MA 02109
p: 857.504.2900
f:617. 589.0914
ecog-acrin.org
August 12, 2019 
Martha Kruhm, MS RAC
Head, Protocol and Information Office
Quality Assurance Section
CTEP, DCT, NCI
6130 Executive Blvd, EPN Room 7000
Bethesda, MD   20892
Dear Ms. Kruhm:
Enclosed is Addendum #22 to EAY131- Z1F, Phase II Study of Copanlisib in Patients with 
Tumors with PIK3CA Mutations (PTEN Loss Allowed).
Please replace your current copy of the protocol and Informed Consent document with these 
updated versions. We recommend that each institution maintain a file containing the original 
protocol, Informed Consent, and all subsequent revisions/versions.
IRB Review Requirements:
This addendum has been reviewed and approved by the Central IRB, which is the sole 
IRB of record for this study. Local IRB review and approval is unnecessary.
Implementation of this addendum must occur on the activation date. Sites are not 
permitted to conduct the study utilizing outdated versions of any MATCH protocol documents 
after the activation date of this addendum.
This addendum is in response to Dr. L. Austin Doyle July 29, 2019 Request for Amendment for 
Copanlisib.
The following revisions to EAY131-Z1F protocol have been made in this addendum:
Section
Change
1.
Cover Page
Updated version date.
2.
3.4
Updated the Copanlisib CAEPR list with version 2.2, June 18, 2019.
The following revisions to EAY131- Z1F Informed Consent Document have been made in this 
addendum:
Section
Change
1.
Page 1
Updated version date.
2.
“What possible risks can 
I expect from taking part 
in this study?”
Updated the Copanlisib risk list with June 18, 2019 version date.
If you have any questions regarding this addendum, please contact Abuchi Agu at aagu@ecog-
acrin.org or 857-504-2900.

ii 
We request review and approval of this addendum to EAY131- Z1F so ECOG-ACRIN may 
activate it promptly.   
Thank you.  
Sincerely, 
Pamela Cogliano 
Senior Director of Protocol Development 
Enclosure 
CC: Senthil Damodaran, MD, PhD  
Dustin Deming, MD 
Alice Chen, MD 
Keith Thomas Flaherty, MD 
Peter O’Dwyer, MD 
Mickey Williams, PhD 
Stanley Hamilton, MD 
Lisa McShane, PhD  
Larry Rubinstein, PhD 
Robert Gray, PhD 
Shuli Li, PhD 
Lalitha Shankar, MD, PhD 
Susanna Lee, MD, PhD 
Constantine Gastonis, PhD 
Paolo Caimi, MD 
Shaji Kumar, MD 
Carlos Arteaga, MD 
Edith Mitchell, MD 
John J. Wright, MD, PhD 
Lyndsay Harris, MD 
James Tricoli, PhD 
 
 
Bruce Giantonio, MD 
Donna Marinucci 
Kerry Higgins 
Gayle Ipock 
Jean MacDonald 
Carol Chami, RN 
Juanita Andrews 
Julianne Human 
Kelly Redmond 
Becky Fillingham 
Jeffrey Zhang 
Kevin Pollard 
Amy Li 
Abuchi Agu 
Elanna Radomyshelsky 
Erin Mendelsohn 
Michael T. Balco 
Lauren Lambert 
Margaret Cavenagh 
Ben Kim 
Alexandra Sachs 
Russell McDaniel 
Cayden Maican  
 
 

 
EAY131-Z1F 
1 
Molecular Analysis for Therapy Choice (MATCH) 
MATCH Treatment Subprotocol Z1F: Phase II Study of 
Copanlisib in Patients with Tumors with PIK3CA 
Mutations (PTEN Loss Allowed) 
COPANLISIB TREATMENT SUBPROTOCOL 
CHAIR: 
 
Senthil Damodaran, MD, PhD 
COPANLISIB TREATMENT SUBPROTOCOL CO-
CHAIR: 
 
Dustin Deming, MD 
Version Date:  August 12, 2019 
 
NOTE: This subprotocol (EAY131-Z1F) should 
be used in conjunction with the 
MATCH Master Protocol (EAY131). 
 
SUBPROTOCOL ACTIVATION DATE 
 
Incorporated in Addendum #13 
Addendum #16 
 
 
Addendum #22 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Agent 
IND# 
NSC# 
Supply 
Copanlisib 
IND Sponsor: DCTD, NCI  
784727 
NCI Supplied 
 

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Table of Contents 
Molecular Analysis for Therapy Choice (MATCH) ...................................................... i 
MATCH Treatment Subprotocol Z1F: Phase II Study of Copanlisib in Patients with 
Tumors with PIK3CA Mutations (PTEN Loss Allowed) ........................................ 1 
Table of Contents ...................................................................................................... 2 
Schema ...................................................................................................................... 4 
1. Introduction ........................................................................................................ 5 
1.1 
Copanlisib .................................................................................................. 5 
1.2 
Supporting Preliminary Data ..................................................................... 5 
2. Selection of Patients ......................................................................................... 12 
2.1 
Eligibility Criteria ..................................................................................... 12 
3. Copanlisib Treatment Plan ................................................................................ 15 
3.1 
Dosage and Administration Schedule ..................................................... 15 
3.2 
General Concomitant Medication and Supportive Care Guidelines ....... 16 
3.3 
Adverse Event Reporting Requirements ................................................. 17 
3.4 
Comprehensive Adverse Events and Potential Risks List (CAEPR) for 
Copanlisib dihydrochloride (BAY 80-6946 dihydrochloride, NSC 784727)20 
3.5 
Dose Modifications ................................................................................. 23 
3.6 
Supportive Care ....................................................................................... 30 
3.7 
Duration of Agent-specific treatment ..................................................... 30 
3.8 
Duration of Follow-Up ............................................................................. 30 
4. Study Parameters .............................................................................................. 31 
4.1 
Therapeutic Parameters for Copanlisib Treatment ................................ 31 
5. Drug Formulation and Procurement ................................................................. 33 
5.1 
Copanlisib (NSC #784727) ....................................................................... 34 
6. Translational Studies ......................................................................................... 37 
7. References ........................................................................................................ 37 
Appendix I  Actionable Mutations for Sub-Protocol EAY131-Z1F ........................... 38 
Appendix II  Patient Drug Information Handout and Wallet Card .......................... 41 
Appendix III  MANAGEMENT OF TRANSIENT GLUCOSE INCREASE ON THE DAY OF 
COPANLISIB INFUSION ...................................................................................... 43 
Appendix IV  DOSE MODIFICATION OF COPANLISIB FOR ARTERIAL HYPERTENSION44 
 

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TREATMENT SUBPROTOCOL CHAIR 
Senthil Damodaran, MD, PhD 
The University of Texas 
1515 Holcombe Boulevard 
Breast Medical Oncology Unit 1354 
Houston, TX. 77030 
Phone #: (713) 792-2817 
Fax #: (713) 794-4385 
E-mail: sdamodaran@mdanderson.org 
 
 
TREATMENT SUBPROTOCOL CO-CHAIR  
Dustin Deming, MD 
Wisconsin Institute for Medical Research 
1111 Highland Avenue, 6057 
Madison, WI. 53705 
Phone #: (608) 265-1042 
Fax #: (608) 265-6020 
E-mail: ddeming@medicine.wisc.edu 
 
 
 
 
Rev. Add16 

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Schema 
 
 
 
 
Long-Term Follow-Up
Copanlisib, 60 mg administered 
intravenously on days 1, 8, and 15 
of each cycle
Until progression or unacceptable 
toxicity
Cycle = 28 days
Accrual Goal: 35

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1. 
Introduction 
1.1 
Copanlisib 
Copanlisib (BAY 80-6946) is a novel, highly selective, PI3K inhibitor with potent 
activity against both the δ and α isoforms. 
1.2 
Supporting Preliminary Data  
1.2.1 
Rationale 
Phosphatidylinositol 3-kinase (PI3K) is involved in tumor cell 
migration, proliferation, and survival. PI3K catalyzes the 
phosphorylation of phosphatidylinositol-4,5-bisphosphate (PIP2) to 
phosphatidylinositol-3,4,5-trisphosphate (PIP3), which subsequently 
leads to downstream activation of Akt and associated proteins in the 
Akt/mammalian target of rapamycin (mTOR) pathway.1,2 PTEN 
(phosphatase and tensin or MMAC, mutated in multiple advanced 
cancers) is a tumor suppressor that negatively regulates the PI3K 
pathway thorough its phosphatase activity, dephosphorylating PIP3 to 
PIP2.3 The loss of PTEN function, observed in multiple tumors, can be 
caused by various mechanisms including mutations, deletions, 
transcriptional silencing and epigenetic changes.4 Activation of the 
PI3K/AKT/mTOR pathway through PIK3CA mutations or PTEN loss is 
observed in many human cancers.5,6 Early studies have suggested 
that PIK3CA mutations predict for increased sensitivity to therapies 
targeting the PI3K/AKT/mTOR signaling pathway.7,8  
Class I PI3K is a heterodimer with a regulatory and catalytic subunit. 
The catalytic subunit, p110, has 4 isotypes: alpha, encoded by 
PIK3CA; beta, encoded by PIK3CB; gamma, encoded by PIK3CG, 
and delta, encoded by PIK3CD. Mutations typically involve the kinase 
and helical domains of the p110alpha of PI3K.9 Janku et al analyzed 
characteristics and outcome of over 1600 patients with diverse 
advanced tumors and PIK3CA mutations. Of 160 patients found to 
have PIK3CA mutations, common mutations included E545K (1633G 
> A) in 32.5%; E542K (1624G > A) in 20% and H1047R (3140A > G) 
in 18%.7 These hotspot mutations in PIK3CA, as well as other less 
common mutations, have been shown to increase the kinase activity 
of PIK3CA and increase phosphorylation of downstream signaling 
targets.10-14 Improved response rates in patients with PIK3CA 
mutations or PTEN loss who were treated with Akt inhibitors and PI3K 
inhibitors compared to patients treated with similar agents but not 
having PIK3CA mutations or PTEN loss, and to patients with PIK3CA 
mutations or PTEN loss treated with agents that do not target the 
PI3K/AKT/mTOR pathway were observed.7,8 Patients with PIK3CA 
mutations treated with PI3K/AKT/mTOR inhibitors had a significantly 
higher partial/complete response (PR/CR) rate (18%) than wild-type 
PIK3CA patients treated with their best phase I therapy (6%), but not 
prolonged progression-free survival. The rate of stable disease > 6 
months/ partial response reached 45% in patients with H1047R 
PIK3CA mutations. PIK3CA mutations were more prevalent in 
patients with KRAS mutations than wild-type (WT) KRAS (19% versus 

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9%). Patients with PIK3CA mutations and concurrent KRAS mutations 
had a shorter median PFS (1.8 months) compared to patients without 
KRAS mutations (2.9 months). Similarly, response rates were inferior 
in patients who had concurrent PIK3CA and KRAS mutations (4%) 
compared to patients without KRAS mutation (24%). This may be due 
to complex feedback loops between the MAPK and PI3K pathways 
such that mTORC1 inhibition leads to ERK1/2 activation via a 
p70S6K/PI3K/RAS dependent signaling or by mutant KRAS activating 
p90Rsk1 which bypasses mTOR to activate EIF4B and RPS6. Thus, 
patients with concurrent KRAS mutations would be excluded from this 
study. This trial will assess whether patients with PIK3CA mutations 
show response or have prolonged stable disease with copanlisib.  
Summary of the available preclinical and clinical data from 
Investigator’s brochure is provided below. For additional details, 
please refer to copanlisib investigator’s brochure dated 01 Feb 2016. 
1.2.2 
Preclinical Data: 
Copanlisib is a pan-class I PI3K inhibitor with dominant PI3Kα (half-
maximal inhibitory concentration [IC50]=0.5 nM) and PI3Kδ (IC50=0.7 
nM) activity compared to PI3Kβ (IC50=3.7 nM) and PI3Kγ (IC50=6.4 
nM) and other protein kinases (inactive at 1 μm, except mammalian 
target of rapamycin (mTOR) with IC50=45 nM) in biochemical assays. 
It is also a strong inducer of apoptosis in tumor cells (half-maximal 
effective concentration [EC50] of 50-400 nM in caspase 9 activation 
assays in BT474 and BT20 breast cancer cell lines).  It has potent and 
broad in vitro anti-tumor activity (IC50 of 1-760 nM for inhibition of 
tumor cell proliferation in human breast, ovary, prostate, colon, lung, 
liver, brain, kidney, melanoma, pancreas, fibrosarcoma, and 
hematological tumors). It has 100 to 1000-fold cellular selectivity for 
PI3K vs. mTOR signaling. Of note, several breast cancers, NHL and 
multiple myeloma cell lines were particularly sensitive to copanlisib 
(IC50 below 10 nM). Copanlisib was efficacious in tumor cells 
resistant to herceptin/lapatinib, such as T47D, ZR-75-1, and MCF7. 
Copanlisib had mean IC50 values of 19 nM against cell lines with 
PIK3CA-activating mutations (N=9), 17 nM against HER2-positive cell 
lines (N=7), and 17 nM against cell lines with PIK3CA-activating 
mutations and/or HER2 overexpression (N=13), while the activity in 
PIK3CA wild type and HER2-negative cells (N=11) was about 40-fold 
less potent (average IC50=774 nM). This suggests potent biochemical 
and cellular activity against PI3Kα, and indicates that PIK3CA 
mutation as a potential biomarker to predict the sensitivity to 
copanlisib. 
In athymic rats, copanlisib showed potent, dose-dependent activity 
against PIK3CA mutation or PTEN-loss xenograft models from 
various tumor histologies including colon cancer (HCT-116), lung 
cancer (H460), glioma (U-87 malignant glioma [U87MG]), and breast 
cancer (KPL-4). The maximum tolerated dose (MTD) in athymic rats 
was 10 mg/kg (every second day [q2d] ×5, i.v.). Complete tumor 
stasis was observed at a dose ≥ 3 mg/kg in the four models 
mentioned above and complete tumor regressions were observed in 
the KPL-4 (HER2, PIK3CAmut]) breast tumor model. At the 3.0 and 

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6.0 mg/kg doses, 10 out of 10 nude rats had complete tumor 
regressions and the animals remained tumor-free (cures) upon 
termination of the study on Day 73. While HCT-116, H460, and KPL-4 
all carry somatic mutation in PIK3CA, no tumor regressions were 
observed in HCT-116 and H460 tumor models. It is possible that the 
lack of tumor regressions observed in the H460 and HCT-116 models 
may be due to coexistent KRAS mutation leading to activation of 
alternate MAPK pathway. Synergistic combinational effects with MEK 
inhibitor refametinib, regorafenib, paclitaxel, and gemcitabine resulted 
in tumor regression and complete tumor growth inhibition without 
enhanced general toxicity in patient-derived xenograft models in mice. 
Synergistic effect of combination of copanlisib with gemcitabine was 
observed in NSCLC Lu7913 xenograft model, which carries an 
activating PIK3CA mutation (E545K). Similarly, synergistic effect was 
observed for the combination of paclitaxel and BAY 84-1236. 
Combination resulted in a 100% response rate with 4/10 animals 
exhibiting CR and 6/10 animals having PR, while 60% and 100% 
animals showed tumor progression in the paclitaxel and BAY 84-1236 
monotherapy groups, respectively.  
1.2.3 
Clinical Data: 
As of February 1, 2016, nearly 627 patients with advanced cancers 
have been treated with copanlisib on multiple studies. Three Phase 1 
clinical trials are ongoing and enrolling patients: Study 16790 
(copanlisib as monotherapy); Study 16270 (copanlisib with 
itraconazole / copanlisib with rifampin / cardiovascular safety) and 
Study 17792 (Japanese indolent NHL patients only). One has 
completed enrollment but still has one patient under treatment for 
more than 3 years (FiM [first-in-man] Study 12871), and five are 
closed (Studies 15205, 12876, 16353, 12874, and 12875). In addition, 
three Phase 2 clinical trials (Studies 16349, 17119 and 17120) and 
three Phase 3 trials (Studies 17322, 17067 and 17833) are ongoing. 
One Phase 2 study has completed enrollment (Study 17119). Study 
16349 is an ongoing open-label uncontrolled, parallel group, signal-
generating, Phase 2 study to evaluate efficacy and safety of 
copanlisib as single agent (0.8 mg/kg, maximum 65 mg, i.v. dosing 
over 1 hour on Days 1, 8, and 15 of each 28-day treatment cycle) in 
patients with relapsed or refractory, indolent or aggressive NHL. Study 
17119 is a single arm, open-label, multicenter Phase II study to 
evaluate efficacy and safety of copanlisib as single agent in patients 
with relapsed or refractory DLBCL or DLBCL transformed from FL. 
Study 17120 is a single-arm, open-label Phase IIa study to evaluate 
the efficacy and safety of copanlisib monotherapy in patients with 
relapsed or refractory MCL who progressed after ibrutinib treatment or 
were unable to tolerate ibrutinib. Study 17322 (CHRONOS-2) is a 
randomized, double-blind, two-arm Phase III study to evaluate the 
efficacy and safety of copanlisib as monotherapy in comparison to 
placebo in patients with rituximab refractory iNHL who have failed at 
least two previous lines of therapy. Study 17067 (CHRONOS 3) is a 
randomized, double-blind, placebo-controlled, two-arm, Phase III 
study to evaluate efficacy and safety of copanlisib in combination with 
rituximab, in comparison to placebo in combination with rituximab, in 

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patients with relapsed iNHL– CHRONOS-3. Study 17833 (CHRONOS 
4) is a double-blind, two-arm Phase III study in patients with relapsed, 
rituximab-sensitive iNHL to evaluate efficacy and safety of copanlisib 
in combination with standard immunochemotherapy (R-B or R-CHOP) 
in comparison to standard immunochemotherapy (R-B or R-CHOP) 
and placebo. Copanlisib has also been studied in healthy volunteers: 
a mass balance study was conducted in 6 healthy male subjects who 
received a single i.v. administration of 12 mg [14C] copanlisib. Based 
on pharmacokinetic and clinical data, the recommended dose is 60 
mg of copanlisib for all patients given intravenously in a 3 weeks on/1 
week off schedule. 
1.2.4 
Preliminary Pharmacokinetics 
Copanlisib demonstrated dose proportional increases in maximum 
concentration (Cmax) and AUC (area under the plasma 
concentration-time curve) from time zero to 25 hours (AUC(0-25)) in 
the dose range 0.1 to 1.2 mg/kg (5 to 93.4 total dose) with a terminal 
phase half-life (t1/2) of 38.2 hours at a dose of 0.8 mg/kg (n=28). 
These data indicate that copanlisib is widely distributed in tissues and 
support a once weekly dosing regimen. No accumulation was 
observed after once weekly dosing when comparing PK on Cycle 1 
Days 1 and 15 and Cycle 3 Day 15. No evidence of time-dependency 
in the PK of copanlisib was observed. Low extent of plasma protein 
binding of copanlisib and metabolite M-1 (metabolite of copanlisib) in 
animals and man with free fractions of 16% (parent compound) and 
20% (M-1) in human plasma. The blood/plasma concentration ratio of 
copanlisib did not change in human blood in the investigated 
concentration range up to ca. 16000)g/L.  
Oxidation and dealkylation at the alkylmorpholine side chain is the 
major biotransformation pathway in liver microsomes and hepatocytes 
of various animal species and man; with no major species differences. 
CYP3A4 is the major metabolizing enzyme in man, while CYP1A1 
contributes to a minor extent. Copanlisib was the predominating 
component in plasma of mouse, rat, dog, and man. M-1 was the only 
relevant circulating metabolite in plasma of rat and man. In man and 
rat, balanced elimination of unchanged copanlisib and oxidative 
biotransformation products via urine and feces were observed. 
Radioactivity was excreted mainly via the biliary/fecal route in rat, dog, 
and man after administration of [14C] copanlisib. In man, 22% of the 
administered radioactivity was excreted via urine. [14C]. Copanlisib-
related radioactivity was secreted into the milk of lactating rats only to 
a low extent (1.7% of dose). Based on in vitro studies with different 
cell lines, copanlisib is a substrate of permeability glycoprotein (P-gp) 
and breast cancer resistance protein (BCRP). There was active 
uptake of copanlisib into hepatocytes. Organic cation transporters 
(OCTs), organic anion transporters (OATs) or organic anion 
transporting polypeptides (OATP) transporters were not involved in 
hepatic uptake of copanlisib. 
There is considered to be low risk for clinical drug-drug interactions 
through inhibition or induction of major CYP and or uridine 
diphosphate glucuronosyltransferase (UGT) isoforms or 

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dihydropyrimidine dehydrogenase by copanlisib. Copanlisib inhibits P-
gp (IC50: 7 μM and 7.6 μM for digoxin and dipyridamole, respectively) 
and BCRP-mediated transport (IC50: 11.5 μM for topotecan); potently 
inhibits MATE2K (IC50: 0.09 μM for metformin) and inhibits MATE1 
(IC50: 10.8μM for metformin). Copanlisib does not inhibit uptake 
transporters including OATP1B1, OATP1B3, OAT1, OAT3, OCT1, 
and OCT2 or bile salt export pump (BSEP). Drug-drug interactions 
through inhibition of major CYP and UGT isoforms or P-gp and BCRP 
by metabolite M-1 are also unlikely. The geometric mean AUC 
increased by 1.53-fold following 60 mg copanlisib in combination with 
the strong CYP3A4 inhibitor itraconazole. This increase is considered 
weak according to FDA drug-drug interaction classification guidance. 
A population PK model to assess the influence of age, sex, race, body 
weight, and other size-related covariates (body mass index [BMI], 
lean body mass [LBM], and BSA) on the pharmacokinetics of 
copanlisib revealed no apparent correlation between clearance and 
any of these covariates. Based on these results, there is no indication 
that a weight-based dose regimen would reduce the variability in 
exposure of copanlisib. 
1.2.5 
Preliminary Pharmacodynamics 
The PI3K pathway is required for downstream signaling from the 
insulin receptor. Inhibition of this pathway is expected to lead to 
impaired cellular uptake of glucose, with a subsequent reactive rise in 
plasma insulin and glucose levels. Intravenous infusion of copanlisib 
also causes vasoconstriction, reduced gastrointestinal motility, 
increased renal volume and electrolyte excretion, and central nervous 
system (CNS) depressant effects. The CNS depressant effects occur 
at high drug plasma concentrations and are considered secondary to 
hyperglycemia. The PD effects on glucose and plasma insulin levels 
as well as 18[F] FDG-CT/PET have been investigated in the Study 
12871 using copanlisib at different doses. PD effect was defined as 
having occurred if, within 2 hours after the completion of the infusion, 
the plasma glucose increased >50 mg/dL from baseline and / or the 
plasma insulin increased to greater than 2 times the baseline value. 
All but 1 of the 47 non-diabetic patients treated at 0.4 mg/kg 
copanlisib experienced a PD effect as well as all 6 diabetic patients 
treated at 0.4 mg/kg copanlisib. Peak plasma glucose values were 
seen 5 to 8 hours after the start of the copanlisib infusion. 
Hyperglycemia was reversible. Dose-related increases in glucose and 
insulin as well as copanlisib exposure-related increases in plasma 
glucose were observed. At pharmacodynamically relevant 
concentrations, copanlisib does not interfere with cardiac 
repolarization in vitro and in vivo. Other hemodynamic parameters 
(e.g., heart rate, stroke volume, cardiac output, central venous 
pressure), ECG intervals (including QT interval) were not affected or 
only slightly affected. There were no physiologically significant effects 
on respiration rate, tidal volume, and minute volume. 
1.2.6 
Safety 
When copanlisib was given as a single agent (Study 12871), All 57 
patients reported at least 1 treatment-emergent adverse event (TEAE) 

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by Medical Dictionary for Regulatory Activities Preferred Term 
(MedDRA PT), regardless of seriousness, severity, and causality, and 
49 (86.0%) patients reported at least 1 drug-related TEAE.  The most 
common TEAEs by MedDRA PT, regardless of seriousness, severity, 
and causality, occurring in ≥ 20% of the 57 patients were: 
hyperglycemia (64.9%); nausea (54.4%); fatigue (40.4%); diarrhea 
(33.3%); hypokalemia (31.6%); hypertension (29.8%); vomiting 
(28.1%); decreased appetite (26.3%); anemia and constipation 
(24.6% each); dyspnea and dehydration (22.8% each); as well as 
cough (21.1%). Rash and pruritus were the most frequently reported 
skin toxicity in 7 (12.3%) These were generally of CTCAE v3.0 Grade 
1 or Grade 2 in severity, only 4 (7.0%) patients experienced Grade 3 
skin/subcutaneous disorders. Rash was generally manageable with 
topical steroids but systemic steroids were sometimes needed.  
The most common drug-related TEAEs by MedDRA PT, regardless of 
seriousness and severity, occurring in ≥20% of the 57 patients (all 
cohorts) were: hyperglycaemia (63.2%), nausea (38.6%), and 
hypertension (21.1%). The most common drug-related TEAEs by 
MedDRA PT with a severity of CTCAE v3.0 Grade ≥ 3 occurring in ≥ 
5% of the 57 patients (all cohorts) were: hyperglycemia (39.0%) and 
hypertension (17.1%). Increased blood pressure (BP) is frequently 
observed within the first 3 hours after start of infusion. Five (8.8%) 
patients experienced any TEAE leading to dose reduction. These 
TEAEs by MedDRA PT were: exfoliative rash, hyperglycemia, 
dyspnea, mucosal inflammation (one patient each), anemia and 
thrombocytopenia in 1 same patient. Ten patients experienced any 
TEAE leading to permanent discontinuation of study drug. The 10 
serious TEAEs leading to permanent discontinuation of study drug in 
the 9 patients were: aspiration pneumonia, ascites/oedema, 
enterococcal sepsis, LVEF dysfunction/cardiac tamponade, 
intracranial hemorrhage, large intestinal obstruction, portal vein 
thrombosis, staphylococcal bacteraemia and pleural effusion. Except 
the LVEF (DLT in Cohort 1.2 mg/kg), none of these TEAEs was 
assessed as drug-related by the investigators. Hyperglycemia due to 
copanlisib is reversible. Copanlisib was not discontinued in any 
patient due to hyperglycemia. The other common laboratory 
abnormalities (occurred in most patients) included: hemoglobin 
decreased in 49 of 57 patients (89.1%); hypoalbuminaemia in 43 of 56 
patients 76.8%); hypocalcaemia in 38 of 55 patients (69.1%); 
leukocytes decreased in 37 of 55 patients (67.3%); AP increased in 
37 of 56 patients (66.1%); lymphopenia was documented in 17 of 28 
patients (60.7%); AST increased in 33 of 56 patients (58.9%); and 
hypercholesterolaemia was seen in 2 of 4 patients (50.0%). AST 
increase, considered a class effect, was observed mainly with a 
severity of CTCAE v3.0 Grade 1 (42.9%). In Study 16349 Part A, the 
most common TEAEs experienced by > 20% of the study population 
were hyperglycemia (59.3%), hypertension (56.8%), diarrhea (40.7%), 
fatigue (35.8%), nausea (32.1%), neutropenia (28.4%) and anemia 
(27.2%). Pneumonitis occurred in 3 patients with FL; no pneumonitis 
was reported in solid tumor patients.  Copanlisib is expected to 
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from the repeat-dose toxicity studies. Due to the mechanism of action 
of copanlisib as a PI3K inhibitor, adverse effects on development and 
reproduction are expected. Copanlisib is not mutagenic in vitro or in 
vivo. There is no evidence for a phototoxic potential of copanlisib. 60 
mg of copanlisib (given in a 3 weeks on/1 week off schedule) is 
expected to have a comparable safety profile to the observed safety 
profile at the MTD of 0.8 mg/kg. 
1.2.7 
Efficacy 
In the Phase 1 monotherapy Study 12871, out of the 48 patients with 
solid tumors, CR as best overall response was achieved in 1 patient 
(2.1%) with endometrial cancer, 2 patients (4%) had PR, 15 (31%) 
achieved SD, and 15 (31%) had disease progression by investigator 
assessment, according to RECIST version 1.1. Seven patients (15%) 
had disease progression by clinical judgment and 8 patients (17%) 
were not assessed. Clinical benefit (CR, PR, or SD) was observed in 
18 patients (38%) overall, by investigator assessment. Patient with 
CR (after 10 cycles of copanlisib) was a 75-year-old woman with 
poorly differentiated uterine adenocarcinoma (Stage IV at study 
entry). The archival tumor tissue of this patient exhibited mutations in 
both PIK3CA and PTEN by next-generation sequencing (NGS) as well 
as complete PTEN loss by IHC. Among the 9 NHL patients, all 6 with 
FL responded (one CR and 5 PRs) and one patient with diffuse large 
B-cell lymphoma had a PR; 2 patients with FL achieved CR (per 
subsequent post hoc independent radiologic review), and 2 FL 
patients were on treatment > 3 years. In the Phase II Study 16349 
Part A, ORR analyzed by histological subtype showed that in the 
indolent NHL group, the ORR was 47.37% in indolent B-cell 
lymphoma (N=19), 40.00% in FL (N=15), 38.46% in CLL (N=13), 
66.67% in MZL (N=3), and 100% in SLL (N=1). In the aggressive NHL 
group, the best ORR (>30%) were observed in MCL (63.64%, N=11) 
and in transformed indolent lymphoma (33.33%, N=6). 
 

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2. 
Selection of Patients 
Each of the criteria in the checklist that follows must be met, along with the eligibility in 
the MATCH Master Protocol, in order for a patient to be considered eligible for this 
study. Use the checklist to confirm a patient’s eligibility. For each patient, this checklist 
must be photocopied, completed and maintained in the patient’s chart.  
In calculating days of tests and measurements, the day a test or measurement is 
done is considered Day 0. Therefore, if a test is done on a Monday, the Monday 
four weeks later would be considered Day 28.  
ECOG-ACRIN Patient No. ____________________________ 
Patient’s Initials (L, F, M) _______________________ 
Physician Signature and Date ___________________ 
NOTE: 
Policy does not allow for the issuance of waivers to any protocol specified 
criteria (http://ctep.cancer.gov/protocolDevelopment/policies_deviations.htm). 
Therefore, all eligibility criteria listed in Section 2 must be met, without 
exception. The registration of individuals who do not meet all criteria listed in 
Section 2 can result in the participant being censored from the analysis of the 
study, and the citation of a major protocol violation during an audit.  All 
questions regarding clarification of eligibility criteria must be directed to the 
Group's Executive Officer (EA.Execofficer@jimmy.harvard.edu) or the 
Group's Regulatory Officer (EA.RegOfficer@jimmy.harvard.edu). 
NOTE: 
Institutions may use the eligibility checklist as source documentation if it has 
been reviewed, signed, and dated prior to registration/randomization by the 
treating physician. 
NOTE: 
All patients must have signed the relevant treatment consent form 
2.1 
Eligibility Criteria 
2.1.1 
Patients must fulfill all eligibility criteria outlined in Section 3.1 of 
MATCH Master Protocol (excluding Section 3.1.6) at the time of 
registration to treatment step (Step 1, 3, 5, 7). 
2.1.2 
Patients must have PIK3CA mutation as determined via the MATCH 
Master Protocol and described in Appendix I. See Appendix I for 
information on the eligible PIK3CA alterations and corresponding 
Levels of Evidence. 
2.1.3 
Patients must have an electrocardiogram (ECG) within 8 weeks prior 
to treatment assignment and must have no clinically important 
abnormalities in rhythm, conduction or morphology of resting ECG 
(e.g. complete left bundle branch block, third degree heart block). 
Date of ECG:  _______________ 
2.1.4 
Patients must not have known hypersensitivity to copanlisib or 
compounds of similar chemical or biologic composition. 
2.1.5 
Patients must not have had prior therapy with copanlisib or other PI3K 
inhibitors, AKT inhibitors or mTOR inhibitors. 
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2.1.6 
Patients must not have activating KRAS mutations. See Appendix I for 
a list excluded KRAS mutations. 
2.1.7 
Patients must not have HER2 positive (3+ by IHC or FISH ratio ≥ 2) 
breast cancer. 
2.1.8 
Patients must not have indolent NHL (follicular lymphoma, SLL/CLL, 
LPL, marginal zone lymphoma) or DLBCL (diffuse large B cell 
lymphoma). 
2.1.9 
Patients must not be on strong inhibitors or inducers of CYP3A4 
within two weeks prior to start of study treatment and for the duration 
of study treatment. 
2.1.10 
Patients should stop using herbal medications at least 7 days prior to 
the first dose of copanlisib.  Herbal medications include, but are not 
limited to: St. John’s Wort, Kava, ephedra, gingko biloba, 
dehydroepiandrosterone (DHEA), yohimbe, saw palmetto, black 
cohosh and ginseng. 
2.1.11 
Patients with Type I or II diabetes mellitus must have HbA1c ≤ 8.5% 
within 28 days from registration. 
2.1.12 
Patients must not be on anti-arrhythmic therapy other than digoxin or 
beta-blockers.  
2.1.13 
Patients must have adequate marrow function as defined below: 
• 
ANC ≥ 1.5x109 /L 
• 
Platelets ≥ 100x109 /L 
• 
Hb > 9 g/dl 
2.1.14 
Patients must have adequate organ function as defined below: 
• 
Total serum bilirubin < 2.0 mg/dL, 
• 
ALT and AST < 2.5x ULN (< 5x ULN in patients with liver 
metastases), 
• 
Serum creatinine < 1.5x ULN 
2.1.15 
Patients with non-healing wound, ulcer, or bone fracture are not 
eligible. 
2.1.16 
Patients with history of or current interstitial pneumonitis are not 
eligible. 
NOTE: 
For solid tumors, CMV PCR can be obtained at the 
discretion of treating physician or local institutional 
guidelines. 
_____
_____
_____
_____
_____
_____
_____
_____
_____
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_____
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2.1.17 
Men and women of child-bearing potential must agree to use 
contraception while receiving study treatment and for 1 month after 
the last dose of copanlisib. 
 
 
 
 
Physician Signature 
 
Date 
OPTIONAL: 
This signature line is provided for use by institutions wishing to 
use the eligibility checklist as source documentation. 
 
 
_____

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3. 
Copanlisib Treatment Plan 
3.1 
Dosage and Administration Schedule 
Copanlisib is given intravenously at a dose of 60 mg over 1 hour on day 1, 8, and 
15 in a 3 week on/1 week off schedule. Each cycle is 28 days and cycles are 
repeated until progression. Please see Section 3.5 for dose modifications. 
The use of corticosteroids as antiemetics prior to copanlisib administration is not 
allowed. After administration, flush the line with 0.9 % sodium chloride to ensure 
complete dose is given. No IV glucose preparations should be administered on 
the days of infusion. 
Blood pressure measurement on treatment days 
Blood pressure will be measured prior to each copanlisib dose (no more than 4 
measurements) until there are two consecutive results <150/90 mmHg with at 
least a 15 min interval between the measurements to be able to start the infusion 
of the study medication (pre-dose). The investigator can consider a medical 
intervention to maintain blood pressure in values appropriate for infusion. The 
investigator must delay the infusion until blood pressure values are below 
150/90. 
On copanlisib infusion days, blood pressure will be measured at pre dose, 30 min 
after the start of infusion, right after the end of infusion; and 1 h and 2 h after the 
end of copanlisib infusion. 
NOTE: 
Time window of ± 10 min is allowed for all post dose blood pressure 
measurements. 
Recommendations on meal timing on copanlisib infusion days 
Because of an inhibitory effect on PI3Kα-isoform, which is implicated in insulin 
metabolism, copanlisib infusions could be associated with temporary increase in 
blood glucose. Consuming meals in close proximity to copanlisib infusion may 
exacerbate a glucose level increase. 
On infusion days a low carbohydrate diet is recommended, the timing and 
content of meal intake and additional glucose testing (if clinically indicated) is 
managed and monitored by the investigators based on glucose response 
patterns during prior treatment days. 
All glucose measurements done at the site, oral glucose lowering medication 
and/or insulin administration, if applicable, pre-dose fasting/non-fasting status 
and meal intake timing on infusion days should be documented.  
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Pre-dose glucose levels 
Period 
Pre-dose glucose levels  
Day 1 of cycle 1 
< 160 mg/dL (fasting) 
< 200 mg/dL (non-fasting) 
Day 1 of subsequent cycles 
< 160 mg/dL (fasting) 
< 200 mg/dL (non-fasting) 
Days 8 and 15 of each cycle 
< 160 mg/dL (fasting) 
< 200 mg/dL (non-fasting) 
The study drug will be administered only if pre-dose glucose level is < 160 mg/dL 
(fasting) or < 200 mg/dL (non-fasting). 
Glucose monitoring is required before and after each copanlisib infusion. The 
glucose testing is scheduled as follows: 
• 
On Cycle 1 Day 1: Glucose test (finger stick or serum glucose) is performed 
before starting copanlisib IV infusion at time 0 hour. Additional measurements 
to be performed at the clinic as clinically indicated at the investigator’s 
discretion. 
• 
On Cycle 1 Days 8 and 15 and all treatment days in subsequent cycles: 
Glucose test (finger stick or serum glucose) is performed before starting 
copanlisib IV infusion at time 0 hour. Additional measurements to be 
performed at the clinic as clinically indicated at the investigator’s discretion). 
• 
Review of the blood glucose measurements/meal timing/insulin 
administration/oral glucose lowering medication, if applicable. 
NOTE: If patient needs to take a meal, then glucose test should be taken prior 
to meal intake. 
Monitoring of diabetic patients 
• 
If the patient already monitors his/her blood glucose as part of routine 
antidiabetic care, the routine measurements should not be replaced by the 
study specific measurements. 
3.2 
General Concomitant Medication and Supportive Care Guidelines 
Because there is a potential for interaction of copanlisib with other concomitantly 
administered drugs, the case report form must capture the concurrent use of all 
other drugs, over-the-counter medications, or alternative therapies. The Principal 
Investigator should be alerted if the patient is taking any agent known to affect or 
with the potential for drug interactions. The known potential targets for drug 
interaction are CYP3A4 inducers or inhibitors, as well as drugs modulating 
glucuronidation, P-gp, BCRP, and MATE2K function. Appendix II (Patient Drug 
Information Handout and Wallet Card) should be provided to patients. 
Substrates of P-gp and/or BCRP with narrow therapeutic index should be used 
with caution and patients monitored for any sign of toxicity.  Furthermore, 
sensitive substrates of the renal drug transporter MATE2K (e.g. metformin) need 
to be used with caution.  Metformin should be interrupted for 48 hours after 
receiving iodinated contrast media. 
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Patients taking medications with narrow therapeutic index should be proactively 
monitored if these medications cannot be avoided.  These medications may 
include quinidine, cyclosporine, and digoxin. 
Patients should stop using herbal medications at least 7 days prior to the first 
dose of copanlisib.  Herbal medications include, but are not limited to: St. John’s 
Wort, Kava, ephedra, gingko biloba, dehydroepiandrosterone (DHEA), yohimbe, 
saw palmetto, black cohosh and ginseng. 
Prophylactic antiemetics may be administered according to standard practice.  
The routine use of standard antiemetics, including 5-HT3 blockers, such as 
granisetron, ondansetron, or an equivalent agent, is allowed as needed. The use 
of corticosteroids as antiemetics prior to copanlisib administration will not be 
allowed. 
3.3 
Adverse Event Reporting Requirements 
The Adverse Event Reporting Requirements for all EAY131 sub-protocols are 
outlined in the MATCH MASTER protocol.  Please refer to those guidelines when 
determining if an event qualifies as a Serious Adverse Event (SAE) and requires 
expedited reporting via CTEP’s Adverse Event Reporting System (CTEP-AERS). 
In addition, the following section outlines agent specific requirements and must 
be followed to ensure all reporting requirements are met. 
3.3.1 
Additional instructions, requirements and exceptions for protocol 
EAY131 – Subprotocol Z1F 
Additional Instructions 
For instructions on how to specifically report events that result in 
persistent or significant disability/incapacity, congenital anomaly, or 
birth defect events via CTEP-AERS, please contact the AEMD Help 
Desk at aemd@tech-res.com or 301-897-7497.  This will need to be 
discussed on a case-by-case basis. 
 
EAY131 – Subprotocol Z1F specific expedited reporting 
requirements: 
• 
Pregnancies:  Pregnancies and suspected pregnancies 
(including a positive or inconclusive pregnancy test, regardless of 
age or disease state) occurring while the subject is on copanlisib, 
or within 28 days of the subject’s last dose of copanlisib, are 
considered immediately reportable events. The pregnancy, 
suspected pregnancy, or positive/ inconclusive pregnancy test 
must be reported via CTEP-AERS within 24 hours of the 
Investigator’s knowledge.  Please refer to Appendix VIII in 
MATCH Master Protocol for detailed instructions on how to report 
the occurrence of a pregnancy as well as the outcome of all 
pregnancies. 
 

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EAY131 – Subprotocol Z1F specific expedited reporting 
exceptions: 
For Subprotocol Z1F, the adverse events listed below do not require 
expedited reporting via CTEP-AERS: 
• 
If an AE meets the reporting requirements of the protocol, and it 
is listed on the SPEER, it should ONLY be reported via CTEP-
AERS if the grade being reported exceeds the grade listed in the 
parentheses next to the event. 
3.3.2 
Second Primary Cancer Reporting Requirements 
All cases of second primary cancers, including acute myeloid 
leukemia (AML) and myelodysplastic syndrome (MDS), that occur 
following treatment on NCI-sponsored trials must be reported to 
ECOG-ACRIN using Medidata Rave 
• 
A second malignancy is a cancer that is UNRELATED to any 
prior anti-cancer treatment (including the treatment on this 
protocol).  Second malignancies require ONLY routine reporting 
as follows: 
1. Complete a Second Primary Form in Medidata Rave within 14 
days. 
2. Upload a copy of the pathology report to ECOG-ACRIN via 
Medidata Rave confirming the diagnosis. 
3. If the patient has been diagnosed with AML/MDS, upload a 
copy of the cytogenetics report (if available) to ECOG-ACRIN 
via Medidata Rave. 
• 
A secondary malignancy is a cancer CAUSED BY any prior anti-
cancer treatment (including the treatment on this protocol). 
Secondary malignancies require both routine and expedited 
reporting as follows: 
1. Complete a Second Primary Form in Medidata Rave within 14 
days 
2. Report the diagnosis via CTEP-AERS at http://ctep.cancer.gov  
Report under a.) leukemia secondary to oncology 
chemotherapy, b.) myelodysplastic syndrome, or c.) treatment 
related secondary malignancy 
3. Upload a copy of the pathology report to ECOG-ACRIN via 
Medidata Rave and submit a copy to NCI/CTEP confirming the 
diagnosis. 
4. If the patient has been diagnosed with AML/MDS, upload a 
copy of the cytogenetics report (if available) to ECOG-ACRIN 
via Medidata Rave and submit a copy to NCI/CTEP. 
NOTE: 
The Second Primary Form and the CTEP-AERS report 
should not be used to report recurrence or development of 
metastatic disease. 
NOTE: 
If a patient has been enrolled in more than one NCI-
sponsored study, the Second Primary Form must be 

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submitted for the most recent trial. ECOG-ACRIN must be 
provided with a copy of the form and the associated 
pathology report and cytogenetics report (if available) even 
if ECOG-ACRIN was not the patient's most recent trial. 
NOTE: 
Once data regarding survival and remission status are no 
longer required by the protocol, no follow-up data should 
be submitted via CTEP-AERS or by the Second Primary 
Form. 

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3.4 
Comprehensive Adverse Events and Potential Risks List (CAEPR) for Copanlisib 
dihydrochloride (BAY 80-6946 dihydrochloride, NSC 784727) 
The Comprehensive Adverse Events and Potential Risks list (CAEPR) provides a 
single list of reported and/or potential adverse events (AE) associated with an 
agent using a uniform presentation of events by body system. In addition to the 
comprehensive list, a subset, the Specific Protocol Exceptions to Expedited 
Reporting (SPEER), appears in a separate column and is identified with bold and 
italicized text. This subset of AEs (SPEER) is a list of events that are protocol 
specific exceptions to expedited reporting to NCI (except as noted below).  Refer 
to the 'CTEP, NCI Guidelines: Adverse Event Reporting Requirements' 
http://ctep.cancer.gov/protocolDevelopment/electronic_applications/docs/aeguide
lines.pdf for further clarification. Frequency is provided based on 702 patients. 
Below is the CAEPR for Copanlisib dihydrochloride (BAY 80-6946 
dihydrochloride). 
NOTE: 
If an AE meets the reporting requirements of the protocol, and it is 
listed on the SPEER, it should ONLY be reported via CTEP-AERS if 
the grade being reported exceeds the grade listed in the parentheses 
next to the event in the SPEER.  
Version 2.2, June 18, 20191 
 
Adverse Events with Possible Relationship to 
Copanlisib dihydrochloride (BAY 80-6946 dihydrochloride) 
(CTCAE 5.0 Term) 
[n= 702] 
 
 
Specific Protocol 
Exceptions to Expedited 
Reporting (SPEER) 
 
Likely (>20%) 
Less Likely (<=20%) 
Rare but Serious (<3%)  
BLOOD AND LYMPHATIC SYSTEM DISORDERS 
  
 
Anemia 
 
 Anemia (Gr 2) 
 
 
Febrile neutropenia 
  
GASTROINTESTINAL DISORDERS 
  
Diarrhea 
 
 
 Diarrhea (Gr 2) 
 
Mucositis oral 
 
  
Nausea 
 
 
 Nausea (Gr 2) 
 
 
Pancreatitis 
  
 
Vomiting 
 
 Vomiting (Gr 2) 
GENERAL DISORDERS AND ADMINISTRATION SITE CONDITIONS 
  
Fatigue 
 
 
 Fatigue (Gr 2) 
INFECTIONS AND INFESTATIONS 
  
Infection2 
 
 
 Infection2 (Gr 2) 
INVESTIGATIONS 
  
Neutrophil count 
decreased 
 
 
 Neutrophil count 
decreased (Gr 2) 
 
Platelet count decreased 
 
 Platelet count decreased 
(Gr 2) 
 
White blood cell decreased  
  
METABOLISM AND NUTRITION DISORDERS 
  
 
Anorexia 
 
 Anorexia (Gr 2) 
Hyperglycemia 
 
 
 Hyperglycemia (Gr 2) 
MUSCULOSKELETAL AND CONNECTIVE TISSUE DISORDERS 
  
 
Muscle cramp 
 
 Muscle cramp (Gr 2) 
RESPIRATORY, THORACIC AND MEDIASTINAL DISORDERS 
  
 
Pneumonitis3 
 
  
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Adverse Events with Possible Relationship to 
Copanlisib dihydrochloride (BAY 80-6946 dihydrochloride) 
(CTCAE 5.0 Term) 
[n= 702] 
 
 
Specific Protocol 
Exceptions to Expedited 
Reporting (SPEER) 
 
Likely (>20%) 
Less Likely (<=20%) 
Rare but Serious (<3%)  
SKIN AND SUBCUTANEOUS TISSUE DISORDERS 
  
 
 
Erythroderma 
  
 
 
Pruritus 
  
 
Rash maculo-papular 
 
 Rash maculo-papular (Gr 2) 
VASCULAR DISORDERS 
  
Hypertension 
 
 
 Hypertension (Gr 2) 
1 This table will be updated as the toxicity profile of the agent is revised.  Updates will be distributed to all 
Principal Investigators at the time of revision.  The current version can be obtained by 
contactingPIO@CTEP.NCI.NIH.GOV.  Your name, the name of the investigator, the protocol and the 
agent should be included in the e-mail. 
2 Infection includes all 75 sites of infection under the INFECTIONS AND INFESTATIONS SOC. 
3 Pneumonitis is a group term that includes interstitial lung disease, dyspnea, dyspnea at rest, and 
dyspnea exertional. 
Adverse events reported on Copanlisib dihydrochloride (BAY 80-6946 dihydrochloride) 
trials, but for which there is insufficient evidence to suggest that there was a reasonable 
possibility that Copanlisib dihydrochloride (BAY 80-6946 dihydrochloride) caused the 
adverse event: 
BLOOD AND LYMPHATIC SYSTEM DISORDERS - Eosinophilia 
CARDIAC DISORDERS - Atrial fibrillation; Cardiac arrest; Left ventricular systolic dysfunction; 
Myocardial infarction; Sinus tachycardia 
GASTROINTESTINAL DISORDERS - Abdominal pain; Colitis; Constipation; Dry mouth; 
Dyspepsia; Esophagitis; Flatulence; Gastritis; Gastroesophageal reflux disease; Oral 
dysesthesia; Oral pain; Upper gastrointestinal hemorrhage 
GENERAL DISORDERS AND ADMINISTRATION SITE CONDITIONS - Chills; Death NOS; 
Fever; General disorders and administration site conditions - Other (failure to thrive); Non-
cardiac chest pain 
IMMUNE SYSTEM DISORDERS - Allergic reaction; Autoimmune disorder 
INJURY, POISONING AND PROCEDURAL COMPLICATIONS - Fracture; Infusion related 
reaction; Injury, poisoning and procedural complications - Other (drug eruption) 
INVESTIGATIONS - Activated partial thromboplastin time prolonged; Alanine aminotransferase 
increased; Alkaline phosphatase increased; Aspartate aminotransferase increased; Blood 
bilirubin increased; CPK increased; Ejection fraction decreased; Electrocardiogram QT 
corrected interval prolonged; Electrocardiogram T wave abnormal; Investigations - Other 
(electrocardiogram U wave abnormal); Lipase increased; Lymphocyte count decreased; Serum 
amylase increased 
METABOLISM AND NUTRITION DISORDERS - Dehydration; Hypertriglyceridemia; 
Hyperuricemia; Hypocalcemia; Hypokalemia; Hypomagnesemia; Hyponatremia; 
Hypophosphatemia; Metabolism and nutrition disorders - Other (blood insulin increased) 
MUSCULOSKELETAL AND CONNECTIVE TISSUE DISORDERS - Arthralgia; Generalized 
muscle weakness; Musculoskeletal and connective tissue disorder - Other (psoriatic 
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NEOPLASMS BENIGN, MALIGNANT AND UNSPECIFIED (INCL CYSTS AND POLYPS) - 
Tumor hemorrhage 
NERVOUS SYSTEM DISORDERS - Amnesia; Dizziness; Dysesthesia; Dysgeusia; Headache; 
Paresthesia; Peripheral sensory neuropathy; Presyncope; Reversible posterior 
leukoencephalopathy syndrome 
PSYCHIATRIC DISORDERS - Confusion 
RENAL AND URINARY DISORDERS - Acute kidney injury; Renal and urinary disorders - Other 
(renal insufficiency) 
RESPIRATORY, THORACIC AND MEDIASTINAL DISORDERS - Cough; Dyspnea3; Hypoxia; 
Pleural effusion; Pulmonary hypertension; Respiratory failure; Respiratory, thoracic and 
mediastinal disorders - Other (pulmonary congestion) 
SKIN AND SUBCUTANEOUS TISSUE DISORDERS - Alopecia; Dry skin; Purpura; Rash 
acneiform; Stevens-Johnson syndrome 
VASCULAR DISORDERS - Hypotension; Thromboembolic event; Vascular disorders - Other 
(circulatory collapse) 
NOTE: 
Copanlisib dihydrochloride (BAY 80-6946 dihydrochloride) in combination with other 
agents could cause an exacerbation of any adverse event currently known to be 
caused by the other agent, or the combination may result in events never previously 
associated with either agent. 
 

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3.5 
Dose Modifications  
All toxicity grades below are described using the NCI Common Terminology 
Criteria for Adverse Events (CTCAE) version 5.0. 
All appropriate treatment areas should have access to a copy of the CTCAE 
version 5.0. A copy of the CTCAE version 5.0 can be downloaded from the 
CTEP website 
(http://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.ht
m). 
The side effects observed with copanlisib (BAY 80-6946) are consistent with 
those observed with other PI3K inhibitors.   
Copanlisib will be administered at fixed dose (60 mg) intravenously on Days 1, 8, 
and 15 on a 28-Day cycle. Copanlisib dose reduction instructions provided in 
Table 1 serve as guidelines to allow ongoing treatment for patients without signs 
or symptoms of progression while monitoring patient safety. If there is need to 
interrupt dosing for grade 3/4 toxicity, then there will be a dose reduction as per 
the table below, once toxicity improves to grade 1 or baseline. Selected toxicities 
/ adverse events of interest for copanlisib include hyperglycemia, rash, 
hypertension, diarrhea. 
Table 1 
Overall Dose Modification Guideline for Copanlisib (BAY 80-
6946)-Related Adverse Events 
 
Copanlisib 
Starting dose 
60 mg  
First reduction 
45 mg 
Second reduction 
30 mg 
Dose may be suspended for up to 4 weeks due to toxicity. Patients requiring 
treatment to be held for >4 weeks will be taken off treatment. If treatment held for 
laboratory abnormality, recheck labs in one week. No dose reduction is allowed 
for patients treated at a dose 30 mg of copanlisib – if there is an indication for 
further dose reduction, the patient must permanently discontinue copanlisib. 
Dose re-escalation is not allowed after a dose reduction. 
Dose Modification rules for transient post-infusion hyperglycemia 
Patients who develop post-infusion glucose increases of grade 2 after study drug 
administration may continue treatment.  However, the next infusion must be 
delayed until the patient’s pre-infusion glucose levels return to < 160 mg/dL 
(fasting) or < 200mg/dL (non-fasting). Guidelines for the management of transient 
glucose increases are given in Appendix III. Continuing occurrence of post-
infusion blood glucose increases of grade ≥ 3, despite optimal glucose lowering 
therapy after 2 infusions of copanlisib, will require dose reduction by one dose 
level. 
• 
Further dose reduction (where appropriate per study design/population) is 
allowed as long as discontinuation criteria was not met. 
• 
Dose re-escalation is allowed when a patient has achieved controlled glucose 
levels per investigator’s judgment. 
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• 
Occurrence of post-infusion non-life threatening hyperglycemia requiring 
interventions at the protocol defined lowest dose level despite optimal 
glucose lowering therapy (after at least one cycle of treatment) requires 
permanent discontinuation of the study drug. 
• 
Occurrence of post infusion life-threatening copanlisib related hyperglycemia 
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Management of Hyperglycemia 
Metformin is the first antihyperglycemic medication of choice because of the 
lower risk of hypoglycemia with this agent.  Because metformin in some patients 
may also cause diarrhea and can be poorly tolerated, other antihyperglycemic 
medications such as sulfonylureas (e.g. glimepiride, glipizide) can be used.  
Extra caution should be used with other drugs such as sulfonylureas because of 
the increased risk for hypoglycemia with these agents. Consultation with an 
endocrinologist can be helpful in managing hyperglycemia.   
Insulin should only be used for patients with persistent, symptomatic 
hyperglycemia. It should not be used to lower glucose level on the day of infusion 
due to the risk of hypoglycemia. On treatment days, it is best to hydrate the 
patient and not give insulin to reduce glucose levels to meet study treatment 
criteria. 
Management guidelines for fasting patients with hyperglycemia are listed below 
in Table 2. 
Table 2: Management of Hyperglycemia 
Grade 
Intervention 
Dose Adjustment 
1 
Initiation of an oral 
anti-hyperglycemic agent 
(e.g., metformin) and 
additional glucose monitoring 
should be considered. 
No change. 
2 
Initiation or increased dose of 
an oral anti-hyperglycemic 
agent (e.g., metformin) and 
additional glucose monitoring 
should be considered. 
Dosing with copanlisib may either 
be held or continued per 
Investigator evaluation. 
3, asymptomatic 
Patient should be managed 
as per standard care, 
including implementation of 
additional glucose monitoring 
and initiation and/or increase 
of anti-hyperglycemic therapy 
(e.g., metformin).   
Consideration should be given to 
suspend copanlisib dosing until the 
hyperglycemia resolves to Grade  
2. Dosing with copanlisib may 
resume at the same dose level or 
at one dose level lower as outlined 
in Table 1 and after discussion with 
the Study Principal Investigator. 
3, symptomatic 
(e.g., blurred vision, 
frequent urination, 
excessive thirst) or 
grade 4 
Patient should be managed 
as per standard care, 
including implementation of 
additional glucose monitoring 
and initiation and/or increase 
of anti-hyperglycemic therapy 
Copanlisib dosing should be 
suspended until the hyperglycemia 
resolves to Grade  2. The patient 
will be discontinued from the study 
if such therapy fails to control their 
hyperglycemia. Dosing with 
copanlisib may otherwise resume 
at one dose level lower as outlined 
in Table 1. 
* Based on fasting glucose level 

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Management of Rash 
Treatment related rash has been reported with copanlisib. While most were 
CTCAE v3.0 Grade 1 or Grade 2 in severity, few patients experienced Grade 3 
rash. Rash is generally macular or maculo-papular with or without pruritus, with 
some having developed desquamation. Patients with severe rash should be 
monitored for associated signs and symptoms, such as fever and hypotension 
that may be suggestive of a systemic hypersensitivity reaction. For severe rash, 
hold all study treatment until Grade  1 (see Table 3 below), and patients should 
be treated with supportive therapy per standard of care. Use of topical 
antihistamine, as well as topical or systemic corticosteroids, may be considered. 
There is no evidence for a phototoxic potential of copanlisib. 
Table 3: Dose Delay and Modification Guidelines for Rash 
Grade 
Intervention 
Dose Adjustment 
Grade 1 
Consider prescribing topical 
corticosteroids a 
Continue dosing at current dose 
and monitor for change in severity. 
Grade 2 
Consider treatment with 
supportive therapy (e.g., topical 
or oral corticosteroids a, b). 
Consider holding copanlisib or 
reducing to the next lower dose if 
rash is troublesome. 
Grade 3 or 4 
Consider treatment with 
supportive therapy (e.g., topical 
or oral corticosteroids a, b). 
Consider dermatological 
consultation. 
Consider obtaining photographs 
of rash if permitted by local 
regulations. 
Hold all study treatment until Grade 
 1.  
For Grade 3, restart copanlisib at 
the next lower dose upon 
discussion with Overall Principal 
Investigator, or permanently 
discontinue treatment. 
For Grade 4, permanently 
discontinue treatment 
a Suggested topical steroids include, hydrocortisone 2.5% to face twice daily, 
triamcinolone 0.1% or fluocinonide 0.1% cream to body bid. 
b Suggested oral steroids include methylprednisolone dose pack or prednisone 60 
mg daily followed by a taper (e.g., 60 mg  2 days, 40 mg  2 days, 20 mg  2 days, 
etc.). 
Management of Hypertension 
Patients receiving copanlisib who have experienced hypertension and blood 
pressure should be monitored at each visit. In subjects with an initial BP reading 
within the hypertensive range, a second reading should be taken at least 2 
minutes later, with the two readings averaged to obtain a final BP measurement.  
For patients who develop HTN or worsening HTN during study treatment, 
antihypertensive medication should be initiated or optimized to achieve target 
blood pressure before interruption or dose reduction of the study treatment at the 
discretion of the investigator.  If hypertension is persistent despite adequate anti-
HTN therapy including titration of anti-HTN medication or introduction of 
additional anti-HTN medications, dose interruption, reduction or discontinuation is 
recommended. If Grade 4 HTN develops, permanently discontinue treatment. 
Patients with prior history of hypertension (on anti-hypertensive agents) should 
monitor/record their BP at home while on copanlisib. 

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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 (BP) increases following copanlisib will 
need to be individualized for each patient, but experience from a Bayer-
sponsored phase 1 study with copanlisib has suggested the benefit of 
dihydropyridine calcium channel blockers (i.e., amlodipine, felodipine). 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 anti-hypertensive 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 Appendix IV. In the event of the occurrence of grade 3 arterial 
hypertension (≥ 160/100 mmHg) during infusion of copanlisib, the infusion should 
be interrupted and anti-hypertensive treatment as suggested above is 
administered.  Infusion can be resumed when BP has returned to < 150/90 
mmHg. 
Blood pressure measurement on treatment days 
Blood pressure will be measured prior to each copanlisib dose (no more than 4 
measurements) until there are two consecutive results < 150/90 mmHg with at 
least a 15 min interval between the measurements to be able to start the infusion 
of the study medication (pre-dose). The investigator can consider a medical 
intervention to maintain blood pressure in values appropriate for infusion. The 
investigator must delay the infusion until blood pressure values are below 
150/90. 
On copanlisib infusion days, blood pressure will be measured at pre dose, 30 min 
after the start of infusion, right after the end of infusion; and 1 h and 2 h after the 
end of copanlisib infusion. 
NOTE: 
Time window of ± 10 min is allowed for all post dose blood pressure 
measurements. 
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Event 
 
Management Guideline 
Dose Modification 
Definitions used in the table: 
- Persistent hypertension:  Hypertension detected in two separate readings during up 
to three subsequent visits. 
- Well-controlled hypertension:  Blood pressure of SBP ≤150 mmHg and DBP ≤90 
mmHg in two separate readings during up to three subsequent visits. 
- Symptomatic hypertension:  Hypertension associated with symptoms (e.g., 
headache, light-headedness, vertigo, tinnitus, episodes of fainting) that resolve after 
the blood pressure is controlled within the normal range. 
- Asymptomatic hypertension: SBP >150 mmHg and/or DBP >90 mmHg in the 
absence of the above symptoms. 
(Scenario A) 
• Asymptomatic and 
persistent SBP of ≥150 and 
<160 mmHg, or DBP ≥90 
and <100 mmHg,  
OR 
• Clinically significant 
increase in DBP of 20 
mmHg (but still below 100 
mmHg). 
• Adjust current or initiate new 
antihypertensive 
medication(s). 
• Titrate antihypertensive 
medication(s) during the next 
2 weeks to achieve well-
controlled BP.  If BP is not 
well-controlled within 2 weeks, 
consider referral to a specialist 
and go to scenario (B). 
• Continue copanlisib 
at the current dose. 
(Scenario B) 
• Asymptomatic SBP ≥ 160 
mmHg, or DBP  
≥ 100mmHg,  
OR 
• Failure to achieve well-
controlled BP within 2 
weeks in Scenario A. 
• Adjust current or initiate new 
antihypertensive 
medication(s). 
• Titrate antihypertensive 
medication(s) during the next 
2 weeks to achieve well-
controlled BP. 
• Interrupt copanlisib. 
• Once BP is well-
controlled, restart 
copanlisib at a 
reduced dose. 
(Scenario C) 
• Symptomatic hypertension  
OR 
• Persistent SBP ≥160 
mmHg, or DBP 
≥100 mmHg, despite 
antihypertensive medication 
and dose reduction of study 
treatment 
• Adjust current or initiate new 
antihypertensive 
medication(s). 
• Titrate antihypertensive 
medication(s) during the next 
2 weeks to achieve well-
controlled BP. 
• Referral to a specialist for 
further evaluation and follow-
up is recommended. 
• Continue follow-up per 
protocol. 
• Discontinue 
copanlisib. 
(Scenario D) 
• 
Refractory hypertension 
unresponsive to above 
interventions or 
hypertensive crisis. 
• Continue follow-up per 
protocol. 
• Discontinue 
copanlisib. 

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Non-infectious pneumonitis 
The investigator is requested to differentiate between non-infectious pneumonitis, 
and infectious pneumonitis (viral, bacterial, or 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 table below. 
Dose adjustment for non-infectious pneumonitis 
Suspected or confirmed 
NIP per CTCAE 
Action Taken 
Re-treatment dose after 
recovery 
Grade 1 
No Change 
NA 
Grade 2 
Dose Interruption Until 
recovery to ≤grade 1 
Decrease dose to the next 
lowest dose level a 
Grade 2 second re-
occurrence 
Permanent Discontinuation 
NA 
Grade 3 
Permanent Discontinuation 
NA 
Grade 4 
Permanent Discontinuation 
NA 
NA = Not applicable; NIP = Non-infectious pneumonitis; CTCAE = Common Terminology Criteria 
for Adverse Events. 
a: Not applicable for 45 mg dose level. No re-escalation is allowed after the dose reduction. 
The lowest dose level for patients with non-infectious pneumonitis is 45 mg; if a patient is already 
on the 45 mg dose level and cannot tolerate treatment study treatment will be discontinued 
permanently. 
Dose modifications for Hematological Toxicities 
Day 
ANC 
 
Platelets 
Dose modifications 
Day 1 
≥ 500/uL 
AND 
≥ 75,000/uL 
Treat at current dose level 
< 500/uL 
OR 
< 75,000/uL 
Delay until count recovery 
Use of WBC growth factors is allowed as per institutional guidelines for treatment 
or prevention of complication. Use of WBC growth factors to maintain dose 
intensity is not allowed. 
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Dose Modifications for General Non-hematologic Toxicities 
This section does not refer to those non-hematologic toxicities for which dose 
modifications are listed above. 
Grade 
Action and Dose Modification 
Grade 1 or transient Grade 2 
No intervention 
Grade 2 lasting ≥ 7 days with 
optimal/best supportive care 
Hold Copanlisib 
Resume at 60 mg after recovery to ≤ grade 1 
Recurrence at 60 mg: Hold Copanlisib 
Resume at 45 mg after recovery to ≤ grade 1 
Recurrence at 45 mg: Hold Copanlisib 
Resume at 30 mg after recovery to ≤ grade 1 
Recurrence at 30 mg: Discontinue Copanlisib 
Grade 3 
Hold Copanlisib 
Resume at 45 mg after recovery to ≤ grade 1 
Recurrence at 45 mg: Hold Copanlisib 
Resume at 30 mg after recovery to ≤ grade 1 
Recurrence at 30 mg: Discontinue Copanlisib 
Grade 4 
Discontinue treatment 
Copanlisib will be discontinued if treatment delay is > 4 weeks 
3.6 
Supportive Care 
All supportive measures consistent with optimal patient care will be given 
throughout the study. Diarrhea, nausea and vomiting have all been reported with 
copanlisib. Supportive measures with anti-diarrheals and anti-emetics are 
recommended per investigator discretion or local institutional guidelines for 
emergence of treatment related symptoms. 
3.7 
Duration of Agent-specific treatment  
In the absence of treatment delays due to adverse event(s), treatment may 
continue until one of the following criteria applies: 
• 
Extraordinary Medical Circumstances: If at any time the constraints of this 
protocol are detrimental to the patient's health, protocol treatment should be 
discontinued. In this event submit forms according to the instructions in the 
MATCH Forms Packet. 
• 
Patient withdraws consent. 
• 
Patient experiences unacceptable toxicity. 
• 
Non-protocol therapies are administered. 
• 
Disease progression 
3.8 
Duration of Follow-Up  
Refer to the MATCH Master Protocol for specifics on the duration of follow-up. 
 

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4. 
Study Parameters 
4.1 
Therapeutic Parameters for Copanlisib Treatment  
NOTE: 
In addition to the study parameters listed in the MATCH Master Protocol, the below parameters must also be 
performed for patients receiving Copanlisib treatment. 
NOTE: 
All assessments required prior to registration to treatment should be done ≤ 4 weeks prior to registration to 
Steps 1, 3, 5, 7, excluding the radiologic evaluation and electrocardiogram (ECG). 
Test/Assessment 
Prior to Registration to 
Treatment 
Treatment 
End of 
Treatment 
Follow UpF 
Every Cycle, prior 
to treatment 
Every 2 
Cycles 
H&P, Weight, Vital signsA 
X 
 XI 
 
 
X 
Performance status 
X 
 XI 
 
 
X 
CBC w/diff, pltsB 
X 
 XI 
 
 
X 
Serum chemistryB 
X 
 XI 
 
 
X 
Glucose monitoringK 
 
X 
 
 
 
Hemoglobin A1cL 
X 
 
 
 
 
Radiologic evaluationD 
X 
 
 XD 
 
 XF 
-HCGC 
X 
 
 
 
 
Toxicity AssessmentG 
 
X 
 
X 
 XF 
ECGJ 
X 
 XH 
 
 
 
Tumor biopsy and blood sample for MATCH Master ProtocolE 
 
 
X 
 X 
 
A. History and physical, including vital signs and weight at the start of each cycle (up to 3 days before start of new cycle). Blood pressure will be 
measured prior to each copanlisib dose (no more than 4 measurements) until there are two consecutive results < 150/90 mmHg. On copanlisib 
infusion days, blood pressure will be measured at pre dose, 30 min after the start of infusion, right after the end of infusion; and 1 h and 2 h after 
the end of copanlisib infusion. Time window of ± 10 min is allowed for all post dose blood pressure measurements. Refer to Section 3.1. 
B. Albumin, alkaline phosphatase, total bilirubin, bicarbonate, BUN, calcium, creatinine, fasting glucose, phosphorus, potassium,  SGOT[AST], 
SGPT[ALT], sodium, magnesium and serum tumor markers (including LDH, PSA if appropriate). For eligibility purposes, participants with 
creatinine levels above institutional normal, Cockcroft-Gault will be used to calculate creatinine clearance. CBC w/diff, platelets and serum 
chemistries should be performed on cycle 1, day 1 (or up to 7 days prior), and at the start of each subsequent cycle (up to 3 days before start of 
new cycle). CBC with differential will be performed more frequently in patients with grade 4 neutropenia or thrombocytopenia until resolution to  
≤ grade 3. CBC and serum chemistries are only required in follow-up until values return to pre-treatment levels or until progressive disease. 
Please refer to the table in Section 3.1 regarding “Pre-dose glucose levels.” 
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C. Blood pregnancy test (women of childbearing potential) required prior to beginning treatment. 
D. Disease measurements are repeated every 2 cycles for the first 26 cycles, and every 3 cycles thereafter until PD or start of another MATCH 
treatment step. The baseline evaluation should be performed as closely as possible to the beginning of treatment and never more than 6 weeks 
before registration to treatment step. For multiple myeloma patients, please refer to Section 6.4 of the MATCH Master Protocol for additional 
information on myeloma response criteria and the required disease assessments. Documentation (radiologic) must be provided for patients 
removed from study for progressive disease. 
E. Additional blood specimens and/or biopsies are to be submitted from consenting patients per Section 9.3.2 of the MATCH Master Protocol. 
Submit at the following time points, as applicable: 
• Blood specimens are to be submitted at the end of Cycle 2 (prior to start of Cycle 3 treatment). If patient progresses or treatment is 
discontinued prior to Cycle 3, collect the blood at that time instead. On-treatment kits for blood sample collections will be automatically shipped 
to sites upon registration to the treatment step. 
• Screening biopsies for additional aMOI assessments after registration to appropriate screening step, if applicable (Step 2 or Step 4). 
• At end of all MATCH study treatments, blood specimens and/or research biopsy after consent and registration to Step 8 
Please refer to Section 4 of the MATCH Master Protocol to determine whether the patient proceeds to the next screening step or to follow-up 
(with a potential end of treatment biopsy for research purposes on Step 8). Samples are to be submitted as outlined in Section 9 of the MATCH 
Master Protocol. To order Step 2/4 Screening or Step 8 kits, complete the EAY131 Collection and Shipping Kit Order Form (See Appendix XII of 
the MATCH Master Protocol) and fax to 713-563-6506. 
F. Every 3 months if patient is < 2 years from study entry, and every 6 months for year 3. Toxicity assessments and radiologic evaluations are not 
required to be done during Follow Up if progression has been previously reported; however if an adverse event occurs post treatment that meets 
the SAE reporting requirements, it still must be reported via CTEP-AERS, even if progression has occurred. 
G. Site personnel should evaluate for toxicity and discuss treatment compliance with the patient in order to ensure the medication is taken correctly; 
this evaluation may be conducted by telephone or in person. The Toxicity Assessment is not required prior to Cycle 1, but is required every 
subsequent cycle. 
H. As clinically indicated. 
I. 
For Cycle 1, if the following tests/assessments occurred within 7 days of Day 1, they do not need to be repeated at this time point: H&P, Weight, 
Vital Signs; Performance Status; CBC w/diff, plts; Serum chemistry; Concomitant Medications. 
J. Within 8 weeks of treatment assignment. 
K. On Cycle 1 Day 1, glucose test (finger stick or serum glucose) is performed before starting copanlisib IV infusion at time 0 hour. On Cycle 1, 
Days 8 and 15 and all treatment days in subsequent cycles, glucose test is performed before starting copanlisib IV infusion at time 0 hour. 
Additional measurements to be performed at the clinic as clinically indicated at the investigator’s discretion. Refer to Section 3.1. 
L. Hemoglobin A1c (HbA1c) is to be tested at screening if patient has Type I or II diabetes mellitus. Refer to Section 2.1.11. 
 

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5. 
Drug Formulation and Procurement 
This information has been prepared by the ECOG-ACRIN Pharmacy and Nursing 
Committees. 
Availability 
NO STARTER SUPPLIES MAY BE ORDERED. Subjects must be enrolled and assigned 
to the treatment subprotocol prior to submitting the clinical drug request to PMB. 
Drug Ordering: NCI supplied agents may be requested by eligible participating 
Investigators (or their authorized designee) at each participating institution.  
Pharmaceutical Management Branch (PMB) policy requires that drug be shipped directly 
to the institution where the patient is to be treated. PMB does not permit the transfer of 
agents between institutions (unless prior approval from PMB is obtained – see general 
information) The CTEP-assigned protocol number must be used for ordering all CTEP-
supplied investigational agents.  The eligible participating investigators at each 
participating institution must be registered with CTEP, DCTD through an annual 
submission of FDA Form 1572 (Statement of Investigator), NCI Biosketch, Agent 
Shipment Form, and Financial Disclosure Form (FDF).  If there are several participating 
investigators at one institution, CTEP-supplied investigational agents for the study 
should be ordered under the name of one lead investigator at that institution. 
Submit agent requests through the PMB Online Agent Order Processing (OAOP) 
application (https://ctepcore.nci.nih.gov/OAOP).  Access to OAOP requires the 
establishment of a CTEP Identity and Access Management (IAM) account 
(https://ctepcore.nci.nih.gov/iam/) and the maintenance of an “active” account status, a 
“current” password, and an active person registration status. 
NCI Supplied Agent(s) – General Information 
Questions about drug orders, transfers, returns, or accountability should be 
addressed to the PMB by calling 240-276-6575 Monday through Friday between 
8:30 AM and 4:30 PM Eastern Time or email PMBAfterHours@mail.nih.gov 
anytime. 
Drug Returns: All undispensed drug supplies should be returned to the PMB. When it is 
necessary to return study drug (e.g., sealed bottles remaining when PMB sends a stock 
recovery letter), investigators should return the study drug to the PMB using the NCI 
Return Agent Form available on the NCI home page (http://ctep.cancer.gov). 
Drug Accountability: The investigator, or a responsible party designated by the 
investigator, must maintain a careful record of the receipt, disposition, and return of 
agent received from the PMB using the NCI Investigational Agent Accountability Record 
Form for Oral Agents available on the NCI home page (http://ctep.cancer.gov). Maintain 
separate NCI Investigational Agent Accountability Records for each agent, strength, 
formulation and ordering investigator on this protocol. 
Investigator Brochure Availability: The current versions of the IBs for PMB-supplied 
agents will be accessible to site investigators and research staff through the PMB Online 
Agent Order Processing (OAOP) application. Access to OAOP requires the 
establishment of a CTEP Identity and Access Management (IAM) account and the 
maintenance of an “active” account status, a “current” password, and active person 
registration status. Questions about IB access may be directed to the PMB IB 
coordinator at IBCoordinator@mail.nih.gov. 

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5.1 
Copanlisib (NSC #784727) 
5.1.1 
Other Names  
BAY 80-6946 (free base); BAY 84-1236 (dihydrochloride salt) 
5.1.2 
Classification  
Pan class I PI3K inhibitor 
5.1.3 
Mode of Action  
Copanlisib is a pan class I PI3K inhibitor with potent activity against 
the delta and alpha isoforms.  Class I PI3K is downstream of most 
cancer associated tyrosine kinase growth factor receptors or 
mesenchymal epithelial transition factor. PI3K delta has a critical role 
in regulating downstream events of the B-cell receptor. 
5.1.4 
Storage and Stability  
Storage: 
Store intact vials between 2°C and 8°C. 
If a storage temperature excursion is identified, promptly 
return copanlisib to between 2°C and 8°C and quarantine 
the supplies.  Provide a detailed report of the excursion 
(including documentation of temperature monitoring and 
duration of the excursion) to PMBAfterHours@mail.nih.gov 
for determination of suitability. 
Stability: 
Stability studies of the vials are ongoing. The diluted 
solution should be used immediately (stored up to 4 hours 
at room temperature including preparation and 
administration). If the diluted solution for infusion is not 
used immediately, it is stable for up to 24 hours 
refrigerated between 2°C and 8°C. It takes approximately 
60 minutes for the 100 mL diluted solution to return to 
room temperature after refrigeration. The infusion should 
be completed within 24 hours of preparation. 
CAUTION: The single-use lyophilized dosage form 
contains no antibacterial preservatives. 
Therefore, it is advised that the reconstituted 
product be discarded 6 hours after initial 
entry. 
5.1.5 
Dose Specifics  
60 mg of intravenous copanlisib (1 hour infusion) would be 
administered on Days 1, 8, 15 every 28 days (3 weeks on/1 week off) 
5.1.6 
How Supplied  
Copanlisib is supplied by Bayer HealthCare AG and distributed by the 
Pharmaceutical Management Branch, CTEP, DCTD, NCI. The agent 
is available as a lyophilized product containing 60 mg of copanlisib in 
a 6 mL injection vial. The excipients are mannitol, sodium hydroxide, 
citric acid, and water for injection. 
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5.1.7 
Preparation 
Using appropriate aseptic technique, reconstitute the 60 mg vial of 
copanlisib with 4.4 mL of 0.9% sodium chloride resulting in a 
concentration of 15 mg/ml. Gently shake well for 30 seconds and 
allow the vial to stand for 1 minute to let bubbles rise to the surface. 
Repeat if undissolved substance is still present. The reconstituted 
solution may be slightly yellow and should be clear prior to being 
withdrawn from the vial. Withdraw the appropriate volume of the 
reconstituted solution and further dilute by adding to a 50-200 mL 
0.9% sodium chloride bag. Mix well by inverting. 
5.1.8 
Route of Administration  
IV infusion. The diluted solution for infusion is administered IV over 1 
hour. After administration, flush the line to ensure complete dose is 
given. No IV glucose preparations should be administered on the days 
of infusion. 
5.1.9 
Incompatibilities  
In vitro, copanlisib is metabolized primarily via CYP 3A4 and to a 
minor extent by CYP1A1.  It is also a substrate of P-gp and BCRP, 
but not a substrate of MATEs, OCTs, OATs, or OATPs. Concomitant 
administration with strong inhibitors or inducers of CYP3A4 should be 
avoided.  Use caution when administered with strong inhibitors and 
inducers of CYP1A1, P-gp, and BCRP. 
In vitro, copanlisib is a strong inhibitor of MATE2K.  Copanlisib and its 
metabolite M-1 have a low risk for inhibition or induction of CYP 
isoforms, inhibition of UGT isoforms, and inhibition of 
dihydropyrimidine dehydrogenase.  Copanlisib does not inhibit P-gp, 
BCRP, OATP1B1, OATP1B3, OAT1, OAT3, OCT1, OCT2, bile salt 
export pump (BSEP), MRP2, or MATE1 at therapeutic 60 mg dose 
plasma concentrations. Use caution when administered with sensitive 
drug substrates of MATE2K.   
Copanlisib is not an inducer of CYP1A2, 2B6, and 3A. 
Copanlisib is not genotoxic in vitro or in vivo. Copanlisib is expected to 
adversely affect male and female reproduction. 
5.1.10 
Side Effects 
See Section 3.4 for side effects 
5.1.11 
Nursing/Patient Implications  
Females of reproductive potential and males must use effective 
contraception while receiving study treatment and for 1 month after 
the last dose of copanlisib. Females should not breastfeed during 
treatment with copanlisib and for at least 1 month after the last dose 
of copanlisib. 
Hypertension is frequently observed within the first 3 hours after start 
of infusion and hyperglycemia is frequently observed persisting for 
approximately 1-3 days after study drug administration. Refer to 
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Section 3.5 and Appendices III and IV for treatment and monitoring 
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6. 
Translational Studies 
Please refer to the MATCH Master Protocol for information on the Translational Studies.  
7. 
References 
1. Cantley LC. The phosphoinositide 3-kinase pathway. Science 2002;296:1655-7. 
2. Guertin DA, Sabatini DM. Defining the role of mTOR in cancer. Cancer Cell 
2007;12:9-22. 
3. Maehama T, Dixon JE. The tumor suppressor, PTEN/MMAC1, dephosphorylates the 
lipid second messenger, phosphatidylinositol 3,4,5-trisphosphate. The Journal of 
biological chemistry 1998;273:13375-8. 
4. Song MS, Salmena L, Pandolfi PP. The functions and regulation of the PTEN tumour 
suppressor. Nature reviews Molecular cell biology 2012;13:283-96. 
5. Engelman JA, Chen L, Tan X, et al. Effective use of PI3K and MEK inhibitors to treat 
mutant Kras G12D and PIK3CA H1047R murine lung cancers. Nature medicine 
2008;14:1351-6. 
6. Samuels Y, Wang Z, Bardelli A, et al. High frequency of mutations of the PIK3CA 
gene in human cancers. Science 2004;304:554. 
7. Janku F, Tsimberidou AM, Garrido-Laguna I, et al. PIK3CA mutations in patients with 
advanced cancers treated with PI3K/AKT/mTOR axis inhibitors. Mol Cancer Ther 
2011;10:558-65. 
8. Janku F, Hong DS, Fu S, et al. Assessing PIK3CA and PTEN in early-phase trials 
with PI3K/AKT/mTOR inhibitors. Cell Rep 2014;6:377-87. 
9. Karakas B, Bachman KE, Park BH. Mutation of the PIK3CA oncogene in human 
cancers. British journal of cancer 2006;94:455-9. 
10. Burke JE, Perisic O, Masson GR, Vadas O, Williams RL. Oncogenic mutations mimic 
and enhance dynamic events in the natural activation of phosphoinositide 3-kinase 
p110alpha (PIK3CA). Proc Natl Acad Sci U S A 2012;109:15259-64. 
11. Gymnopoulos M, Elsliger MA, Vogt PK. Rare cancer-specific mutations in PIK3CA 
show gain of function. Proc Natl Acad Sci U S A 2007;104:5569-74. 
12. Hon WC, Berndt A, Williams RL. Regulation of lipid binding underlies the activation 
mechanism of class IA PI3-kinases. Oncogene 2012;31:3655-66. 
13. Murugan AK, Hong NT, Fukui Y, Munirajan AK, Tsuchida N. Oncogenic mutations of 
the PIK3CA gene in head and neck squamous cell carcinomas. Int J Oncol 
2008;32:101-11. 
14. Rudd ML, Price JC, Fogoros S, et al. A unique spectrum of somatic PIK3CA 
(p110alpha) mutations within primary endometrial carcinomas. Clin Cancer Res 
2011;17:1331-40. 
 

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Molecular Analysis for Therapy Choice (MATCH) 
MATCH Treatment Subprotocol Z1F: Copanlisib, PIK3CA 
Appendix I 
 
Actionable Mutations for Sub-Protocol EAY131-Z1F 
Inclusion Variants 
Other novel PIK3CA activating mutations not listed in the table below but identified by one of the 
designated outside laboratories as described in the MATCH Master Protocol will also be 
considered actionable mutations (aMOIs) at Level of Evidence Code 3.  Please refer to Section 
1.4.2 of the MATCH Master Protocol for more information. 
Gene Name 
Variant ID 
Variant Type Level of Evidence Code 
Variant Description 
PIK3CA 
COSM746 
SNV 
2 
p.R88Q 
PIK3CA 
COSM754 
SNV 
2 
p.N345K 
PIK3CA 
COSM757 
SNV 
3 
p.C420R 
PIK3CA 
COSM759 
SNV 
3 
p.P539R 
PIK3CA 
COSM760 
SNV 
3 
p.E542K  
PIK3CA 
COSM763 
SNV 
3 
p.E545K 
PIK3CA 
COSM764 
SNV 
3 
p.E545G 
PIK3CA 
COSM765 
SNV 
2 
p.E545D 
PIK3CA 
COSM767 
SNV 
3 
p.Q546P 
PIK3CA 
COSM775 
SNV 
2 
p.H1047R 
PIK3CA 
COSM776 
SNV 
3 
p.H1047L 
PIK3CA 
COSM12458 
SNV 
3 
p.E545A 
PIK3CA 
COSM766 
SNV 
3 
p.Q546K 
PIK3CA 
COSM12590 
SNV 
3 
p.T1025S 
PIK3CA 
COSM12591 
SNV 
3 
p.M1043V 
PIK3CA 
COSM29313 
SNV 
3 
p.M1043I 
PIK3CA 
COSM94984 
SNV 
3 
p.M1043I 
PIK3CA 
COSM773 
SNV 
3 
p.M1043I 
PIK3CA 
COSM774 
SNV 
3 
p.H1047Y 
PIK3CA 
COSM27493 
SNV 
3 
p.R93W 
PIK3CA 
COSM748 
SNV 
3 
p.G106V 
PIK3CA 
COSM13570 
SNV 
3 
p.K111E 
PIK3CA 
COSM751 
SNV 
3 
p.G118D 
PIK3CA 
COSM94978 
SNV 
3 
p.N345I 
PIK3CA 
COSM762  
SNV 
3 
p.E542V 
PIK3CA 
COSM6147 
SNV 
3 
p.Q546E 

ECOG-ACRIN 
EAY131-Z1F 
Cancer Research Group 
Version Date: August 12, 2019 
39 
Gene Name 
Variant ID 
Variant Type Level of Evidence Code 
Variant Description 
PIK3CA 
COSM12459  SNV 
3 
p.Q546R 
PIK3CA 
COSM27504 
SNV 
3 
p.N1044K 
PIK3CA 
COSM12592 
SNV 
3 
p.N1044K 
PIK3CA 
COSM12597 
SNV 
3 
p.G1049R 
PIK3CA 
COSM12584  SNV 
3 
p.E453K 
PIK3CA 
COSM27133  SNV 
3 
p.E545Q 
PIK3CA 
COSM27505  SNV 
3 
p.K111N 
PIK3CA 
COSM12580  SNV 
3 
p.K111N 
Exclusion Variants 
Gene Name 
Variant ID 
Variant Type 
Level of Evidence Code 
Variant Description 
KRAS 
COSM555 
SNV 
2 
p.Q61H 
KRAS 
COSM554 
SNV 
2 
p.Q61H 
KRAS 
COSM553 
SNV 
2 
p.Q61L 
KRAS 
COSM552 
SNV 
2 
p.Q61R 
KRAS 
COSM551 
SNV 
2 
p.Q61P 
KRAS 
COSM550 
SNV 
2 
p.Q61E 
KRAS 
COSM549 
SNV 
2 
p.Q61K 
KRAS 
COSM539 
SNV 
2 
p.G15D 
KRAS 
COSM538 
SNV 
2 
p.G15S 
KRAS 
COSM30567 
SNV 
2 
p.G13E 
KRAS 
COSM87280 
SNV 
2 
p.G13E 
KRAS 
COSM534 
SNV 
2 
p.G13V 
KRAS 
COSM533 
SNV 
2 
p.G13A 
KRAS 
COSM532 
SNV 
2 
p.G13D 
KRAS 
COSM527 
SNV 
2 
p.G13C 
KRAS 
COSM529 
SNV 
2 
p.G13R 
KRAS 
COSM528 
SNV 
2 
p.G13S 
KRAS 
COSM512 
SNV 
2 
p.G12F 
KRAS 
COSM514 
SNV 
2 
p.G12L 
KRAS 
COSM13643 
SNV 
2 
p.G12N 
KRAS 
COSM520 
SNV 
2 
p.G12V 
KRAS 
COSM522 
SNV 
2 
p.G12A 
KRAS 
COSM521 
SNV 
2 
p.G12D 
KRAS 
COSM516 
SNV 
2 
p.G12C 

ECOG-ACRIN 
EAY131-Z1F 
Cancer Research Group 
Version Date: August 12, 2019 
40 
Gene Name 
Variant ID 
Variant Type 
Level of Evidence Code 
Variant Description 
KRAS 
COSM518 
SNV 
2 
p.G12R 
KRAS 
COSM517 
SNV 
2 
p.G12S 
KRAS 
COSM19404 
SNV 
3 
p. A146T 
 

ECOG-ACRIN 
EAY131-Z1F 
Cancer Research Group 
Version Date: August 12, 2019 
41 
Molecular Analysis for Therapy Choice (MATCH) 
MATCH Treatment Subprotocol Z1F: Copanlisib, PIK3CA 
Appendix II 
 
Patient Drug Information Handout and Wallet Card 
Information for Patients, Their Caregivers and Non-Study Healthcare Team on Possible 
Interactions with Other Drugs and Herbal Supplements 
The patient ____________________________ is enrolled on a clinical trial using the 
experimental study drug, copanlisib. This clinical trial is sponsored by the National Cancer 
Institute.  This form is addressed to the patient, but includes important information for others 
who care for this patient. 
These are the things that you as a healthcare provider need to know: 
Copanlisib interacts with certain specific enzymes in your liver and certain transport proteins 
that help move drugs in and out of cells. 
• 
The enzymes in question are CYP3A4 and 1A1. Copanlisib is broken down by these 
enzymes and may be affected by other drugs that inhibit or induce these enzymes. 
• 
The proteins in question are P-gp, BCRP, and MATE2K. Copanlisib is moved in and out of 
cells/organs by P-gp and BCRP. Copanlisib also inhibits MATE2K and may affect the 
clearance of other drugs that are dependent on this transport protein. 
To the patient: Take this paper with you to your medical appointments and keep the 
attached information card in your wallet. 
Copanlisib may interact with other drugs which can cause side effects. For this reason, it is very 
important to tell your study doctors of any medicines you are taking before you enroll onto this 
clinical trial.  It is also very important to tell your doctors if you stop taking any regular 
medicines, or if you start taking a new medicine while you take part in this study.  When you talk 
about your current medications with your doctors, include medicine you buy without a 
prescription (over-the-counter remedy), or any herbal supplements such as St. John’s Wort.  It 
is helpful to bring your medication bottles or an updated medication list with you. 
Many health care providers can write prescriptions.  You must tell all of your health care 
providers (doctors, physician assistants, nurse practitioners, pharmacists) you are taking part in 
a clinical trial. 
These are the things that you and they need to know: 
Copanlisib must be used very carefully with other medicines that use certain liver enzymes or 
transport proteins to be effective or to be cleared from your system.  Before you enroll onto the 
clinical trial, your study doctor will work with your regular health care providers to review any 
medicines and herbal supplements that are considered strong inducers/inhibitors of 
CYP3A4, 1A1, P-gp, and BCRP or substrates of MATE2K. 
• 
Please be very careful! Over-the-counter drugs (including herbal supplements) may contain 
ingredients that could interact with your study drug.  Speak to your doctors or pharmacist to 
determine if there could be any side effects. 
• 
Your regular health care provider should check a frequently updated medical reference or 
call your study doctor before prescribing any new medicine or discontinuing any medicine. 

ECOG-ACRIN 
EAY131-Z1F 
Cancer Research Group 
Version Date: August 12, 2019 
42 
Your study doctor’s name is 
_____________________________________  
and he or she can be contacted at: 
_____________________________________. 
 
 
 
 
 
 
 
 
 
 
STUDY DRUG INFORMATION WALLET CARD   
You are enrolled on a clinical trial using the 
experimental study drug copanlisib.  This clinical trial 
is sponsored by the NCI.  Copanlisib may interact with 
drugs that are processed by your liver or use certain 
transport proteins in your body. Because of this, it is 
very important to: 
➢ Tell your doctors if you stop taking any medicines or if you 
start taking any new medicines. 
➢ Tell all of your health care providers (doctors, physician 
assistants, nurse practitioners, or pharmacists) that you are 
taking part in a clinical trial. 
➢ Check with your doctor or pharmacist whenever you need 
to use an over-the-counter medicine or herbal supplement. 
Copanlisib interacts with specific liver enzymes 
called CYP3A4 and 1A1, transport proteins P-gp, 
BCRP, and MATE2K, and must be used very 
carefully with other medicines that interact with these 
enzymes and transporters.  
➢ Before you enroll onto the clinical trial, your study 
doctor will work with your regular health care 
providers to review any medicines and herbal 
supplements that are considered “strong 
inducers/inhibitors of CYP3A4, 1A1, P-gp, and 
BCRP.” Copanlisib inhibits “MATE2K” and may 
affect how other medicines work in your body. 
➢ Before prescribing new medicines, your regular 
health care providers should go to a frequently-
updated medical reference for a list of drugs to 
avoid, or contact your study doctor.   
➢ Your study doctor’s name is 
_____________________________ and can be 
contacted at 
_________________________________.  

ECOG-ACRIN 
EAY131-Z1F 
Cancer Research Group 
Version Date: August 12, 2019 
43 
Molecular Analysis for Therapy Choice (MATCH) 
MATCH Treatment Subprotocol Z1F: Copanlisib, PIK3CA 
Appendix III 
 
MANAGEMENT OF TRANSIENT GLUCOSE INCREASE ON THE DAY OF 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 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 
 
Rev. Add16 

ECOG-ACRIN 
EAY131-Z1F 
Cancer Research Group 
Version Date: August 12, 2019 
44 
Molecular Analysis for Therapy Choice (MATCH) 
MATCH Treatment Subprotocol Z1F: Copanlisib, PIK3CA 
Appendix IV 
 
DOSE MODIFICATION OF COPANLISIB FOR ARTERIAL HYPERTENSION 
 
Toxicity (CTCAE) 
Study drug action 
Recommendation 
Pre-dose measurements 
BP ≥150/90 mmHg 
No dose should be given 
until recovery to  
< 150/90mmHg. 
Consider BP lowering medication. 
Dosing can proceed on the 
scheduled day if after at least 2 
consecutive measurements BP 
returns to < 150/90mmHg. If BP 
doesn’t return to < 150/90mmHg, 
delay dosing until next visit. 
During infusion: 
CTCAE hypertension of 
grade 3  
or ≥160/100 mmHg 
Infusion can be interrupted 
or slowed down and 
administration of BP 
lowering therapy should be 
initiated. 
Infusion may be resumed when BP 
has returned to < 150/90mmHg at 
the investigator’s discretion or 
skipped. 
Subsequent study drug 
administrations may be reduced by 
1 dose level at the investigator’s 
discretion.b 
Post-dose: 
Drug-related 
CTCAE hypertension of 
grade 3 
or ≥160/100 mmHg a 
– 
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 <150/90mmHg. 
Subsequent study drug 
administrations may be reduced by 
1 dose level at the investigator’s 
discretion.b 
CTCAE hypertension of 
grade 4 
 
Permanent discontinuation 
– 
CTCAE = Common Terminology Criteria for Adverse Events; BP = Blood pressure 
a  Not manageable despite optimal antihypertensive treatment. 
b  The lowest dose level is 30mg. 
 
Rev. Add16