MATCH Treatment Subprotocol Z1H: Phase II Study of Copanlisib in Patients With Tumors With Deleterious PTEN Sequencing Result and PTEN Expression by IHC
Phase: PHASE2
Conditions: Advanced Lymphoma, Advanced Malignant Solid 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 19, 2020
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 #25 to EAY131- Z1H, Phase II Study of Copanlisib in Patients with 
Tumors with Deleterious PTEN Sequencing Result and PTEN Expression by IHC.
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permitted to conduct the study utilizing outdated versions of any MATCH protocol documents 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.
The following revisions to EAY131-Z1H protocol have been made in this addendum:
Section
Change
1.
Cover Page
Updated version date.
2.
3.1
Under sub –section,” Pre-Dose glucose levels”, revised language in the 
second paragraph and the associated bullets regarding glucose 
monitoring. 
3.
3.3.1
Revised language in the second box referencing “subject’ to “female 
patient”
The following revisions to EAY131- Z1H Informed Consent Document have been made in this 
addendum:
Section
Change
1.
Page 1
Updated 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- Z1H so ECOG-ACRIN may 
activate it promptly.   
Thank you.  
Sincerely, 
Pamela Cogliano 
Senior Director of Protocol Development 
 
 

EAY131-Z1H
1
Molecular Analysis for Therapy Choice (MATCH)
MATCH Treatment Subprotocol Z1H: Phase II Study of 
Copanlisib in Patients with Tumors with Deleterious PTEN 
Sequencing Result and PTEN Expression by IHC
COPANLISIB TREATMENT SUBPROTOCOL
CHAIR:
Filip Janku, MD, PhD
COPANLISIB TREATMENT SUBPROTOCOL
CO-CHAIR:
Michael Davies, MD, PhD
Version Date: August 19, 2020
NOTE: This subprotocol (EAY131-Z1H) 
should be used in conjunction with 
the MATCH Master Protocol (EAY131).
SUBPROTOCOL ACTIVATION DATE
Incorporated in Addendum #13
Addendum #16
Addendum #22
Addendum #25
Agent
IND#
NSC#
Supply
Copanlisib
IND Sponsor: DCTD, NCI IND#: 
784727
NCI Supplied

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Table of Contents 
Schema ...................................................................................................................... 4 
1. Introduction ........................................................................................................ 5 
1.1 
PI3K/AKT/mTOR Pathway in Cancer ......................................................... 5 
1.2 
Copanlisib .................................................................................................. 6 
1.3 
Safety: ....................................................................................................... 8 
1.4 
Efficacy: ..................................................................................................... 9 
2. Selection of Patients ......................................................................................... 11 
2.1 
Eligibility Criteria ..................................................................................... 11 
3. Copanlisib Treatment Plan ................................................................................ 14 
3.1 
Dosage and Administration Schedule ..................................................... 14 
3.2 
General Concomitant Medication and Supportive Care Guidelines ....... 15 
3.3 
Adverse Event Reporting Requirements ................................................. 16 
3.4 
Comprehensive Adverse Events and Potential Risks List (CAEPR) for 
Copanlisib dihydrochloride (BAY 80-6946 dihydrochloride, NSC 784727)19 
3.5 
Dose Modifications ................................................................................. 22 
3.6 
Supportive Care ....................................................................................... 28 
3.7 
Duration of Agent-specific treatment ..................................................... 28 
3.8 
Duration of Follow-Up ............................................................................. 28 
4. Study Parameters .............................................................................................. 29 
4.1 
Therapeutic Parameters for Copanlisib Treatment ................................ 29 
5. Drug Formulation and Procurement ................................................................. 31 
5.1 
Copanlisib (NSC #784727) ....................................................................... 32 
6. Translational Studies ......................................................................................... 35 
7. References ........................................................................................................ 35 
Appendix I  Actionable Mutations for Sub-Protocol EAY131-Z1H ........................... 37 
Appendix II  Patient Drug Information Handout and Wallet Card .......................... 52 
Appendix III  MANAGEMENT OF TRANSIENT GLUCOSE INCREASE ON THE DAY OF 
COPANLISIB INFUSION ...................................................................................... 54 
Appendix IV  DOSE MODIFICATION OF COPANLISIB FOR ARTERIAL HYPERTENSION55 
 
 
 

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TREATMENT SUBPROTOCOL CHAIR 
Filip Janku, MD, PhD 
The University of Texas 
MD Anderson Cancer Center 
The Department of Investigational Cancer 
Therapeutics 
(Phase I Clinical Trials Program)  
1515 Holcombe Blvd. Houston, TX 
Phone: 713-563-0803 
Fax: 713-792-5576 
Email: FJanku@mdanderson.org 
 
TREATMENT SUBPROTOCOL CO-CHAIR  
Michael Davies, MD, Ph.D 
MD Anderson Cancer Center 
Department of Melanoma Medical Oncology 
1515 Holcombe Boulevard, Unit 904 
Houston, TX 77030 
Phone #: (713) 563-5270 
Fax #: (713) 563-3424 
E-mail: mdavies@mdanderson.org 
 
 
 
 

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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 
PI3K/AKT/mTOR Pathway in Cancer 
The PI3K/AKT/mTOR signaling pathway is one of the most frequently activated 
signaling cascades in cancer.1,2 Class I PI3K is activated by a variety of signals, 
including many receptor tyrosine kinases (RTKs), cell-cell contacts, and activated 
RAS proteins, among others (reviewed in (Davies 2011).3 The activated PI3K 
phosphorylates phosphatidylinositols in the cell membrane at the 3’-OH position. 
These phospholipids interact with proteins that contain a pleckstrin homology 
(PH) domain, including the serine-threonine kinase AKT, also known as protein 
kinase B (PKB). Interactions of PH domain-containing proteins cause them to co-
localize at the cell surface, where they often interact and activate each other (i.e. 
activation of AKT by phosphorylation of PDK1). The activated AKT acts on 
multiple effectors to regulate a number of key cellular functions, including 
angiogenesis, proliferation, survival, motility, and metabolism. PTEN, a lipid 
phosphatase that dephosphorylates phosphatidylinositols at the 3’OH position, is 
a critical negative regulator of PI3K activity. 
The PI3K/AKT/mTOR signaling pathway is activated by many oncogenic 
events.4,5 The PI3K/AKT/mTOR pathway is a key effector of activating oncogenic 
events that occur upstream of the pathway, including activating hotspot 
mutations (i.e EGFR) and gene amplifications (i.e. HER2/neu) affecting RTKs, 
and hotspot mutations in RAS family proteins (i.e. Kras). The pathway may also 
be activated by hotspot mutations in components of the pathway, including 
PIK3CA, AKT1, and AKT3. Signaling through the PI3K/AKT/mTOR signaling 
pathway can also be activated by loss of function of PTEN. Previous studies 
support that loss of PTEN function most commonly results from somatic 
mutations and gene deletions that cause loss of PTEN protein expression, with 
>95% loss of PTEN protein expression correlating with increased activation of 
AKT and other pathway effectors.6-8 PTEN function can also be disrupted by 
mutations that disrupt the phosphatase domain of the PTEN protein, thus 
causing a loss of catalytic function without causing loss of PTEN protein 
expression.9-11 These mutations include: (1) substitution mutations affecting 
residues 123-130 of the PTEN protein, which comprise the P-loop of the protein, 
that have been shown in functional assays to abrogate the catalytic function of 
PTEN, and (2) missense mutations, and deletions and insertions that cause 
frameshifts, that result in a truncated protein [Table 1]. 
The high frequency of activation of the PI3K/AKT/mTOR signaling pathway in 
cancer makes it an attractive target for therapeutic development. In particular, 
there is a strong rationale to test the hypothesis that agents that inhibit the 
pathway will achieve clinical benefit in patients with alterations in the pathway 
itself, particularly PIK3CA mutations and PTEN loss.12 However, preclinical data 
suggest that different oncogenic events in this pathway (i.e. PIK3CA mutations 
and PTEN loss) may have different functional consequences, a hypothesis that is 
further supported by the frequently observed overlap of mutations of this pathway 
in tumors.12-14 Thus, this protocol is designed to specifically test the hypothesis 
that loss of PTEN protein function (without loss of PTEN protein expression) will 
predict clinical benefit from treatment with the pan-PI3K inhibitor copanlisib in 
patients that do not have a PIK3CA mutation 

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1.2 
Copanlisib 
Copanlisib (BAY 80-6946) is a novel, highly selective, pan-class 
phosphatidylinositol 3-kinase (PI3K) inhibitor with potent activity against both the 
δ and α isoforms. A summary of the available relevant non-clinical and clinical 
data is provided below. Study details and additional information can be found in 
the Investigator Brochure.   
1.2.1 
Pre-Clinical Data 
The pharmacodynamic effects of copanlisib have been characterized 
extensively in preclinical cancer models, including cell lines and 
xenografts with loss of PTEN (see Investigator Brochure for detailed 
description of results). In enzymatic assays, copanlisib inhibited all 
PI3K isoforms with single digit nanomolar IC50, whereas no 
significant activity was seen against a panel of 220 other kinases, 
except mTOR (IC50 45 nM). Further testing supports a 100- to 1000-
fold cellular selectivity for inhibition of PI3K versus mTOR signaling by 
copanlisib.  Inhibition of both AKT activation and cell proliferation in 
vitro was achieved with copanlisib treatment in cancer cell lines of 
multiple types, including several with PTEN loss (Investigator 
Brochure, Table 4-4 and Figure 4-1, and (Liu, Rowley et al. 2013).15  
In vivo preclinical testing also demonstrated efficacy in multiple cancer 
xenograft models. Notably, partial tumor regression was observed in 
the U87 glioblastoma model, which has loss of PTEN function due to 
an in-frame PTEN deletion that results in a truncated protein.9 
1.2.2 
Clinical Data 
As of Feb 01, 2016, 627 patients with advanced cancer have been 
treated across eight phase 1, three phase 2 and three phase 3 
studies. Copanlisib has also been studied in healthy volunteers. 
1.2.3 
Pharmacodynamics: 
The PD effects on glucose and plasma insulin levels as well as 
18[F]FDG-CT/PET have been investigated in the first-in-man Study 
12871 using copanlisib monotherapy at different doses.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, i.e., not observed after copanlisib treatment had been 
permanently discontinued. Dose-related increases in glucose and 
insulin as well as copanlisib exposure-related increases in plasma 
glucose were observed.Plasma insulin increase to greater than 2 
times the baseline value was reported in 90% of the patients, starting 
at the 0.2 mg/kg dose level. 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.
Paired FDG-PET scans were available in 21 patients.Between 
baseline and Cycle 1 Day 3 or Cycle 1 Day 4, 7 patients (33%) 
showed a reduction of more than 25% in FDG uptake. There was a 
weak correlation between changes in maximum standard uptake 

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value (maximum standard uptake value [SUVmax]) and AUC(0-25) of 
copanlisib. 
1.2.4 
Pharmacokinetics: 
Copanlisib (BAY 80-6946) PK have been characterized in the 
following studies in cancer patients: (i) single agent dose escalation 
study in cancer patients in the US (Study 12871), (ii) a dose 
escalation study in combination with refametinib (BAY 86-9766) in the 
US and Europe (Study 12876), (iii) a single agent dose escalation 
study in cancer patients in Japan (Study 15205), in two studies in 
combination with chemotherapy, either with paclitaxel (Study 12874), 
or with gemcitabine and gemcitabine/cisplatin (Study 12875). 
Furthermore, Study 16790 a PD study with copanlisib as monotherapy 
in patients with NHL and solid tumors as well as a Study 16270 to 
evaluate potential drug-drug interaction of copanlisib with itraconazole 
(a strong CYP3A4 inhibitor) and rifampin (a strong CYP3A4 inducer) 
are ongoing. Results on single agent studies is summarized below. 
Please refer to the IB for pharmacokinetics of copanlisib in 
combination with other drugs. 
In Study 12871, copanlisib PK were characterized on Cycle 1 Day 1 
and 15 and Cycle 3 Day 15. In general, PK data indicate similar 
copanlisib Cmax and AUC(0-25) on Day 1 and Day 15, indicating lack 
of significant accumulation after once weekly administration. Dose 
proportional increase in copanlisib exposure (Cmax and AUC(0-25)) 
was observed between 0.1 mg/kg to 1.2 mg/kg with moderate to high 
inter-subject variability. At the MTD of 0.8 mg/kg (n=28), the 
geometric mean copanlisib terminal phase t1/2 was 38.2 hours (CV: 
42.5%), which supports once weekly dosing. 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. 
In Study 15205, copanlisib doses of 0.4 mg/kg and 0.8 mg/kg were 
evaluated in Japanese patients. Pharmacokinetic results at the 0.4 
and 0.8 mg/kg dose level indicate generally comparable (slightly 
lower) exposure in Japanese patients and non-Japanese patients 
enrolled in the US Study 12871.  
Study 16270 is an ongoing 2 armed Phase 1 study aims to evaluate 
the effect of itraconazole (a strong CYP3A4 inhibitor) or rifampin (a 
strong CYP3A4 inducer) on the PK of single i.v .doses of copanlisib 
and evaluates parameters of cardiac safety in patients with advanced 
solid tumors. Cycle duration is 4 weeks. Arm A evaluates the effect of 
itraconazole on copanlisib PK. Arm B evaluates the effect of rifampin 
on copanlisib PK and the effect of copanlisib on QTc and left 
ventricular ejection fraction (LVEF). 
The PK of copanlisib were characterized after a 1 hour i.v. infusion 
administered once weekly. In the dose escalation cohorts, serial PK 
samples were collected on Cycle 1 Day 1 (up to 48 hours after end of 
infusion at dose levels ≤ 0.2 mg/kg and approximately 168 hours after 
the start of infusion at dose levels >0.2 mg/kg) and Cycle 1 Day 15 
(up to 24 hours after the end of infusion).In general, PK data indicate 

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similar copanlisib Cmax and AUC(0-25) on Day 1 and Day 15, 
indicating lack of significant accumulation after once weekly 
administration. Nearly dose proportional increase in copanlisib 
exposure (Cmax and AUC(0-25)) was observed between 0.1 mg/kg to 
1.2 mg/kg with moderate to high inter-subject variability. In the MTD 
expansion cohort, serial PK samples were collected on Cycle 1 Day 1 
and 15 and Cycle 3 Day 15 (up to 8 hours after the end of infusion). At 
the MTD of 0.8 mg/kg, Cycle 1 Day 1, geometric mean (n=41) Cmax 
was 454 )g/L and AUC(0-tlast), exposure covering the 1-week dosing 
interval, was 2880 )g•h/L. Inter-patient variability in copanlisib Cmax 
and AUC(0-tlast) at 0.8 mg/kg was high with values of 73.3% CV for 
Cmax and about 46.5% for AUC(0-tlast). The geometric mean 
copanlisib terminal phase t1/2 was 38.2 hours (CV: 42.5%), which 
supports once weekly dosing. Reliable terminal t1/2 could only be 
calculated in 28 patients.After administration of 0.4 mg/kg copanlisib 
to 6 diabetic patients, geometric mean Cmax was 138 )g/L (CV: 
36.7%) on Cycle 1 Day 1 and 151 )g/L (CV: 23.4%) on Cycle 1 Day 
15. Geometric mean AUC(0-25) was 607 )g0hour/L (CV: 43.6%) on 
Cycle 1 Day 1 and 687 )g0hour/L (CV: 36.0%) on Cycle 1 Day 15. 
Inter-subject variability for copanlisib Cmax and AUC(0-25) was 
moderate to high and similar to variability in other cohorts with PK 
parameters varying by a factor of about 3.Applying a adjusted body 
weight dosing, AUC(0-25) values on Cycle 1 Day 1 in obese patients 
were similar to AUC(0-25) values of other patients with normal BMI 
(130 mg/m2). 
1.2.5 
Distribution:  
Plasma protein binding of copanlisib was determined in vitro with a 
free fraction of 15.8% in human plasma. Similar protein binding of the 
M-1 metabolite was observed with the free fraction of 20%. 
1.2.6 
Metabolism:  
In vitro, oxidation, dehydrogenation, and dealkylation reactions were 
identified as the major oxidative pathways in liver microsomes and 
hepatocytes of different animal species and human. Based on in vitro 
experiments, CYP3A4 is the major metabolizing enzyme, while 
CYP1A1 also contributes to a minor extent. 
1.2.7 
Elimination:  
In Study 12871, copanlisib at the MTD (0.8 mg/kg was eliminated 
from plasma with a geometric mean of 38.2 hours (CV: 42.5%). 
Copanlisib is excreted in feces and urine as unchanged drug and 
metabolites. 
1.3 
Safety:  
The relationship between individual random effects on clearance and selected 
covariates body weight, age, BMI, BSA, LBM, race, and sex on CL was explored 
across studies. Formal covariate analysis confirmed that there is no statistically 
significant (p<0.001) correlation between clearance and any of the selected 
covariates. Based on the lack of significant impact of body weight and other 

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covariates on clearance of copanlisib a flat dose regimen of 60 mg weekly on a 3 
week on, one week off was recommended for future studies.    
Based on pre-clinical data, copanlisib began testing in a phase 1 dose escalation 
first in human study, 12871 in patients with advanced cancers. A dose of 
0.8mg/kg was determined to be the maximum tolerated dose in non-diabetic 
patients. Dose limiting toxicity was acute hypertension at 0.4mg/kg in one patient 
and left ventricular systolic dysfunction with ischemic EKG changes and lactic 
acidosis at 1.2 mg/kg in another patient consistent with safety studies in dogs. 
Increased BP was frequently observed within the first 3 hours of infusion which 
needed antihypertensive therapy. Adverse events noted in more than 20% of 
patients include hyperglycemia (63.2%), nausea (38.6%) and hypertension 
(21.1%). Most common grade 3 AE but regardless of seriousness and causality, 
occurring in >5% of the 57 patients were: hyperglycemia (33.3%), hypertension 
(19.3%), anemia (7.0%) and AST increased (5.3%).Three Follicular Lymphoma 
patients experienced any treatment-emergent interstitial pneumonitis, all with a 
severity of Grade 3 and assessed as serious.Of note, no pneumonitis was 
reported in the 48 patients with solid tumors treated in this study. Study 16790 is 
a phase 1 PD study to evaluate effects of PD biomarkers in patients with NHL 
and selected solid tumors at 2 dose levels, 0.4mg/kg and 0.8 mg/kg. Diabetic 
patients are allowed to be treated on 2 cohorts in this study at a flat dose of 45 
mg and 60mg and only one patient has been treated so far. Most common 
TEAEs of any grade occurring in more than 20% of patients on study 16790 were 
hyperglycemia and fatigue (37.5%), hypertension (33%), anemia and nausea 
(25%), as well as diarrhea (20.8%). This study is ongoing and PTEN or PI3K 
mutation status is unknown at this time. Three phase 1 studies, (12874, 12875 
and 1276) are ongoing which were done to determine MTD of copanlisib in 
combination with paclitaxel, gemcitabine+ cisplatin and refametinib (MEK 
inhibitor). Study 16270 is evaluating potential drug interactions of copanlisib with 
itraconazole (a strong CYP3A4 inhibitor) and rifampin (a strong CYP3A4 
inducer). A healthy volunteer study, 16353 was completed with a dose of 12 mg 
of copanlisib and was well tolerated. Study 15205 is a single agent dose 
escalation study in 10 Japanese patients with advanced solid tumors. In this 
study, PK samples were collected from 3 Japanese patients at the 0.4 mg/kg 
dose level and seven patients at the 0.8 mg/kg dose level. Exposures of 
copanlisib increased in a roughly dose proportional manner. The plasma 
concentration-time profiles were similar between Japanese and non-Japanese 
patients at both the 0.4 mg/kg and 0.8 mg/kg dose level. Treatment emergent AE 
of all grade in more than 20% of patients in study 16349 which is limited to non-
Hodgkin’s lymphoma included hyperglycemia (56.8%), hypertension (53.1%), 
diarrhea (33.3%), neutropenia (23.5%), and fatigue (21.0%). Hyperglycemia 
peaked 5 to 8 hours after treatment and was reversible. This is an expected on 
target effect as PI3K is required for downstream signaling from the insulin 
receptor. Inhibition of this pathway leads to impaired uptake of glucose with a 
reactive rise in plasma insulin and glucose levels.   
1.4 
Efficacy: 
The data so far from copanlisib trials in lymphoma imply that low or total loss of 
PTEN expression predicts for response. Four of six patients with null or low  
(< 5%) PTEN expression by IHC had a response (66%) whereas only 15% of 
patients with higher PTEN expression by IHC responded (Bayer data). There is 
not as much data available for solid tumors, but the latest data is from the 

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expansion of study 12871 in 25 solid tumors. One patient with endometrial 
cancer had a complete response, and she had PTEN loss by IHC, as well as 
PTEN and PIK3CA mutations. Two patients with extended stable disease also 
had PTEN loss by IHC. Due to the small number of patients with solid tumors 
entered, and the very few responses in these patients, we have very little data on 
the relationship of PTEN loss to response rate with this agent. However, the data 
that do exist conform to our level of evidence 3: at least one patient with PTEN 
loss by IHC responded to copanlisib with solid tumors (and several did so with 
lymphomas). Although we do not have data on PTEN mutations, it is likely that a 
good number of patients with PTEN loss by IHC will have PTEN mutations. We 
are studying patients who have PTEN mutations with some expression of PTEN 
IHC, and the mutations that are eligibility criterion have level of evidence 3 that 
they will be damaging mutations. 
Out of 46 patients in study 16790 clinical benefit rate (CR, PR or SD) was seen in 
38% of patients with solid tumors. Interestingly, all 6 patients with follicular 
lymphoma experienced an objective response. One patient is still on treatment 
for over 3 years now. On exploratory analysis of the lymphoma patients, one 
patient had complete PTEN loss and four patients had low PTEN (1-5 % staining 
of tumor cells). The only patient in solid tumor cohort who experienced a CR 
interestingly had mutations in PIK3CA and PTEN as well as complete loss of 
PTEN by IHC. 
Based on this a phase 2 study, 16349 was undertaken. 29 out of 32 patients with 
indolent lymphoma had a clinical benefit rate with an objective response rate of 
44%. Among patients with aggressive lymphomas, 20 out of 46 patients had a 
clinical benefit with an objective response rate of 26%. Analysis of PTEN and 
mutations in study 12871 showed about 50% of solid tumors had complete loss 
of PTEN by IHC. Copanlisib is being tested in combination with chemotherapy in 
studies 12874, 12875 and 12876 and 2 patients in study 12875 with complete 
loss of PTEN achieved partial response or prolonged disease stabilization. 
Multiple phase 2 and 3 studies have been launched in Non-Hodgkin’s lymphoma 
but none of the studies require tumors to have PI3K mutations or PTEN loss by 
IHC. Based on our data the anticipated response rate should be around 20% 
(Janku et al. Cell Rep 2014). 
Arm Z1F will allow patients with PTEN loss to enroll, but Z1H and Z1G do not 
allow patients with PIK3CA mutation. If patients have both a PIK3CA and PTEN 
IHC loss, patients will be assigned to Z1F. Arms Z1F, Z1H, and Z1G will provide 
complementary information as there are very likely to be patients across all these 
arms with PIK3CA mutation but PTEN intact; PIK3CA mutation and loss of PTEN 
expression and PIK3CA mutation and PTEN mutations but retained expression 
of PTEN by IHC (the latter two conditions occur in half or less of patients, 
depending on tumor types enrolled). However, the arms Z1H and Z1G will only 
have patients with PTEN loss or mutation. We will thus get a signal as to whether 
the agent is active when there are coexisting abnormalities in PTEN and 
PIK3CA, PIK3CA abnormalities alone, or PTEN abnormalities alone (as well as if 
expression of PTEN is null). 
 

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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 mutations in the PTEN gene with 1% or more 
expression of PTEN by IHC as determined via the MATCH Master 
Protocol and as described in Appendix I. See Appendix I for 
information on the PTEN mutations and corresponding Levels of 
Evidence. 
NOTE: 
For patients entering the study, all patients must have 
PTEN IHC performed as described in the MATCH Master 
Protocol. This includes patients entering the study via the 
outside assay process (Appendix XIV of the MATCH 
Master Protocol). 
2.1.3 
Patients must not have co-existing aberrations in the MAPK or 
PI3K/MTOR pathways as determined by the MATCH screening 
assessment in NRAS, HRAS, KRAS, BRAF, PIK3CA, AKT or mTOR. 
See Appendix I for a list of and the corresponding Levels of Evidence. 
_____ 
_____ 
_____ 

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2.1.4 
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:  _______________ 
2.1.5 
Patients must not have known hypersensitivity to copanlisib or 
compounds of similar chemical or biologic composition. 
2.1.6 
Patients must not have had prior treatment with copanlisib or other 
PI3K inhibitors, AKT inhibitors or mTOR inhibitors. 
2.1.7 
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. 
2.1.8 
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. 
2.1.9 
Patients with Type I or II diabetes mellitus must have a HbA1c ≤ 8.5% 
within 28 days from registration. 
2.1.10 
Patients must not have uncontrolled hypertension defined as SBP 
greater than 160 mmHg or diastolic BP greater than 100 mmHg or 
use of more than 2 anti-hypertensive medications. 
2.1.11 
Patients must not have HER2 positive (3+ by IHC or FISH ratio ≥ 2) 
breast cancer. 
2.1.12 
Patients must not have indolent NHL (Non-Hodgkin’s Lymphoma) or 
DLBCL (diffuse large B cell lymphoma) because other studies are 
ongoing with this agent in this group of patients. 
2.1.13 
Patients must not be on anti-arrhythmic therapy other than digoxin or 
beta-blockers. 
2.1.14 
Patients must have adequate marrow function as defined below: 
x 
ANC ≥ 1.5x109 /L 
x 
Platelets ≥ 100x109 /L 
x 
Hb > 9 g/dl 
2.1.15 
Patients must have adequate organ function as defined below: 
x 
Total serum bilirubin < 2.0 mg/dL, 
x 
ALT and AST < 2.5x ULN (< 5x ULN in patients with liver 
metastases), 
x 
Serum creatinine < 1.5x ULN 
2.1.16 
Patients with non-healing wound, ulcer, or bone fracture are not 
eligible. 
2.1.17 
Patients with history of or current interstitial pneumonitis are not 
eligible. 
_____ 
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NOTE: 
For solid tumors, CMV PCR can be obtained at the 
discretion of treating physician or local institutional 
guidelines. 
2.1.18 
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 (finger stick or serum glucose) is required before each 
copanlisib infusion. The glucose testing is scheduled as follows: 
x 
On Cycle 1 Day 1: Glucose test is performed before starting copanlisib IV 
infusion at time 0 hour and at the end of the infusion (1 hour after starting 
infusion). 
x 
On all subsequent infusion days: Glucose test is performed before starting 
copanlisib IV infusion. Post-dose glucose monitoring after C1D1 may be 
performed as clinically indicated at the investigator’s discretion 
NOTE: 
If patient needs to take a meal, then glucose test should be taken 
prior to meal intake 
Monitoring of diabetic patients 
x 
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. 
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. 
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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 subprotocols 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. 

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3.3.1 
Additional instructions, requirements and exceptions for protocol 
EAY131 – Subprotocol Z1H 
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 Z1H specific expedited reporting 
requirements: 
x 
Pregnancies: Pregnancies and suspected pregnancies 
(including a positive or inconclusive pregnancy test, regardless 
of age or disease state) occurring while the female patient is on 
copanlisib, or within 28 days of the female patient’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. 
 
EAY131 – Subprotocol Z1H specific expedited reporting 
exceptions: 
For Subprotocol Z1H, the adverse events listed below do not 
require expedited reporting via CTEP-AERS: 
x 
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.  
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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 
x 
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. 
x 
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 
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 
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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 Event 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 via CTEP-AERS (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, NSC 784727). 
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) 
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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%)  
MUSCULOSKELETAL AND CONNECTIVE TISSUE DISORDERS 
  
 
Muscle cramp 
 
 Muscle cramp (Gr 2) 
RESPIRATORY, THORACIC AND MEDIASTINAL DISORDERS 
  
 
Pneumonitis3 
 
  
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 contacting 
PIO@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) 

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MUSCULOSKELETAL AND CONNECTIVE TISSUE DISORDERS - Arthralgia; Generalized 
muscle weakness; Musculoskeletal and connective tissue disorder - Other (psoriatic 
arthropathy); Myalgia 
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.htm) 
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 < 160mg/dL 
(fasting) or < 200 mg/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. 
x 
Further dose reduction (where appropriate per study design/population) is 
allowed as long as discontinuation criteria was not met. 
x 
Dose re-escalation is allowed when a patient has achieved controlled glucose 
levels per investigator’s judgment. 
x 
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. 
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x 
Occurrence of post infusion life-threatening copanlisib related hyperglycemia 
requires permanent discontinuation of the study drug. 
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 d 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 d 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 d 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 d 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 u 2 days, 40 mg u 2 days, 20 mg u 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) 
x Asymptomatic and 
persistent SBP of ≥ 150 
and < 160mmHg, or DBP 
≥ 90 and < 100 mmHg,  
OR 
x Clinically significant 
increase in DBP of 20 
mmHg (but still below 100 
mmHg). 
x Adjust current or initiate new 
antihypertensive 
medication(s). 
x 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). 
x Continue copanlisib at 
the current dose. 
(Scenario B) 
x Asymptomatic SBP  
≥ 160 mmHg, or DBP  
≥ 100 mmHg,  
OR 
x Failure to achieve well-
controlled BP within 2 
weeks in Scenario A. 
x Adjust current or initiate new 
antihypertensive 
medication(s). 
x Titrate antihypertensive 
medication(s) during the next 
2 weeks to achieve well-
controlled BP. 
x Interrupt copanlisib. 
x Once BP is well-
controlled, restart 
copanlisib at a 
reduced dose. 
(Scenario C) 
x Symptomatic hypertension  
OR 
x Persistent SBP  
≥ 160mmHg, or DBP  
≥ 100mmHg, despite 
antihypertensive 
medication and dose 
reduction of study 
treatment 
x Adjust current or initiate new 
antihypertensive 
medication(s). 
x Titrate antihypertensive 
medication(s) during the next 
2 weeks to achieve well-
controlled BP. 
x Referral to a specialist for 
further evaluation and follow-
up is recommended.  
x Continue follow-up per 
protocol. 
x Discontinue 
copanlisib. 
(Scenario D) 
x Refractory hypertension 
unresponsive to above 
interventions or 
hypertensive crisis. 
x Continue follow-up per 
protocol. 
x 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: 
x 
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. 
x 
Patient withdraws consent. 
x 
Patient experiences unacceptable toxicity. 
x 
Non-protocol therapies are administered. 
x 
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 
E-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: 
x For patients entering the study via the outside assay process (Appendix XIV of the MATCH Master Protocol), central IHC testing by the MD 
Anderson MATCH trial laboratory confirming expression of PTEN is required prior to receiving treatment assignment. 
x 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. 
x Screening biopsies for additional aMOI assessments after registration to appropriate screening step, if applicable (Step 2 or Step 4). 
x 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 timepoint: 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 2.1.9. 
 

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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. 
Hanahan, D., & Weinberg, R. A. (2011). Hallmarks of cancer: the next generation. 
Cell, 144(5), 646-674. doi: 10.1016/j.cell.2011.02.013 
2. 
Millis, S. Z., Ikeda, S., Reddy, S., Gatalica, Z., & Kurzrock, R. (2016). Landscape of 
phosphatidylinositol-3-kinase pathway alterations across 19 784 diverse solid 
tumors. JAMA Oncology. doi: 10.1001/jamaoncol.2016.0891 
3. 
Davies, M. A. (2011). Regulation, Role, and Targeting of Akt in Cancer. J Clin 
Oncol, 29(35), 4715-4717. doi: JCO.2011.37.4751 [pii]10.1200/JCO.2011.37.4751 
4. 
Thorpe, L. M., Yuzugullu, H., & Zhao, J. J. (2015). PI3K in cancer: divergent roles of 
isoforms, modes of activation and therapeutic targeting. Nat Rev Cancer, 15(1), 7-
24. doi: 10.1038/nrc3860 
5. 
Vanhaesebroeck, B., Stephens, L., & Hawkins, P. (2012). PI3K signalling: the path 
to discovery and understanding. Nat Rev Mol Cell Biol, 13(3), 195-203. 
6. 
Bucheit, A. D., Chen, G., Siroy, A., Tetzlaff, M., Broaddus, R., Milton, D., Davies, M. 
A., et al. (2014). Complete loss of PTEN protein expression correlates with shorter 
time to brain metastasis and survival in stage IIIB/C melanoma patients with 
BRAFV600 mutations. Clin Cancer Res, 20(21), 5527-5536. doi: 10.1158/1078-
0432.CCR-14-1027\1078-0432.CCR-14-1027 [pii] 
 
7. 
Djordjevic, B., Hennessy, B. T., Li, J., Barkoh, B. A., Luthra, R., Mills, G. B., & 
Broaddus, R. R. (2012). Clinical assessment of PTEN loss in endometrial 
carcinoma: immunohistochemistry outperforms gene sequencing. Mod Pathol, 
25(5), 699-708.  
8. 
Roszik, J., Wu, C.-J., Siroy, A. E., Lazar, A. J., Davies, M. A., Woodman, S. E., & 
Kwong, L. N. (2016). Somatic Copy Number Alterations at Oncogenic Loci Show 
Diverse Correlations with Gene Expression. Scientific Reports, 6, 19649. doi: 
10.1038/srep19649 
9. 
Furnari, F. B., Lin, H., Huang, H. J. S., & Cavenee, W. K. (1997). Growth 
suppression of glioma cells by PTEN requires a functional phosphatase 
catalytic domain. Proceedings of the National Academy of Sciences of the United 
States of America, 94(23), 12479-12484.  
10. Han, S.-Y., Kato, H., Kato, S., Suzuki, T., Shibata, H., Ishii, S., . . . Ishioka, C. 
(2000). Functional Evaluation of PTEN Missense Mutations Using in Vitro 
Phosphoinositide Phosphatase Assay. Cancer Research, 60(12), 3147-3151.  
11. Rodríguez-Escudero, I., Oliver, M. D., Andrés-Pons, A., Molina, M., Cid, V. J., & 
Pulido, R. (2011). A comprehensive functional analysis of PTEN mutations: 
implications in tumor- and autism-related syndromes. Human Molecular Genetics, 
20(21), 4132-4142. doi: 10.1093/hmg/ddr337 
12. Janku, F., Hong, David S., Fu, S., Piha-Paul, Sarina A., Naing, A., Falchook, Gerald 
S., Kurzrock, R. (2014). Assessing PIK3CA and PTEN in Early-Phase Trials with 
PI3K/AKT/mTOR Inhibitors. Cell Reports, 6(2), 377-387. doi: 
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13. Stemke-Hale, K., Gonzalez-Angulo, A. M., Lluch, A., Neve, R. M., Kuo, W. L., 
Davies, M., Hennessy, B. T. (2008). An integrative genomic and proteomic analysis 
of PIK3CA, PTEN, and AKT mutations in breast cancer. Cancer Res, 68(15), 6084-
6091. doi: 68/15/6084 [pii] 10.1158/0008-5472.CAN-07-6854 
14. Vasudevan, K. M., Barbie, D. A., Davies, M. A., Rabinovsky, R., McNear, C. J., Kim, 
J. J., Garraway, L. A. (2009). AKT-independent signaling downstream of oncogenic 
PIK3CA mutations in human cancer. Cancer Cell, 16(1), 21-32. doi: S1535-
6108(09)00177-9 [pii] 10.1016/j.ccr.2009.04.012 
15. Liu, N., Rowley, B. R., Bull, C. O., Schneider, C., Haegebarth, A., Schatz, C. A., . . . 
Ziegelbauer, K. (2013). BAY 80-6946 Is a Highly Selective Intravenous PI3K 
Inhibitor with Potent p110α and p110δ Activities in Tumor Cell Lines and Xenograft 
Models. Molecular Cancer Therapeutics, 12(11), 2319-2330. doi: 10.1158/1535-
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Molecular Analysis for Therapy Choice (MATCH) 
MATCH Treatment Subprotocol Z1H: Copanlisib, PTEN Expression 
 
Appendix I 
 
Actionable Mutations for Sub-Protocol EAY131-Z1H 
A. Inclusion Mutations:  
The actionable mutations in PTEN have been detailed in the table below. These listed mutations 
have been categorized as pathogenic in a genomic database such as COSMIC or OMIM. In 
addition, novel mutations that are predicted to result in a nonfunctional protein will be classed as 
LOE 3 (which denoted preclinical information of damaging result). Patients who have such 
mutations will have IHC done as described in the Master Protocol. This protocol REQUIRES 
that PTEN protein be detected by IHC. 
NOTE: 
A function has been implemented in MATCHBOX to identify any deleterious 
mutations in PTEN genes at Level of Evidence code 3. This function also includes 
any deleterious aberrations in PTEN genes with Level of Evidence code 3 or higher 
not listed in the table below. 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 
PTEN 
COSM86058 
SNV 
3 
p.A34D 
PTEN 
COSM5223 
SNV 
3 
p.M35R 
PTEN 
COSM5135 
SNV 
3 
p.G36R 
PTEN 
OM1539 
SNV 
3 
p.N48K 
PTEN 
MCH13 
SNV 
3 
p.H61D 
PTEN 
MCH14 
SNV 
3 
p.Y68D 
PTEN 
COSM5264 
SNV 
3 
p.D92A 
PTEN 
COSM35759 
SNV 
3 
p.D92E 
PTEN 
COSM125653 
SNV 
3 
p.D92E 
PTEN 
COSM5099 
SNV 
3 
p.D92G 
PTEN 
COSM23566 
SNV 
3 
p.D92H 
PTEN 
COSM5236 
SNV 
3 
p.D92V 
PTEN 
COSM5283 
SNV 
3 
p.H93D 
PTEN 
COSM5043 
SNV 
3 
p.H93Y 
PTEN 
COSM5265 
SNV 
3 
p.P96Q 
PTEN 
COSM5273 
SNV 
3 
p.A121E 
PTEN 
COSM5234 
SNV 
3 
p.I122S 
PTEN 
COSM921088 
SNV 
3 
p.H123D 
PTEN 
COSM5082 
SNV 
3 
p.K125E 
PTEN 
COSM5041 
SNV 
3 
p.A126V 

ECOG-ACRIN 
EAY131-Z1H 
Cancer Research Group 
Version Date: August 19, 2020 
38 
Gene Name 
Variant ID 
Variant Type 
Level of 
Evidence Code 
Variant 
Description 
PTEN 
COSM5143 
SNV 
3 
p.G127E 
PTEN 
COSM28917 
SNV 
3 
p.G129E 
PTEN 
COSM5276 
SNV 
3 
p.G129V 
PTEN 
COSM5104 
SNV 
3 
p.T131I 
PTEN 
COSM5144 
SNV 
3 
p.Y155C 
PTEN 
COSM5114 
SNV 
3 
p.G165E 
PTEN 
COSM249877 
SNV 
3 
p.G165V 
PTEN 
MCH20 
SNV 
3 
p.S170R 
PTEN 
MCH17 
SNV 
3 
p.L181P 
PTEN 
MCH18 
SNV 
3 
p.V343E 
PTEN 
COSM5133 
SNV 
3 
p.Y16C 
PTEN 
COSM5247 
SNV 
3 
p.Y27S 
PTEN 
COSM5042 
SNV 
3 
p.H61R 
PTEN 
COSM5036 
SNV 
3 
p.Y68H 
PTEN 
COSM5102 
SNV 
3 
p.C71Y 
PTEN 
COSM5266 
SNV 
3 
p.C105F 
PTEN 
COSM5212 
SNV 
3 
p.D107Y 
PTEN 
COSM5106 
SNV 
3 
p.L112P 
PTEN 
MCH15 
SNV 
3 
p.L112R 
PTEN 
COSM5214 
SNV 
3 
p.A121P 
PTEN 
COSM921089 
SNV 
3 
p.C124R 
PTEN 
COSM5224 
SNV 
3 
p.C124S 
PTEN 
COSM5219 
SNV 
3 
p.R130G 
PTEN 
COSM5033 
SNV 
3 
p.R130Q 
PTEN 
COSM5216 
SNV 
3 
p.R130L 
PTEN 
COSM5044 
SNV 
3 
p.V133I 
PTEN 
COSM12734 
SNV 
3 
p.C136Y 
PTEN 
COSM5091 
SNV 
3 
p.G165R 
PTEN 
COSM5045 
SNV 
3 
p.S170N 
PTEN 
COSM5089 
SNV 
3 
p.R173C 
PTEN 
COSM5039 
SNV 
3 
p.R173H 
PTEN 
MCH16 
SNV 
3 
p.R173P 
PTEN 
COSM5221 
SNV 
3 
p.Y174N 
PTEN 
COSM5220 
SNV 
3 
p.G251C 

ECOG-ACRIN 
EAY131-Z1H 
Cancer Research Group 
Version Date: August 19, 2020 
39 
Gene Name 
Variant ID 
Variant Type 
Level of 
Evidence Code 
Variant 
Description 
PTEN 
COSM5255 
SNV 
3 
p.F341V 
PTEN 
COSM5213 
SNV 
3 
p.L345Q 
PTEN 
MCH21 
SNV 
3 
p.S170R 
PTEN 
MCH22 
SNV 
3 
p.S170R 
 
 

ECOG-ACRIN 
EAY131-Z1H 
Cancer Research Group 
Version Date: August 19, 2020 
40 
Exclusion Variants 
Gene Name 
Variant ID 
Variant Type 
Variant 
Description 
Level of 
Evidence 
Code 
NRAS 
COSM585 
SNV 
p.Q61H 
2 
NRAS 
COSM586 
SNV 
p.Q61H 
2 
NRAS 
COSM583 
SNV 
p.Q61L 
2 
NRAS 
COSM584 
SNV 
p.Q61R 
2 
NRAS 
COSM582 
SNV 
p.Q61P 
2 
NRAS 
COSM581 
SNV 
p.Q61E 
2 
NRAS 
COSM580 
SNV 
p.Q61K 
2 
NRAS 
COSM574 
SNV 
p.G13V 
2 
NRAS 
COSM575 
SNV 
p.G13A 
2 
NRAS 
COSM573 
SNV 
p.G13D 
2 
NRAS 
COSM570 
SNV 
p.G13C 
2 
NRAS 
COSM569 
SNV 
p.G13R 
2 
NRAS 
COSM571 
SNV 
p.G13S 
2 
NRAS 
COSM566 
SNV 
p.G12V 
2 
NRAS 
COSM565 
SNV 
p.G12A 
2 
NRAS 
COSM564 
SNV 
p.G12D 
2 
NRAS 
COSM562 
SNV 
p.G12C 
2 
NRAS 
COSM561 
SNV 
p.G12R 
2 
NRAS 
COSM563 
SNV 
p.G12S 
2 
HRAS 
COSM502 
SNV 
p.Q61H 
2 
HRAS 
COSM503 
SNV 
p.Q61H 
2 
HRAS 
COSM498 
SNV 
p.Q61L 
2 
HRAS 
COSM499 
SNV 
p.Q61R 
2 
HRAS 
COSM500 
SNV 
p.Q61P 
2 
HRAS 
COSM497 
SNV 
p.Q61E 
2 
HRAS 
COSM496 
SNV 
p.Q61K 
2 
HRAS 
COSM489 
SNV 
p.G13V 
2 
HRAS 
COSM490 
SNV 
p.G13D 
2 
HRAS 
COSM488 
SNV 
p.G13C 
2 
HRAS 
COSM486 
SNV 
p.G13R 
2 
HRAS 
COSM487 
SNV 
p.G13S 
2 
HRAS 
COSM483 
SNV 
p.G12V 
2 
HRAS 
COSM485 
SNV 
p.G12A 
2 

ECOG-ACRIN 
EAY131-Z1H 
Cancer Research Group 
Version Date: August 19, 2020 
41 
Exclusion Variants 
Gene Name 
Variant ID 
Variant Type 
Variant 
Description 
Level of 
Evidence 
Code 
HRAS 
COSM484 
SNV 
p.G12D 
2 
HRAS 
COSM481 
SNV 
p.G12C 
2 
HRAS 
COSM482 
SNV 
p.G12R 
2 
HRAS 
COSM480 
SNV 
p.G12S 
2 
KRAS 
COSM555 
SNV 
p.Q61H 
2 
KRAS 
COSM554 
SNV 
p.Q61H 
2 
KRAS 
COSM553 
SNV 
p.Q61L 
2 
KRAS 
COSM552 
SNV 
p.Q61R 
2 
KRAS 
COSM551 
SNV 
p.Q61P 
2 
KRAS 
COSM550 
SNV 
p.Q61E 
2 
KRAS 
COSM549 
SNV 
p.Q61K 
2 
KRAS 
COSM539 
SNV 
p.G15D 
2 
KRAS 
COSM538 
SNV 
p.G15S 
2 
KRAS 
COSM30567 
SNV 
p.G13E 
2 
KRAS 
COSM87280 
SNV 
p.G13E 
2 
KRAS 
COSM534 
SNV 
p.G13V 
2 
KRAS 
COSM533 
SNV 
p.G13A 
2 
KRAS 
COSM532 
SNV 
p.G13D 
2 
KRAS 
COSM527 
SNV 
p.G13C 
2 
KRAS 
COSM529 
SNV 
p.G13R 
2 
KRAS 
COSM528 
SNV 
p.G13S 
2 
KRAS 
COSM512 
SNV 
p.G12F 
2 
KRAS 
COSM514 
SNV 
p.G12L 
2 
KRAS 
COSM13643 
SNV 
p.G12N 
2 
KRAS 
COSM520 
SNV 
p.G12V 
2 
KRAS 
COSM522 
SNV 
p.G12A 
2 
KRAS 
COSM521 
SNV 
p.G12D 
2 
KRAS 
COSM516 
SNV 
p.G12C 
2 
KRAS 
COSM518 
SNV 
p.G12R 
2 
KRAS 
COSM517 
SNV 
p.G12S 
2 
KRAS 
COSM19404 
SNV 
p. A146T 
3 
BRAF 
COSM1127 
SNV 
p.V600R 
2 
BRAF 
COSM1583011 
SNV 
p.V600R 
2 

ECOG-ACRIN 
EAY131-Z1H 
Cancer Research Group 
Version Date: August 19, 2020 
42 
Exclusion Variants 
Gene Name 
Variant ID 
Variant Type 
Variant 
Description 
Level of 
Evidence 
Code 
BRAF 
COSM308550 
SNV 
p.V600D 
2 
BRAF 
COSM473 
SNV 
p.V600K 
1 
BRAF 
COSM474 
SNV 
p.V600R 
2 
BRAF 
COSM476 
SNV 
p.V600E 
1 
BRAF 
COSM477 
SNV 
p.V600D 
2 
BRAF 
AGTRAP-
BRAF.A5B8.COSF828 
Fusion 
AGTRAP-
BRAF.A5B8.C
OSF828 
3 
BRAF 
AKAP9-
BRAF.A8B9.COSF1013 
Fusion 
AKAP9-
BRAF.A8B9.C
OSF1013 
3 
BRAF 
CDC27-BRAF.C16B9 
Fusion 
CDC27-
BRAF.C16B9 
3 
BRAF 
FAM131B-
BRAF.F2B9.COSF1189 
Fusion 
FAM131B-
BRAF.F2B9.C
OSF1189 
3 
BRAF 
FCHSD1-
BRAF.F13B9.COSF404 
Fusion 
FCHSD1-
BRAF.F13B9.
COSF404 
3 
BRAF 
KIAA1549-
BRAF.K16B11 
Fusion 
KIAA1549-
BRAF.K16B11 
3 
BRAF 
KIAA1549-BRAF.K16B9 
Fusion 
KIAA1549-
BRAF.K16B9 
3 
BRAF 
KIAA1549-
BRAF.K17B10.COSF50
9 
Fusion 
KIAA1549-
BRAF.K17B10
.COSF509 
3 
BRAF 
KIAA1549-
BRAF.K18B10 
Fusion 
KIAA1549-
BRAF.K18B10 
3 
BRAF 
KIAA1549-BRAF.K19B9 
Fusion 
KIAA1549-
BRAF.K19B9 
3 
BRAF 
PAPSS1-BRAF.P5B9 
Fusion 
PAPSS1-
BRAF.P5B9 
3 
BRAF 
SLC45A3-
BRAF.S1B8.COSF871 
Fusion 
SLC45A3-
BRAF.S1B8.C
OSF871 
3 
BRAF 
SND1-BRAF.S16B9 
Fusion 
SND1-
BRAF.S16B9 
3 
BRAF 
TAX1BP1-BRAF.T8B11 
Fusion 
TAX1BP1-
BRAF.T8B11 
3 

ECOG-ACRIN 
EAY131-Z1H 
Cancer Research Group 
Version Date: August 19, 2020 
43 
Exclusion Variants 
Gene Name 
Variant ID 
Variant Type 
Variant 
Description 
Level of 
Evidence 
Code 
BRAF 
TRIM24-BRAF.T9B9 
Fusion 
TRIM24-
BRAF.T9B9 
3 
BRAF 
AGAP3-BRAF.A10B11 
Fusion 
AGAP3-
BRAF.A10B11 
3 
BRAF 
AGAP3-BRAF.A9B9 
Fusion 
AGAP3-
BRAF.A9B9 
3 
BRAF 
AGK-BRAF.A2B8 
Fusion 
AGK-
BRAF.A2B8 
3 
BRAF 
AGTRAP-
BRAF.A5B8.COSF828.1 
Fusion 
AGTRAP-
BRAF.A5B8.C
OSF828.1 
3 
BRAF 
AKAP9-BRAF.A21B10 
Fusion 
AKAP9-
BRAF.A21B10 
3 
BRAF 
AKAP9-BRAF.A22B9 
Fusion 
AKAP9-
BRAF.A22B9 
3 
BRAF 
AKAP9-BRAF.A28B9 
Fusion 
AKAP9-
BRAF.A28B9 
3 
BRAF 
AKAP9-BRAF.A7B11 
Fusion 
AKAP9-
BRAF.A7B11 
3 
BRAF 
AKAP9-
BRAF.A8B9.COSF1013.
1 
Fusion 
AKAP9-
BRAF.A8B9.C
OSF1013.1 
3 
BRAF 
AP3B1-BRAF.A22B9 
Fusion 
AP3B1-
BRAF.A22B9 
3 
BRAF 
ARMC10-BRAF.A4B11 
Fusion 
ARMC10-
BRAF.A4B11 
3 
BRAF 
ATG7-BRAF.A18B9 
Fusion 
ATG7-
BRAF.A18B9 
3 
BRAF 
BAIAP2L1-BRAF.B12B9 
Fusion 
BAIAP2L1-
BRAF.B12B9 
3 
BRAF 
BBS9-BRAF.B19B4 
Fusion 
BBS9-
BRAF.B19B4 
3 
BRAF 
BCL2L11-BRAF.B3B10 
Fusion 
BCL2L11-
BRAF.B3B10 
3 
BRAF 
BRAF-AP3B1.B8A23 
Fusion 
BRAF-
AP3B1.B8A23 
3 
BRAF 
BRAF-CIITA.B9C6 
Fusion 
BRAF-
CIITA.B9C6 
3 
BRAF 
BRAF-MACF1.B8M15 
Fusion 
BRAF-
MACF1.B8M1
5 
3 

ECOG-ACRIN 
EAY131-Z1H 
Cancer Research Group 
Version Date: August 19, 2020 
44 
Exclusion Variants 
Gene Name 
Variant ID 
Variant Type 
Variant 
Description 
Level of 
Evidence 
Code 
BRAF 
BRAF-MRPS33.B1M2 
Fusion 
BRAF-
MRPS33.B1M
2 
3 
BRAF 
BRAF-SLC26A4.B3S7 
Fusion 
BRAF-
SLC26A4.B3S
7 
3 
BRAF 
BRAF-SUGCT.B1S13 
Fusion 
BRAF-
SUGCT.B1S1
3 
3 
BRAF 
BTF3L4-BRAF.B3B11 
Fusion 
BTF3L4-
BRAF.B3B11 
3 
BRAF 
C7orf73-BRAF.C2B9 
Fusion 
C7orf73-
BRAF.C2B9 
3 
BRAF 
CCDC6-BRAF.C1B9 
Fusion 
CCDC6-
BRAF.C1B9 
3 
BRAF 
CCDC91-BRAF.C11B9 
Fusion 
CCDC91-
BRAF.C11B9 
3 
BRAF 
CCNY-BRAF.C1B10 
Fusion 
CCNY-
BRAF.C1B10 
3 
BRAF 
CDC27-BRAF.C16B9.1 
Fusion 
CDC27-
BRAF.C16B9.
1 
3 
BRAF 
CEP89-BRAF.C16B9 
Fusion 
CEP89-
BRAF.C16B9 
3 
BRAF 
CLCN6-
BRAF.C2B11.COSF144
0 
Fusion 
CLCN6-
BRAF.C2B11.
COSF1440 
3 
BRAF 
CLIP2-BRAF.C6B11 
Fusion 
CLIP2-
BRAF.C6B11 
3 
BRAF 
CUL1-BRAF.C7B9 
Fusion 
CUL1-
BRAF.C7B9 
3 
BRAF 
CUX1-BRAF.C10B9 
Fusion 
CUX1-
BRAF.C10B9 
3 
BRAF 
DYNC1I2-BRAF.D7B10 
Fusion 
DYNC1I2-
BRAF.D7B10 
3 
BRAF 
EML4-BRAF.E6B10 
Fusion 
EML4-
BRAF.E6B10 
3 
BRAF 
EPS15-BRAF.E22B10 
Fusion 
EPS15-
BRAF.E22B10 
3 
BRAF 
ERC1-BRAF.E12B10 
Fusion 
ERC1-
BRAF.E12B10 
3 

ECOG-ACRIN 
EAY131-Z1H 
Cancer Research Group 
Version Date: August 19, 2020 
45 
Exclusion Variants 
Gene Name 
Variant ID 
Variant Type 
Variant 
Description 
Level of 
Evidence 
Code 
BRAF 
ERC1-BRAF.E17B8 
Fusion 
ERC1-
BRAF.E17B8 
3 
BRAF 
FAM114A2-
BRAF.F9B11 
Fusion 
FAM114A2-
BRAF.F9B11 
3 
BRAF 
FAM131B-
BRAF.F1B10.COSF119
1 
Fusion 
FAM131B-
BRAF.F1B10.
COSF1191 
3 
BRAF 
FAM131B-
BRAF.F2B9.COSF1189.
1 
Fusion 
FAM131B-
BRAF.F2B9.C
OSF1189.1 
3 
BRAF 
FAM131B-
BRAF.F3B9.COSF1193 
Fusion 
FAM131B-
BRAF.F3B9.C
OSF1193 
3 
BRAF 
FCHSD1-
BRAF.F13B9.COSF403 
Fusion 
FCHSD1-
BRAF.F13B9.
COSF403 
3 
BRAF 
FXR1-BRAF.F13B10 
Fusion 
FXR1-
BRAF.F13B10 
3 
BRAF 
GATM-BRAF.G2B11 
Fusion 
GATM-
BRAF.G2B11 
3 
BRAF 
GHR-BRAF.G1B10 
Fusion 
GHR-
BRAF.G1B10 
3 
BRAF 
GNAI1-
BRAF.G1B10.COSF144
2 
Fusion 
GNAI1-
BRAF.G1B10.
COSF1442 
3 
BRAF 
GTF2I-BRAF.G4B10 
Fusion 
GTF2I-
BRAF.G4B10 
3 
BRAF 
HERPUD1-BRAF.H4B7 
Fusion 
HERPUD1-
BRAF.H4B7 
3 
BRAF 
KCTD7-BRAF.K3B8 
Fusion 
KCTD7-
BRAF.K3B8 
3 
BRAF 
KCTD7-BRAF.K4B8 
Fusion 
KCTD7-
BRAF.K4B8 
3 
BRAF 
KDM7A-BRAF.K11B11 
Fusion 
KDM7A-
BRAF.K11B11 
3 
BRAF 
KIAA1549-
BRAF.K12B11 
Fusion 
KIAA1549-
BRAF.K12B11 
3 
BRAF 
KIAA1549-
BRAF.K12B9.COSF147
4 
Fusion 
KIAA1549-
BRAF.K12B9.
COSF1474 
3 

ECOG-ACRIN 
EAY131-Z1H 
Cancer Research Group 
Version Date: August 19, 2020 
46 
Exclusion Variants 
Gene Name 
Variant ID 
Variant Type 
Variant 
Description 
Level of 
Evidence 
Code 
BRAF 
KIAA1549-BRAF.K13B9 
Fusion 
KIAA1549-
BRAF.K13B9 
3 
BRAF 
KIAA1549-
BRAF.K14B11.COSF12
26 
Fusion 
KIAA1549-
BRAF.K14B11
.COSF1226 
3 
BRAF 
KIAA1549-
BRAF.K14B9.COSF483 
Fusion 
KIAA1549-
BRAF.K14B9.
COSF483 
3 
BRAF 
KIAA1549-
BRAF.K15B10.COSF12
83.1 
Fusion 
KIAA1549-
BRAF.K15B10
.COSF1283.1 
3 
BRAF 
KIAA1549-
BRAF.K15B11.COSF48
5.1 
Fusion 
KIAA1549-
BRAF.K15B11
.COSF485.1 
3 
BRAF 
KIAA1549-
BRAF.K15B9.COSF481.
1 
Fusion 
KIAA1549-
BRAF.K15B9.
COSF481.1 
3 
BRAF 
KIAA1549-
BRAF.K16B10 
Fusion 
KIAA1549-
BRAF.K16B10 
3 
BRAF 
KIAA1549-
BRAF.K17B10.COSF50
9 
Fusion 
KIAA1549-
BRAF.K17B10
.COSF509 
3 
BRAF 
KIAA1549-
BRAF.K18B9.COSF511 
Fusion 
KIAA1549-
BRAF.K18B9.
COSF511 
3 
BRAF 
KIAA1549-BRAF.K9B9 
Fusion 
KIAA1549-
BRAF.K9B9 
3 
BRAF 
KLHL7-BRAF.K5B9 
Fusion 
KLHL7-
BRAF.K5B9 
3 
BRAF 
LSM12-BRAF.L3B9 
Fusion 
LSM12-
BRAF.L3B9 
3 
BRAF 
LSM14A-BRAF.L9B9 
Fusion 
LSM14A-
BRAF.L9B9 
3 
BRAF 
MACF1-BRAF.M60B9 
Fusion 
MACF1-
BRAF.M60B9 
3 
BRAF 
MAD1L1-BRAF.M16B9 
Fusion 
MAD1L1-
BRAF.M16B9 
3 
BRAF 
MAD1L1-BRAF.M17B10 
Fusion 
MAD1L1-
BRAF.M17B1
0 
3 

ECOG-ACRIN 
EAY131-Z1H 
Cancer Research Group 
Version Date: August 19, 2020 
47 
Exclusion Variants 
Gene Name 
Variant ID 
Variant Type 
Variant 
Description 
Level of 
Evidence 
Code 
BRAF 
MKRN1-
BRAF.M4B11.COSF144
4 
Fusion 
MKRN1-
BRAF.M4B11.
COSF1444 
3 
BRAF 
MKRN1-BRAF.M4B9 
Fusion 
MKRN1-
BRAF.M4B9 
3 
BRAF 
MYRIP-BRAF.M16B9 
Fusion 
MYRIP-
BRAF.M16B9 
3 
BRAF 
MZT1-BRAF.M2B11 
Fusion 
MZT1-
BRAF.M2B11 
3 
BRAF 
NUB1-BRAF.N3B9 
Fusion 
NUB1-
BRAF.N3B9 
3 
BRAF 
NUDCD3-BRAF.N4B9 
Fusion 
NUDCD3-
BRAF.N4B9 
3 
BRAF 
NUP214-BRAF.N21B10 
Fusion 
NUP214-
BRAF.N21B10 
3 
BRAF 
PAPSS1-BRAF.P5B9.1 
Fusion 
PAPSS1-
BRAF.P5B9.1 
3 
BRAF 
PLIN3-BRAF.P1B9 
Fusion 
PLIN3-
BRAF.P1B9 
3 
BRAF 
RAD18-BRAF.R7B10 
Fusion 
RAD18-
BRAF.R7B10 
3 
BRAF 
RBMS3-BRAF.R11B11 
Fusion 
RBMS3-
BRAF.R11B11 
3 
BRAF 
RNF11-BRAF.R1B11 
Fusion 
RNF11-
BRAF.R1B11 
3 
BRAF 
RNF130-
BRAF.R3B9.COSF1483 
Fusion 
RNF130-
BRAF.R3B9.C
OSF1483 
3 
BRAF 
RP2-BRAF.R3B10 
Fusion 
RP2-
BRAF.R3B10 
3 
BRAF 
SLC12A7-
BRAF.S17B11 
Fusion 
SLC12A7-
BRAF.S17B11 
3 
BRAF 
SLC45A3-
BRAF.S1B8.COSF871 
Fusion 
SLC45A3-
BRAF.S1B8.C
OSF871 
3 
BRAF 
SND1-BRAF.S10B11 
Fusion 
SND1-
BRAF.S10B11 
3 
BRAF 
SND1-BRAF.S10B9 
Fusion 
SND1-
BRAF.S10B9 
3 
BRAF 
SND1-BRAF.S11B11 
Fusion 
SND1-
BRAF.S11B11 
3 

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Version Date: August 19, 2020 
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Exclusion Variants 
Gene Name 
Variant ID 
Variant Type 
Variant 
Description 
Level of 
Evidence 
Code 
BRAF 
SND1-BRAF.S14B11 
Fusion 
SND1-
BRAF.S14B11 
3 
BRAF 
SND1-BRAF.S14B9 
Fusion 
SND1-
BRAF.S14B9 
3 
BRAF 
SND1-BRAF.S16B9.1 
Fusion 
SND1-
BRAF.S16B9.
1 
3 
BRAF 
SND1-BRAF.S18B10 
Fusion 
SND1-
BRAF.S18B10 
3 
BRAF 
SND1-BRAF.S9B2 
Fusion 
SND1-
BRAF.S9B2 
3 
BRAF 
SND1-BRAF.S9B9 
Fusion 
SND1-
BRAF.S9B9 
3 
BRAF 
SOX6-BRAF.S5B9 
Fusion 
SOX6-
BRAF.S5B9 
3 
BRAF 
SOX6-BRAF.S6B9 
Fusion 
SOX6-
BRAF.S6B9 
3 
BRAF 
STRN3-BRAF.S3B10 
Fusion 
STRN3-
BRAF.S3B10 
3 
BRAF 
TANK-BRAF.T4B9 
Fusion 
TANK-
BRAF.T4B9 
3 
BRAF 
TAX1BP1-
BRAF.T8B11.1 
Fusion 
TAX1BP1-
BRAF.T8B11.
1 
3 
BRAF 
TMEM178B-BRAF.T2B9 
Fusion 
TMEM178B-
BRAF.T2B9 
3 
BRAF 
TMPRSS2-BRAF.T3B11 
Fusion 
TMPRSS2-
BRAF.T3B11 
3 
BRAF 
TRIM24-BRAF.T10B9 
Fusion 
TRIM24-
BRAF.T10B9 
3 
BRAF 
TRIM24-BRAF.T11B2 
Fusion 
TRIM24-
BRAF.T11B2 
3 
BRAF 
TRIM24-BRAF.T3B10 
Fusion 
TRIM24-
BRAF.T3B10 
3 
BRAF 
TRIM24-BRAF.T3B11 
Fusion 
TRIM24-
BRAF.T3B11 
3 
BRAF 
TRIM24-BRAF.T5B8 
Fusion 
TRIM24-
BRAF.T5B8 
3 
BRAF 
TRIM24-BRAF.T9B9.1 
Fusion 
TRIM24-
BRAF.T9B9.1 
3 

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Version Date: August 19, 2020 
49 
Exclusion Variants 
Gene Name 
Variant ID 
Variant Type 
Variant 
Description 
Level of 
Evidence 
Code 
BRAF 
TRIM4-BRAF.T6B10 
Fusion 
TRIM4-
BRAF.T6B10 
3 
BRAF 
UBN2-BRAF.U3B11 
Fusion 
UBN2-
BRAF.U3B11 
3 
BRAF 
ZC3HAV1-BRAF.Z3B10 
Fusion 
ZC3HAV1-
BRAF.Z3B10 
3 
BRAF 
ZC3HAV1-BRAF.Z7B11 
Fusion 
ZC3HAV1-
BRAF.Z7B11 
3 
BRAF 
ZKSCAN5-BRAF.Z2B9 
Fusion 
ZKSCAN5-
BRAF.Z2B9 
3 
BRAF 
ZSCAN30-BRAF.Z3B10 
Fusion 
ZSCAN30-
BRAF.Z3B10 
3 
BRAF 
AGAP3-BRAF.A10B11 
Fusion 
AGAP3-
BRAF.A10B11 
3 
BRAF 
AGAP3-BRAF.A9B9 
Fusion 
AGAP3-
BRAF.A9B9 
3 
BRAF 
COSM1125 
SNV 
L597Q 
3 
BRAF 
COSM1126 
SNV 
L597S 
3 
BRAF 
COSM21612 
SNV 
F595L 
3 
BRAF 
COSM449 
SNV 
G464E 
3 
BRAF 
COSM451 
SNV 
G466V 
3 
BRAF 
COSM450 
SNV 
G464V 
3 
BRAF 
COSM459 
SNV 
G469V 
3 
BRAF 
COSM460 
SNV 
G469A 
3 
BRAF 
COSM461 
SNV 
G469E 
3 
BRAF 
COSM462 
SNV 
N581S 
3 
BRAF 
COSM466 
SNV 
D594V 
3 
BRAF 
COSM467 
SNV 
D594G 
3 
BRAF 
COSM470 
SNV 
L597V 
3 
BRAF 
COSM471 
SNV 
L597R 
3 
BRAF 
COSM472 
SNV 
T599I 
3 
BRAF 
COSM478 
SNV 
K601E 
3 
PIK3CA 
COSM746 
SNV 
p.R88Q 
2 
PIK3CA 
COSM754 
SNV 
p.N345K 
2 
PIK3CA 
COSM757 
SNV 
p.C420R 
3 
PIK3CA 
COSM759 
SNV 
p.P539R 
3 

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Cancer Research Group 
Version Date: August 19, 2020 
50 
Exclusion Variants 
Gene Name 
Variant ID 
Variant Type 
Variant 
Description 
Level of 
Evidence 
Code 
PIK3CA 
COSM760 
SNV 
p.E542K 
3 
PIK3CA 
COSM763 
SNV 
p.E545K 
3 
PIK3CA 
COSM764 
SNV 
p.E545G 
3 
PIK3CA 
COSM765 
SNV 
p.E545D 
2 
PIK3CA 
COSM767 
SNV 
p.Q546P 
3 
PIK3CA 
COSM775 
SNV 
p.H1047R 
2 
PIK3CA 
COSM776 
SNV 
p.H1047L 
3 
PIK3CA 
PIK3CA 
CNV 
PIK3CA 
amplification 
3 
PIK3CA 
COSM12458 
SNV 
p.E545A 
3 
PIK3CA 
COSM766 
SNV 
p.Q546K 
3 
PIK3CA 
COSM12590 
SNV 
p.T1025S 
3 
PIK3CA 
COSM12591 
SNV 
p.M1043V 
3 
PIK3CA 
COSM29313 
SNV 
p.M1043I 
3 
PIK3CA 
COSM94984 
SNV 
p.M1043I 
3 
PIK3CA 
COSM773 
SNV 
p.M1043I 
3 
PIK3CA 
COSM774 
SNV 
p.H1047Y 
3 
PIK3R1 
COSM85926 
SNV 
p.R348* 
3 
AKT1 
COSM33765 
SNV 
p.E17K 
3 
MTOR 
COSM1686998 
SNV 
p.S2215F 
3 
MTOR 
COSM20417 
SNV 
p.S2215Y 
3 
MTOR 
COSM462604 
SNV 
p.F1888L 
3 
MTOR 
COSM893813 
SNV 
p.F1888L 
3 
MTOR 
OM5 
SNV 
p.F1888L 
3 
MTOR 
OM7 
SNV 
p.F1888I 
3 
MTOR 
COSM180789 
SNV 
p.E1799K 
3 
MTOR 
OM9 
SNV 
p.C1483W 
3 
MTOR 
COSM462616 
SNV 
p.C1483F 
3 
MTOR 
COSM462615 
SNV 
p.C1483Y 
3 
MTOR 
OM12 
SNV 
p.C1483R 
3 
MTOR 
COSM180789 
SNV 
p.E1799K 
3 
MTOR 
COSM414183 
SNV 
p.L2209V 
3 
MTOR 
COSM462592 
SNV 
p.A2210P 
3 

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Version Date: August 19, 2020 
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Exclusion Variants 
Gene Name 
Variant ID 
Variant Type 
Variant 
Description 
Level of 
Evidence 
Code 
MTOR 
COSM462618 
SNV 
p.L1460P 
3 
MTOR 
COSM462619 
SNV 
p.A1459P 
3 
MTOR 
COSM527403 
SNV 
p.N2206S 
3 
MTOR 
COSM1560108 
SNV 
p.S2215P 
3 
MTOR 
COSM3965698 
SNV 
p.L2216P 
3 
MTOR 
MCH4 
SNV 
p.R2217W 
3 

ECOG-ACRIN 
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Version Date: August 19, 2020 
52 
Molecular Analysis for Therapy Choice (MATCH) 
MATCH Treatment Subprotocol Z1H: Copanlisib, PTEN Expression 
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. 
x 
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.  
x 
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. 
x 
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.  
x 
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.   

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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: 
¾ Tell your doctors if you stop taking any medicines or if 
you start taking any new medicines. 
¾ Tell all of your health care providers (doctors, physician 
assistants, nurse practitioners, or pharmacists) that you are 
taking part in a clinical trial. 
¾ 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.  
¾ 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. 
¾ 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.   
¾ Your study doctor’s name is _____________________________ 
and can be contacted at 
_________________________________.  

ECOG-ACRIN 
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Version Date: August 19, 2020 
54 
Molecular Analysis for Therapy Choice (MATCH) 
MATCH Treatment Subprotocol Z1H: Copanlisib, PTEN Expression 
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 
 
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ECOG-ACRIN 
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Version Date: August 19, 2020 
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Molecular Analysis for Therapy Choice (MATCH) 
MATCH Treatment Subprotocol Z1H: Copanlisib, PTEN Expression 
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 <150/90 mmHg 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 <150/90 mmHg. 
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. 
 
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