A Phase I/II Trial Evaluating the Safety and Efficacy of Eribulin in Combination With Copanlisib in Patients With Metastatic Triple Negative Breast Cancer
Phase: PHASE1
Conditions: Anatomic Stage III Breast Cancer AJCC v8, Anatomic Stage IV Breast Cancer AJCC v8, Metastatic Triple-Negative Breast Carcinoma, Unresectable Triple-Negative Breast Carcinoma
Sponsor: National Cancer Institute (NCI)

NCI Protocol #:10382 
Version Date: March 18, 2025 
 
i 
To:  
CTEP Protocol and Information Office  
From: 
Nusayba Bagegni, M.D. 
Date:  
March 18, 2025 
Re: 
A Phase I/II Trial Evaluating the Safety and Efficacy of Eribulin in Combination 
with Copanlisib in Patients with Metastatic Triple Negative Breast Cancer 
 
# 
Section 
Changes 
1. Title Page 
Added A5 dated March 18, 2025. 
2. Running 
header 
Updated Version date to March 18, 2025 
3. Table of 
Contents 
Updated pagination. 
4. Section 1.2 and 
1.3 
Moved secondary objectives #2 through #7 down to exploratory. Due to the 
early study closure, the sample size for these objectives is too small for 
statistical analysis but the correlative analyses are ongoing. 
5. Section 9.1 
Moved secondary endpoints #2 through #7 down to exploratory. Due to the 
early study closure, the sample size for these objectives is too small for 
statistical analysis but the correlative analyses are ongoing. 
6. Section 9.1.2 
Clarified how the primary endpoint in phase II will be analyzed due to the 
small sample size resulting from early study closure. 
Updated gender to sex. 
7. Section 9.4 and 
9.5 
Moved the analyses for secondary endpoints #2 through #7 down to 
exploratory. 
Corrected a typographical error by adding the definition of CBR. 
 
 
 
 
 

NCI Protocol #:10382 
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1 
 
 
 
 
NCI Protocol #: 
10382 
 
Local Protocol #: 
202010089 
 
ClinicalTrials.gov Identifier:   NCT04345913 
 
TITLE:  A Phase I/II Trial Evaluating the Safety and Efficacy of Eribulin in Combination with 
Copanlisib in Patients with Metastatic Triple Negative Breast Cancer 
 
Corresponding Organization: LAO-CT018 / Yale University Cancer Center LAO    
 
Principal Investigator: 
Nusayba Bagegni, M.D.
Washington University School of Medicine  
600 S. Euclid Ave. 
Campus Box 8056 
St. Louis, MO 63110 
Phone: 314-362-5654 
Fax: 314-362-7086 
nbagegni@wustl.edu 
 
Translational PI: 
Cynthia X. Ma, M.D., Ph.D. 
Washington University School of Medicine  
660 S. Euclid Ave. 
Campus Box 8076 
St. Louis, MO 63110 
Phone: 314-362-9383 
Fax:  314-362-7086 
cynthiaxma@wustl.edu 
 
Phase 1 Participating Organization 
LAO-CT018 / Yale University Cancer Center LAO 
LAO-MD017 / JHU Sidney Kimmel Comprehensive Cancer Center LAO 
            RESTRICTED TO: GA005 Emory University Hospital / Winship Cancer Institute 
 
Phase 2 Participating Organizations  
LAO-11030 / University Health Network Princess Margaret Cancer Center LAO 
LAO-CA043 / City of Hope Comprehensive Cancer Center LAO 
LAO-CT018 / Yale University Cancer Center LAO 
LAO-MA036 / Dana-Farber - Harvard Cancer Center LAO 

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LAO-MD017 / JHU Sidney Kimmel Comprehensive Cancer Center LAO 
LAO-OH007 / Ohio State University Comprehensive Cancer Center LAO 
LAO-PA015 / UPMC Hillman Cancer Center LAO 
LAO-TX035 / University of Texas MD Anderson Cancer Center LAO 
LAO-NCI / National Cancer Institute LAO 
 
 
 
Statistician: 
 
 
Jingqin (Rosy) Luo, Ph.D. 
 
 
Washington University School of Medicine 
 
 
 
 
 
Suite 2421E, Div. of Public Health Science 
 
 
 
 
 
 
Department of Surgery 
 
 
 
 
 
 
 
600 South Taylor Ave. 
 
 
Saint Louis, MO 63110 
 
 
 
 
 
 
 
Telephone: 314-362-3718 
 
 
 
 
 
 
 
Fax:  314-747-3936 
 
 
 
 
 
 
Email: jingqinluo@wustl.edu 
 
Study Coordinator: 
 
 
 
Leslie Nehring 
 
 
Washington University School of Medicine 
 
 
Telephone:  314-362-9679  
 
 
Fax:  314-362-0206 
 
 
Email:  lnehring@wustl.edu 
 
 
 
 
Responsible Data Coordinator: 
 
 
Jessica Porzel, BS, CCRP 
 
Washington University School of Medicine 
 
4921 Parkview Place 
 
Telephone: 314-362-8246 
 
Fax: 314-747-9211 
 
Email: jporzel@wustl.edu  
 
Co-investigators: 
Yiling Lu, M.D. 
 
 
Wei-Lien Wang, Ph.D. 
MD Anderson Cancer Center RPPA Core                 Clinical Immunohistochemistry Laboratory 
Email:  yilinglu@mdanderson.org 
MD Anderson Cancer Center 
 
 
Telephone:  713-792-4240 
 
 
Email:  wlwang@mdanderson.org  
Gerburg Wulf, M.D., Ph.D. 
Beth Israel Deaconess Medical Center 
Harvard Medical School 
Telephone:  617-667-1910 
Email:  gwulf@bidmc.harvard.edu 
 

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NCI-Supplied Agent:  Copanlisib ([BAY 80-6946 dihydrochloride] NSC 784727) 
Other Agent(s):  Eribulin mesylate (NSC 707389, Commercial) 
 
IND #:  
 
IND Sponsor:  DCTD, NCI   
 
 
Protocol Type / Version # / Version Date: 
 
Original / November 27, 2019 
 
 
 
 
 
Revision 1 / February 3, 2020 
 
 
 
 
 
Revision 2 / March 12, 2020 
 
 
 
 
 
Revision 3a / May 6, 2020 
 
 
 
 
 
Revision 4 / May 27, 2020 
 
 
 
 
 
Revision 5 / July 9, 2020 
 
 
 
 
 
Amendment 1 / March 12, 2021 
 
 
 
 
 
Amendment 2 / September 21, 2022 
 
 
 
 
 
Amendment 3 / April 26, 2023 
 
 
 
 
 
Amendment 4 / October 18, 2023 (disapproved) 
 
 
 
 
 
Amendment 4a / July 17, 2024 (disapproved) 
 
 
 
 
 
Amendment 4b / October 5, 2024 
 
 
 
 
 
Amendment 5 / March 18, 2025 
 
 
 
 
 

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SCHEMA 
 
Phase 1: 
 
 
 
Dose Escalation Schedule 
Dose Level 
Dose 
Copanlisib 
Eribulin** 
Schedule*** 
Cycle Length 
Level -1 
45 mg IV 
1.1 mg/m2 IV 
Days 1 and 15 
28 days 
Level 1* 
45 mg IV 
1.1 mg/m2 IV 
Days 1 and 8 
21 days 
Level 2 
45 mg IV 
1.4 mg/m2 IV 
Days 1 and 8 
21 days 
Level 3 
60 mg IV 
1.4 mg/m2 IV 
Days 1 and 8 
21 days 
*Starting Dose Level 
** Eribulin doses are based on actual body weight. Baseline weight on cycle 1, day 1 should 
be used for eribulin dosing. Weight must be obtained on each day of treatment. Dose 
recalculation must occur only if weight changes greater than or equal to 10% from baseline 
weight.***Treatment window +/- 2 days.  Ensure minimum of 7 days between any two 
consecutive infusions. 
 
 
 

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Phase 2: 

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TABLE OF CONTENTS 
 
 
 
SCHEMA 
......................................................................................................................4 
1. 
OBJECTIVES ....................................................................................................................10 
1.1 
Primary Objectives .................................................................................................10 
1.2 
Secondary Objectives .............................................................................................10 
1.3 
Exploratory Objectives ..........................................................................................10 
2. 
BACKGROUND ...............................................................................................................11 
2.1 
Study Disease .........................................................................................................11 
2.2 
CTEP IND Agent ...................................................................................................12 
2.3 
Commercial Agent .................................................................................................17 
2.4 
Rationale ................................................................................................................17 
2.5 
Correlative Studies Background ............................................................................24 
2.6 
Rationale for Protocol Amendment #4a and Study Closure ..................................29 
3. 
PATIENT SELECTION ....................................................................................................29 
3.1 
Eligibility Criteria ..................................................................................................29 
3.2 
Exclusion Criteria ..................................................................................................31 
3.3 
Inclusion of Women and Minorities ......................................................................34 
4. 
REGISTRATION PROCEDURES ...................................................................................34 
4.1 
Investigator and Research Associate Registration with CTEP ..............................34 
4.2 
Site Registration .....................................................................................................35 
4.3 
Patient Registration ................................................................................................38 
4.4 
General Guidelines .................................................................................................40 
5. 
BIOMARKER, CORRELATIVE, AND SPECIAL STUDIES ........................................41 
5.1 
Summary Table for Specimen Collection ..............................................................41 
5.2 
Summary Table(s) for Research Biopsies ..............................................................42 
5.3 
Specimen Procurement Kits and Scheduling .........................................................43 
5.4 
Specimen Tracking System Instructions ................................................................43 
5.5 
Specimen Collection ..............................................................................................47 
5.6 
Shipping Specimens from Clinical Site to the EET Biobank ................................52 
5.7 
Biomarker Plan ......................................................................................................56 
5.8 
Integral Correlative Studies ...................................................................................61 
5.9 
Integrated Correlative Studies ................................................................................61 
5.10 
Exploratory/Ancillary Correlative Studies ............................................................62 
6. 
TREATMENT PLAN ........................................................................................................65 
6.1 
Agent Administration .............................................................................................65 
6.2 
Definition of Dose-Limiting Toxicity ....................................................................70 
6.3 
General Concomitant Medication and Supportive Care Guidelines ......................71 

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6.4 
Duration of Therapy ...............................................................................................73 
6.5 
Duration of Follow-Up ..........................................................................................73 
7. 
DOSING DELAYS/DOSE MODIFICATIONS................................................................74 
7.1 
Dose Modification Schemas ..................................................................................74 
7.2 
Copanlisib ..............................................................................................................76 
7.3 
Eribulin ..................................................................................................................80 
7.4 
Eribulin + Copanlisib .............................................................................................84 
8. 
PHARMACEUTICAL INFORMATION ..........................................................................93 
8.1 
CTEP IND Agent ...................................................................................................93 
8.2 
Commercial Agent .................................................................................................96 
9. 
STATISTICAL CONSIDERATIONS...............................................................................97 
9.1 
Study Design/Endpoints.........................................................................................97 
9.2 
Sample Size/Accrual Rate ....................................................................................100 
9.3 
Stratification Factors ............................................................................................102 
9.4 
Analysis of Secondary Endpoints ........................................................................102 
9.5 
Analysis of Exploratory Correlatives ...................................................................102 
9.6 
For phase 2 portion: Reporting and Exclusions ...................................................103 
9.7 
Data Safety Monitoring Board .............................................................................103 
9.8 
Interim Futility Analysis ......................................................................................104 
9.9 
Continuous monitoring for toxicity using a Pocock-type boundary. ...................105 
9.10 
Planned Subset Analysis ......................................................................................105 
9.11 
Population for Analysis........................................................................................106 
10. 
ADVERSE EVENTS:  LIST AND REPORTING REQUIREMENTS ..........................106 
10.1 
Comprehensive Adverse Events and Potential Risks List (CAEPR) ...................106 
10.2 
Adverse Event Characteristics .............................................................................112 
10.3 
Expedited Adverse Event Reporting ....................................................................113 
10.4 
Routine Adverse Event Reporting .......................................................................116 
10.5 
Pregnancy .............................................................................................................116 
10.6 
Secondary Malignancy .........................................................................................117 
10.7 
Second Malignancy ..............................................................................................117 
11. 
STUDY CALENDAR .....................................................................................................117 
12. 
MEASUREMENT OF EFFECT......................................................................................120 
12.1 
Antitumor Effect – Solid Tumors ........................................................................120 
12.2 
Other Response Parameters .................................................................................126 
13. 
STUDY OVERSIGHT AND DATA REPORTING / REGULATORY 
REQUIREMENTS ...........................................................................................................126 
13.1 
Study Oversight ...................................................................................................126 
13.2 
Data Reporting .....................................................................................................127 
13.3 
Data Quality Portal ..............................................................................................129 
13.4 
CTEP Multicenter Guidelines ..............................................................................130 

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13.5 
Collaborative Agreements Language ...................................................................130 
14. 
REFERENCES ................................................................................................................132 
APPENDIX A 
PERFORMANCE STATUS CRITERIA ................................................138 
APPENDIX B 
FORMULA TO ESTIMATE RENAL FUNCTION USING 
SERUM CREATININE ...................................................................................................139 
APPENDIX C 
LIST OF PROHIBITED MEDICATIONS WHILE ON 
COPANLISIB TREATMENT .........................................................................................140 
APPENDIX D 
PATIENT CLINICAL TRIAL WALLET CARD ...................................141 
APPENDIX E 
MANAGEMENT OF TRANSIENT GLUCOSE 
INCREASE ON THE DAY OF COPANLISIB INFUSION ..........................................142 
APPENDIX F 
MANAGEMENT OF TRANSIENT GLUCOSE 
INCREASE ON SUBSEQUENT DAYS FOLLOWING COPANLISIB 
INFUSION 
..................................................................................................................143 
APPENDIX G 
DOSE MODIFICATION OF COPANLISIB FOR 
ARTERIAL HYPERTENSION.......................................................................................144 
APPENDIX H 
TISSUE BIOPSY VERIFICATION .....................................................146 
 
 
 

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1. OBJECTIVES 
 
1.1 
Primary Objectives 
 
1.1.1 Phase 1 
 
1.1.1.1 
To determine the safety, toxicity profile, dose limiting toxicity (DLT), maximum 
tolerated dose (MTD) and recommended phase 2 dose (RP2D) of copanlisib in 
combination with eribulin in metastatic triple negative breast cancer (TNBC) 
 
1.1.2 Phase 2 
 
1.1.2.1 
To compare progression free survival (PFS) between eribulin and eribulin plus 
copanlisib arms in patients with metastatic TNBC treated with prior taxane and 
anthracycline. 
 
1.2 
Secondary Objectives 
 
1.2.1 Phase 1 
 
1.2.1.1 
To determine the objective response rate (ORR) and clinical benefit rate (CBR) of the 
combination. 
 
1.2.1.2 
To observe and record anti-tumor activity.  Although the clinical benefit of these 
drugs has not yet been established, the intent of offering this treatment is to provide a 
possible therapeutic benefit, and thus the patient will be carefully monitored for 
tumor response and symptom relief in addition to safety and tolerability. 
 
1.2.2 Phase 2 
 
1.2.2.1 
To compare the ORR, CBR (complete response [CR]+partial response [PR]+stable 
disease [SD] ≥24 weeks) and safety of eribulin and eribulin plus copanlisib arms. 
 
 
 
1.3 
Exploratory Objectives 
 
1.3.1 To compare PTEN IHC results between paired baseline tumor biopsy versus at time of 
disease progression.  
 
1.3.2 Assess baseline (pre-treatment) tumor tissue mutation or gene expression profiles to 
correlate treatment response 
 
1.3.3 Assess intrinsic and adaptive resistance mechanisms by analyzing pre and post treatment 
biopsies for gene expression and proteomic changes. 
 

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1.3.4 Determine circulating tumor DNA (ctDNA) mutation profiles at baseline and changes in 
mutation profile and variant allele frequencies (VAFs) on C2D1 and at disease 
progression compared to baseline to correlate with treatment response 
 
1.3.5 Assess circulating biomarkers predictive of treatment response.  
 
1.3.6 Assess plasma and serum proteomics and metabolomics predictive of treatment response 
 
1.3.7 To compare the ORR, CBR, PFS of eribulin and eribulin plus copanlisib arms in patients 
with tumors harboring mutations in PIK3CA/ PTEN or with loss of PTEN expression by 
IHC on baseline tumor biopsy.  (If a baseline tumor biopsy cannot be safely performed, 
PTEN IHC will be performed on archival tumor sample.) 
 
1.3.8 To compare the ORR, CBR, PFS of eribulin and eribulin plus copanlisib arms in patients 
with tumors lacking PIK3CA/ PTEN pathway alterations. 
 
1.3.9 To compare the ORR, CBR, PFS of eribulin and eribulin plus copanlisib arms in patients 
with tumors harboring loss of PTEN expression by IHC in pre-treatment metastatic site 
(in patients with available tissue from metastatic site). 
 
1.3.10 To compare PTEN IHC results between paired archival primary tumor vs. baseline tumor 
biopsies. 
 
1.3.11 To assess targeted inhibition by copanlisib and eribulin by measuring treatment induced 
changes in phospho-AKT (T308), phospho-AKT (S473), phospho-histone H3, and 
inhibition of apoptosis (cleaved caspase 3) between post-treatment tumor (C2D1-2) 
versus baseline. 
 
1.3.12 To compare the ORR, CBR, PFS of eribulin and eribulin plus copanlisib arms in patients 
with tumors harboring mutations in PIK3CA/PTEN by ctDNA at baseline, and potential 
changes over time. 
 
 
 
2. 
BACKGROUND 
 
2.1 
Study Disease 
 
Breast cancer (BC) is the most commonly diagnosed malignancy in women.  Approximately 
268,600 new cases of invasive BC are estimated to be diagnosed in the United States in 2019 
alone (Cancer Stat Facts: Female Breast Cancer).  BC is biologically heterogeneous.  Gene 
expression profiling has identified five molecular subtypes with distinct behaviors and clinical 
outcomes: luminal A, luminal B, human epidermal growth factor receptor 2 (HER2) enriched, 
basal-like, and normal-like tumors (Perou et al., 2000; Sorlie et al., 2001).  Basal-like tumors are 
predominately represented by the triple negative phenotype, characterized by the lack of estrogen 
receptor (ER), progesterone receptor (PR), and HER2/neu oncogene.  These triple negative 

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breast cancers (TNBC) account for 15-20% of all BC cases.  Although targeted therapies have 
improved management of ER-positive and HER2-positive BC, cytotoxic chemotherapy remains 
the mainstay of systemic therapy for TNBC patients.  Unlike hormone receptor positive and 
HER-2 positive tumors, little progress has been made for the treatment of TNBC.  Only recently, 
the FDA approved atezolizumab in combination with nab-paclitaxel chemotherapy in 
programmed death ligand 1 (PD-L1) positive tumors based on results reported in the 
IMpassion130 study (Schmid et al., 2018b).  The paucity of effective targeted therapies and 
subsequent chemotherapeutic resistance, in addition to the aggressive nature of TNBC, poses an 
unprecedented clinical challenge with significant unmet need. 
 
2.2 
CTEP IND Agent 
 
2.2.1 Copanlisib 
 
PI3K/AKT signaling is commonly dysregulated in human cancers via various mechanisms, e.g., 
gene amplification, rearrangement, or activating and/or loss-of-function mutations of the 
pathway’s molecular components (Westin, 2014).  Aberrant activation of class I PI3Ks has been 
associated with intrinsic and acquired resistance of tumors to targeted agents, chemotherapy, and 
radiotherapy (Liu et al., 2013).   
 
Four PI3K isoforms (PI3K, PI3K, PI3K, and PI3K), all of which have a catalytic p110 
subunit (p110), comprise the class I PI3K subfamily (Liu et al., 2013; Westin, 2014).  
Tumors with mutations in PIK3CA or loss of PTEN have been found to be sensitive to inhibitors 
targeting PI3Kα.  PI3K-specific  inhibitors have shown remarkable therapeutic efficacy in some 
human leukemias and lymphomas (Yang et al., 2015).  Inhibition of PI3Kδ in the B-cell 
malignancies was shown to attenuate the responsiveness of the tumor cells to supportive stimuli 
from the microenvironment (Okkenhaug and Burger, 2016).  Inactivation of PI3Kδ appears to 
break regulatory T-cell (Treg)-mediated immune tolerance unleashing cytotoxic T-cell response 
that leads to tumor regression (Ali et al., 2014).   
 
Copanlisib is a novel intravenous (IV) pan-class I PI3K inhibitor with predominant inhibitory 
potency against δ and α PI3K isoforms (Copanlisib Investigator’s Brochure, 2018).  Preclinical 
data suggest that copanlisib may be more efficient in inhibiting survival of leukemia cells than 
idelalisib (PI3K inhibitor) or duvelisib (PI3K/) (Gockeritz et al., 2015). 
 
Nonclinical Studies 
 
Copanlisib free base (BAY 80-6946) is an active ingredient of copanlisib dihydrochloride salt 
(BAY 84-1236).  A majority of nonclinical data were produced using the copanlisib free-base.  
 
Mechanism of Action 
Copanlisib is a stronger inhibitor of PI3K and PI3K than of PI3K or PI3K as demonstrated 
by copanlisib 50% inhibitory concentrations (IC50s) for PI3K PI3K PI3K and PI3K (IC50s 
0.5, 0.7, 3.7, and 6.4 nmol/L, respectively) (Liu et al., 2013).  Compared to the PI3K isoforms, 
copanlisib is a much weaker inhibitor of mTOR (IC50=45 nmol/L).  In a panel of ~220 kinases, 
copanlisib (1 mcmol/L) failed to inhibit any kinase other than PI3K isoforms and mTOR by 

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50%.  In tumor cell lines with hyperactive PI3K signaling, copanlisib antitumor activity was 
paralleled by a robust decrease in basal levels of phosphorylated AKT, both at serine 473 
(AKTpS473) and threonine 308 (AKTpT308), and by increases in caspase-9 levels, which is 
suggestive of induction of apoptosis.  
 
Copanlisib has potent and broad in vitro antitumor activity (IC50 of 1-760 nmol/L) in cancers of 
the breast, ovary, ovary, prostate, colon, lung, liver, brain, kidney, melanoma, pancreas, 
fibrosarcoma, and in various hematological cancers (Copanlisib Investigator’s Brochure, 2018).  
Copanlisib effectively inhibits tumor growth in diffuse large B-cell lymphoma (DLBCL) animal 
models where the PI3K-selective inhibitor idelalisib is not active.  Intermittent dosing results in 
improved efficacy with better tolerability.   
 
Nonclinical Pharmacokinetics  
 
Copanlisib plasma-free fraction across species was as follows:  35% in rats, 14% in mice, 33% in 
dogs, and 16% in humans (Liu et al., 2013).  The pharmacokinetic (PK) profile of copanlisib was 
evaluated following single and multiple IV doses in nude rats.  Single-dosed copanlisib exhibited 
a very large volume of distribution (Vd=32 L/kg), high plasma clearance (3.95 L/kg/h) and a long 
half-life (t1/2=6.0 h).  The copanlisib PK parameters at repeat dosing (Q2D x 5 doses), were 
similar to those from single-dosing studies and suggested no drug accumulation in plasma.   
 
In tumor xenograft model studies, the efficacious exposure of copanlisib, expressed as the area 
under the concentration-time curve (AUC) for the unbound/free drug (AUCu) in plasma, was 
estimated to be 370 mcg•h/L in rats and 170-460 mcg•h/L in mice based on weekly dosing 
(Investigator’s Brochure, 2018).  
 
Copanlisib had a higher clearance (16 L/kg/h), shorter t1/2 (0.7 h) and smaller Vd (12.9 L/kg) in 
mice than rats (Liu et al., 2013).  A single bolus IV dose of copanlisib (6 mg/kg) in the H460 
NSCLC xenograft rat model produced 100 times higher concentration of the drug in tumor tissue 
than in plasma at 48 hours post-dosing; the drug clearance from the tumor was slower than from 
plasma.  The pharmacodynamics analysis showed 90% inhibition of AKTpS473 at 24 hours 
post-dosing compared to the control animals, and the AKTpS473 level remained suppressed up 
to 72 hours. 
 
Nonclinical Pharmacology and Metabolism  
 
The extent of plasma protein binding of copanlisib was low in various species with free 
fractions between 10% and 42% (15.8% in human plasma).  Copanlisib demonstrated high 
distribution from blood to the organs and tissues and moderate penetration of the blood-brain 
barrier (BBB) and placental barrier, and high affinity to melanin-bearing tissues (Copanlisib 
Investigator’s Brochure, 2018). 
 
Copanlisib is primarily metabolized by the cytochrome P450 (CYP) isoform 3A4 (CYP3A4), 
while CYP1A1 contributes to a minor extent (<10%) based on in vitro data (Copanlisib 
Investigator’s Brochure, 2018).  Copanlisib is a weak substrate of permeability 
glycoprotein (P-gp) and of breast cancer resistance protein (BCRP).  There is a low risk for 

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clinically relevant PK drug-drug interactions (DDI) through inhibition or induction of CYP 
enzymes, inhibition of uridine diphosphate glucuronosyltransferase (UGT) enzymes and 
inhibition of dihydropyrimidine dehydrogenase by copanlisib.  Copanlisib also inhibits P-gp 
(IC50 7-7.6 mcmol/L) and BCRP (IC50=11.5 mcmol/L).  Furthermore, copanlisib was a strong 
inhibitor of the drug transporter multidrug and toxin extrusion protein 2 (MATE2K).  
 
Nonclinical Safety and Toxicity  
 
Based on clinical pathology and morphological findings in repeat-dosing IV studies, target 
organs were lymphoid and hematopoietic system, liver, kidneys, teeth, bone, heart, male, and 
female genital systems in the rat (Copanlisib Investigator’s Brochure, 2018).  Dogs showed 
adverse effects in the lymphoid and hematopoietic system, stomach, and male genital system.  
Intravenous infusion of copanlisib caused vasoconstriction, enhanced insulin and glucose levels, 
impaired glucose tolerance, reduced gastrointestinal (GI) motility, increased renal volume and 
electrolyte excretion, and central nervous system (CNS) depressant effects in nonclinical species.  
A majority of these effects could be explained by inhibition of PI3K-dependent signaling, and 
they occurred at or slightly above the plasma concentrations shown to be efficacious in tumor 
xenograft rat models (maximum concentration [Cmax]=30-80 mcg/L; Cmax of unbound fraction 
[Cmax,u] 11-28 mcg/L).  The CNS depressant effects occurred at high plasma concentrations and 
are considered secondary to hyperglycemia.  At pharmacodynamically relevant concentrations, 
copanlisib does not interfere with cardiac repolarization in vitro or in vivo. 
 
Based on the findings from repeat-dose toxicity studies in nonclinical species, copanlisib is 
expected to adversely affect male and female reproduction (Copanlisib Investigator’s Brochure, 
2018).  Developmental and reproductive toxicity of PI3K inhibitors is known.  Maternal toxicity 
of increasing severity, severe post-implantation loss, and developmental toxicity, including 
teratogenicity were seen in the rat starting at low doses.  Copanlisib was not genotoxic in vitro or 
in vivo.  Appropriate precautions should be taken to avoid pregnancy in female subjects included 
in the clinical trials.   
 
There is no evidence that copanlisib has phototoxic potential (Copanlisib Investigator’s 
Brochure, 2018).   
 
Effects in Humans 
 
Drug-Drug Interactions 
 
In vitro studies in human hepatocytes indicate that CYP3A4 is a major metabolizer (>90%) while 
CYP1A1 contributes <10% to metabolism of copanlisib (Investigator’s Brochure, 2018).  
Preliminary results of copanlisib co-administered with rifampin, a strong inducer of CYP3A4, 
resulted in 63% decrease in the mean AUC of copanlisib with a minor effect on Cmax (15%).  
Therefore, the concomitant use of copanlisib and strong inducers of CYP3A4 (rifampin, 
phenytoin, carbamazepine, phenobarbital, enzalutamide, mitotane, and St. John’s Wort, etc.) 
should be avoided.  Co-administration of itraconazole (200 mg), a strong inhibitor of CYP3A4 
with copanlisib (60 mg IV) resulted in 1.53-fold increase in copanlisib AUC but had no effect on 
its Cmax.  Increases in AUC between 1.25-fold and 2-fold are considered weak.  No dose 

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adjustment of copanlisib is necessary when co-administered with CYP3A4 inhibitors but patients 
need to be closely monitored for toxicity when co-administered with strong CYP3A4 inhibitors 
(ketoconazole, itraconazole, clarithromycin, ritonavir, indinavir, nelfinavir, saquinavir, etc.).  
Because copanlisib is a substrate of P-gp and BCRP, inducers/inhibitors of these transporters 
have potential to affect copanlisib exposure. 
 
Summary of Clinical Safety of Copanlisib and Special Warnings (Copanlisib Investigator’s 
Brochure, 2018) 
 
In clinical studies, the most serious adverse events (SAEs) reported in patients with NHL 
(indolent and aggressive) and solid tumors treated with copanlisib monotherapy included 
pneumonitis, lower respiratory tract infections (including pneumonia), and febrile neutropenia 
(Copanlisib Investigator’s Brochure, 2018).  In clinical studies, the most common adverse 
reactions (≥20%) were hyperglycemia, decreased general strength and energy (including fatigue 
and asthenia), hypertension, diarrhea, nausea, leukopenia and neutropenia. 
 
Infections  
 
Serious infections (including fatal infections) occurred in 19% of patients treated with copanlisib 
monotherapy (Copanlisib Investigator’s Brochure, 2018).  The most common infections were 
pneumonia, lung infection and lower respiratory tract infection.  Patients should be monitored 
for symptoms of infection and copanlisib dosing should be interrupted for Grade ≥3 infections 
until resolution.  Pneumocystis jirovecii pneumonia occurred in 0.6% of patients treated with 
copanlisib.  Prophylaxis should be considered for patients at risk for this infection, and 
copanlisib should be interrupted for any grade of this infection. 
 
Non-Infectious Pneumonitis 
 
Non-infectious pneumonitis (all events were Grade ≤3) occurred in 5% of patients (Copanlisib 
Investigator’s Brochure, 2018).  Treatment with copanlisib should be permanently discontinued 
in patients experiencing non-infectious pneumonitis of Grade ≥3 and if Grade 2 recurs.   
 
Neutropenia and Febrile Neutropenia 
 
Grade 4 neutropenia occurred in 9.1% of patients, including 1.9% of patients having febrile 
neutropenia (Copanlisib Investigator’s Brochure, 2018).  
 
Transient Hypertension 
 
Treatment with copanlisib may result in transient hypertension; blood pressure increases were 
seen after cycle 1 day1 infusion of copanlisib and started to decrease approximately 2 hours post-
infusion.   Serious hypertension (Grade ≥3) occurred in 0.9% of patients (Copanlisib 
Investigator’s Brochure, 2018).  Copanlisib should be permanently discontinued for uncontrolled 
hypersensitivity or the Grade 4 event.  
 
Transient Hyperglycemia 

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Treatment with copanlisib may result in transient hyperglycemia, with a peak in blood glucose 
level peak observed at 5-8 hours post-infusion followed by subsequent decline to baseline 
(Copanlisib Investigator’s Brochure, 2018).  More serious hyperglycemia (Grade ≥3) occurred in 
0.9% of patients.  Optimal glucose levels should be achieved before each infusion of copanlisib.  
Copanlisib dosing should be delayed, reduced, or permanently discontinued depending on 
severity of the event.  
 
Embryo-Fetal Toxicity 
 
Based on the mechanism of action and non-clinical studies finding in rats, copanlisib may cause 
embryo-fetal harm (Copanlisib Investigator’s Brochure, 2018).  Copanlisib should not be used 
during pregnancy.  Highly effective contraception in addition to a barrier method should be used 
by males and females of child bearing potential.   
 
Pregnancy and Lactation 
 
There are no data on the use of copanlisib in pregnant women (Copanlisib Investigator’s 
Brochure, 2018).  It is not known whether copanlisib is excreted in human milk.  Nonclinical 
studies in lactating rats showed that ~2% of radioactively labeled copanlisib was excreted into 
milk.  Therefore, copanlisib can potentially harm infants and breastfeeding must be discontinued 
while on copanlisib treatment. 
 
Recommended Phase 2 Dose of Copanlisib as Monotherapy (Copanlisib Investigator’s 
Brochure, 2018) 
 
The maximum tolerated dose (MTD) of a single-agent copanlisib in non-diabetic patients with 
solid malignancies was 0.8 mg/kg 1-hour IV administered once weekly for 3 weeks (days 1, 8, 
and 15) on a 28-day cycle (Copanlisib Investigator’s Brochure, 2018).  No impact of either body 
weight, body surface area (BSA), or other body size-related factors was found on the clearance 
of copanlisib, which was the basis to switch to a fixed-dose regimen of copanlisib based on the 
population PK. 
 
The recommended phase 2 dose (RP2D) of copanlisib monotherapy is 60 mg 1-hour IV given 
once weekly for 3 weeks (days 1, 8, and 15) on 4-week cycle.  A dose reduction to 45 mg for 
toxicities is allowed.  No dose adjustment is required in patients with mild or moderate renal 
impairment or patients with mild hepatic impairment.  
 
However, as of November 2023, Bayer has decided to voluntarily withdraw the NDA for 
copanlisib. Copanlisib was previously approved for the treatment of relapsed follicular 
lymphoma. The FDA required clinical benefit to be confirmed by further studies when this 
original approval for copanlisib was issued in 2017, and the CHRONOS-4 study failed to meet 
the primary endpoint of progression-free survival benefit in comparison with the control arm in 
patients with relapsed follicular lymphoma. 
 
 

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2.3 
Commercial Agent 
 
2.3.1 Eribulin 
 
Eribulin mesylate (eribulin mesilate, halichondrin B analog, E7389, Halaven®) is a synthetic 
analog of halichondrin B, a natural product isolated from the marine sponge Halichondria 
okadai.  Eribulin mesylate encompasses biologically active macrolide portion of Halichondrin B 
and shows similar or identical anticancer properties in preclinical models.  Eribulin mesylate is a 
potent inhibitor of tubulin polymerization into microtubules as well as microtubule dynamics.  
Nonclinical data show that sub- to low nanomolar concentrations of eribulin mesylate inhibits 
cell proliferation via induction of irreversible cell cycle blocks at G2/M phase of cell cycle, 
disruption of mitotic spindles, and initiation of apoptosis (Towle et al. 2001, Kuznetsov et al. 
2004).  Among tubulin-targeted agents, it exerts mechanistically unique effects on microtubule 
dynamics by inhibition of microtubule growth in the absence of effects on microtubule 
shortening at microtubule plus ends, and formation of nonproductive tubulin aggregates (Jordan 
et al., 2005).   
 
Eribulin mesylate demonstrated antiproliferative effects against a wide range of human cancer 
cell lines, including breast, colon, prostate, ovarian, small cell lung cancer (NSCLC), squamous 
cell carcinoma of head and neck (SCCHN), and various soft tissue sarcoma cell lines.  Eribulin 
treatment of human breast cancer cells caused changes in morphology, and gene expression, as 
well as decreased cell migration and invasiveness in vitro.  In mouse xenograft models of human 
breast cancer, eribulin increased vascular perfusion and permeability in tumor cores, resulting in 
reduced hypoxia and changes in gene expression and tumor phenotype (Funahashi et al. 2014).  
These finding suggest that eribulin mesylate, in addition to having primary anticancer effects, 
renders residual tumors less aggressive and less likely to metastasize.   
 
Eribulin is indicated for the treatment of patients with metastatic breast cancer who have 
previously received at least two chemotherapeutic regimens to treat metastatic disease.  Eribulin 
is also indicated for the treatment of patients with unresectable or metastatic liposarcoma who 
have received a prior anthracycline-containing regimen. 
 
2.4 
Rationale 
 
Signaling through the phosphoinositide 3-kinase (PI3K) pathway plays a crucial regulatory role 
in most hallmarks of cancer, including cell survival, growth, metabolism, differentiation, 
motility, genomic instability, and angiogenesis (Vivanco and Sawyers, 2002; Engelman, 2009).  
Aberrant PI3K/AKT pathway signaling has been frequently observed in TNBC (Marty et al., 
2008; López-Knowles et al., 2010).  Per The Cancer Genome Atlas (TCGA) TNBC data set, 
activation of this key pathway occurs by various mechanisms, including PIK3CA mutations 
(7%), and more frequently, deficient or loss of expression of tumor suppressor phosphatase and 
tensin homolog PTEN (35%) (Saal et al., 2005; Bose et al., 2006; Leary and Dowsett, 2006; 
Fedele et al., 2010; López-Knowles et al., 2010).  A significantly higher level of Akt 
phosphorylation has been observed in TNBC patient specimens compared with non–TNBC cases 
(Umemura et al., 2007; Marty et al., 2008).  In addition, PI3K pathway activation has been 
linked to promotion of tumor cell growth and chemotherapy resistance (West et al., 2002).  

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Various preclinical models have illustrated how inhibition of PI3K pathway signaling could 
enhance and synergize the cytotoxicity of a variety of chemotherapy agents (Shi et al., 1995; 
Geoerger et al., 2001; Xu et al., 2003).  Furthermore, increasing evidence indicates that 
activation of the PI3K/AKT pathway serves a role to maintain the stemness and chemoresistance 
of breast cancer stem cells (CSCs) (Zhou et al., 2007; Hu et al., 2015).  Importantly, previous 
studies have shown that PI3K inhibition sensitizes these CSCs to chemotherapy and molecular 
targeted therapy in several cancers, including breast cancer (Zhang et al., 2012).  Manipulating 
this pathway via combination chemotherapy plus PI3K inhibitors thereby renders it an attractive 
therapeutic target in TNBC.   
 
PI3KCA/AKT pathway inhibitors are attractive therapeutic agents for TNBC due to the high 
frequency of aberrant PI3K pathway activation observed as discussed above.  Indeed, promising 
data has been demonstrated in phase 2 randomized trials of AKT inhibitors when added to 
chemotherapeutic agents.  The addition of AKT pathway inhibitors have been shown to improve 
the pathologic complete response (pCR) rate and progression free survival (PFS) in combination 
with taxane chemotherapy in patients with TNBC in the neoadjuvant (Tripathy et al., 2015) and 
metastatic setting (Kim et al., 2017), respectively.  Specifically, the addition of the oral highly 
selective AKT inhibitor ipatasertib versus placebo to paclitaxel significantly improved median 
PFS from 4.9 months to 6.2 months (HR 0.6, 95% CI 0.37-0.98), p=0.037) in a randomized 
phase 2 trial of 166 patients with advanced TNBC in the first line setting (Kim et al., 2017).  The 
benefit of ipatasertib appeared to be more pronounced in patients with PI3K pathway alterations.  
There was a trend toward improved PFS with the addition of ipatasertib compared to placebo 
(6.2 months vs 3.7 months, HR 0.59, 95% CI 0.26-1.32, p=0.18) in the 48 patients with low 
PTEN expression by immunohistochemistry.  In addition, the duration of response was 
significantly longer with the addition of ipatasertib (11.2 vs 6.1 months) in the 
PIK3CA/AKT/PTEN-altered tumor population by next generation sequencing (NGS).  Similarly, 
in the PAKT trial, the addition of the AKT inhibitor, AZD5363, to paclitaxel versus placebo as 
first line therapy for metastatic TNBC resulted in robust improvement in PFS in the 
PIK3CA/AKT1/PTEN altered group (9.3 versus 3.8 months, 2-sided p=0.01), as compared to the 
intention-to-treat cohort (5.9 versus 4.2 months) and PIK3CA/AKT1/PTEN unalerted tumors 
(5.3 versus 4.4 months, 2 sided p=0.61) (Schmid et al., 2018a). There have not been reports of 
clinical trials that assessed the efficacy of adding a PI3K pathway inhibitor for TNBC following 
progression on prior taxane regimens.   
 
Copanlisib is potent pan-class I PI3K inhibitor that is highly selective against α and δ isoform 
PI3K (IC50 0.5 and 0.7 nmol/L, respectively) than β or γ isoform (IC50 3.7 and 6.4 nmol/L, 
respectively) (Liu et al., 2013).  Copanlisib also exhibits preferential inhibition (~10-fold) of 
AKT phosphorylation by PI3Kα compared with PI3Kβ in cells, and with superior antitumor 
activity (>40-fold) in PIK3CA mutant and/or HER2+ compared to HER2-/PIK3CA WT BC cell 
lines.  Copanlisib is under investigation as monotherapy or in combination with other agents 
(paclitaxel, trastuzumab, gemcitabine/cisplatin, refametinib) in clinical studies.  The most 
common drug-related adverse effects reported were metabolic (hyperglycemia, all-grade 63%, 
grade 3 29%), gastrointestinal (diarrhea, all-grade 16%, grade 3 2%), and cardiovascular 
(hypertension).  Overall, there was a higher incidence of hyperglycemia that was manageable, 
and much lower incidence of diarrhea compared to other pan-PI3K inhibitors.  Abnormal liver 
function tests were incidental findings, and most were grade 1.  The difference in adverse effect 

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profile amongst PI3K inhibitors may be due to the weekly doing of copanlisib rather than the 
continuous dosing of other agents in this category.  
 
Eribulin mesylate (Halaven®, Eisai Inc) is a non-taxane microtubule dynamics inhibitor approved 
for the treatment of metastatic breast cancer previously treated with an anthracycline and taxane 
(Smith et al., 2010).  In the phase 3 EMBRACE study, eribulin mesylate was associated with 
significant improvement in overall survival (OS) compared with treatment of physician's choice 
(TPC) in this heavily pre-treated patient population (Cortes et al. 2011).  Median PFS with 
eribulin versus TPC was 3.7 versus 2.2 months, per independent review.  The efficacy of eribulin 
in TNBC was demonstrated in the pooled analysis of two phase 3 studies (EMBRACE/Study 
305), which revealed a 4.7 month improvement in median survival with eribulin as compared to 
control chemotherapy (median OS: 12.9 vs 8.2 months; HR 0.74; P = 0.006) (Twelves et al., 
2014).  In addition to the induction of an irreversible mitotic block, eribulin has been shown to 
impact tumor vascular remodeling (Funahashi et al., 2014) and inhibition of epithelial-to-
mesenchymal transition (EMT) and metastasis in experimental models (Yoshida et al., 2014). 
These mechanisms have been implicated in therapeutic resistance to cancer drugs including 
growth factor receptor and PI3K inhibitors (Byers et al., 2013).  With the recent FDA approval 
of nab-paclitaxel in combination of atezolizumab as first line therapy in PD-L1 positive 
metastatic TNBC and the frequent use of taxanes in the first line setting regardless of PD-L1 
status, eribulin becomes a logical choice in subsequent treatments.  Strategies to improve the 
efficacy of eribulin are of unmet clinical need.  
 
We are particularly interested in combining eribulin as the chemotherapy agent of choice due to 
its unique mechanisms of action and potential effect on EMT.  There is increasing evidence in 
the literature indicating that CSCs play a crucial role in therapy resistance (Dean et al., 2005; 
Ailles and Prince, 2009; Calcagno et al., 2010) and that activation of the PI3K/AKT pathway is 
indispensable for maintaining the stemness and chemoresistance of breast CSCs (Zhou et al., 
2007; Hu et al., 2015).  Moreover, previous studies have also shown that PI3K inhibition 
sensitizes CSCs to chemotherapy and molecular targeted therapy in several cancers including 
leukemia, hepatocellular carcinoma and breast cancer (Wang et al., 2010; Zhang et al., 2012; 
Airiau et al., 2013).  The synergistic anti-tumor effect of eribulin in combination with PI3K 
inhibitors has also been reported in the literature.  In a cell-based, high-throughput screening in a 
panel of twenty-five human cancer cell lines representing a variety of tumor types, the PI3K 
inhibitor BKM120 was identified to exert synergistic killing with eribulin in both eribulin 
sensitive and resistant cancer cell lines, 3 of which being TNBC (Rickles et al., 2015).  Our 
group also previously demonstrated that BKM120 enhanced the anti-tumor effect of eribulin in 
TNBC both in vitro and in vivo in PDX models (Rajput et al., 2019).  Combination therapy 
resulted in synergistic reduction of markers of EMT and cancer stem cell population and 
enhanced mitotic arrest and apoptosis (Figure 1).  As BKM120 is no longer in clinical 
development, we chose copanlisib because of its more favorable toxicity profile.  

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Synergistic antitumor effect was also observed between eribulin and copanlisib in 3-D cultures 
of organoids derived from TNBC PDX models.  Figure 6 shows the data on WHIM34 derived 
organoid, treated with vehicle, or eribulin and copanlisib, either alone or in combination at 
various concentrations for 6 days followed by Alamar Blue for cell survival.  Combination index 
indicated synergism. 
 
 
These data provide strong preclinical rationale for clinical investigation of eribulin and 
copanlisib in the metastatic TNBC population. 
 
We hypothesize that the addition of copanlisib to eribulin in patients with metastatic TNBC will 
be a safe and clinically meaningful combination regimen.  We are testing this hypothesis in this 
phase 1/2 trial, wherein we will determine the recommended phase 2 dose of both drugs in the 
dose escalation portion and test the safety and response rate in the dose expansion portion.  The 
dose escalation portion will be conducted in a standard 3+3 design with 3 planned dose levels.  
 
2.5 
Correlative Studies Background 
 
2.5.1 Tumor Genomic Profiling  
 
Biologic rationale:  
Mutations in PIK3CA or PTEN or loss of PTEN protein expression activate PI3K signaling, 
therefore are potential predictive markers for PI3K inhibitors.  The phase 2 portion of this study 
will utilize a stratified randomized two-arm design on patients with metastatic TNBC, stratified 
by PTEN/PIK3CA mutation status per archival tumor tissue analysis to further elucidate the 
potential implications of baseline tumor genomic alteration status on therapeutic response.  As a 
secondary objective, we will compare the ORR, CBR, PFS of eribulin and eribulin plus 
copanlisib arms in tumors harboring and lacking mutations in PIK3CA/PTEN per baseline tumor 
biopsy.   
 
Figure 6 Synergistic antitumor effect observed with the combination of 
Eribulin and Copanlisib in 3-D cultures of organoids derived from TNBC 
PDX models 
 
Drug Combination
Combination 
Index
Eribulin (1nM)+Copanlisib (10nM)
0.12
Eribulin (1nM)+Copanlisib (50nM)
0.48
Eribulin (1nM)+Copanlisib (100nM)
0.52
Eribulin (1nM)+Copanlisib (500nM)
0.67
Eribulin (1nM)+Copanlisib (1000nM)
0.98
Eribulin (10nM)+Copanlisib (10nM)
0.04
Eribulin (10nM)+Copanlisib (50nM)
0.11
Eribulin (10nM)+Copanlisib (100nM)
0.16
Eribulin (10nM)+Copanlisib (500nM)
0.40
Eribulin (10nM)+Copanlisib (1000nM)
1.17

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Hypothesis: 
We hypothesize that the addition of copanlisib to eribulin has superior antitumor activity, in 
particular in the subset of patients with tumors harboring PIK3CA mutation or PTEN 
mutation/loss. 
 
2.5.2 PTEN Immunohistochemistry (IHC) 
 
Biologic Rationale: 
Per The Cancer Genome Atlas (TCGA) TNBC data set, deficient or loss of tumor suppressor 
phosphatase and tensin homolog PTEN expression occurs in approximately 35% of TNBC (Saal 
et al., 2005; Bose et al., 2006; Leary and Dowsett, 2006; Fedele et al., 2010; López-Knowles et 
al., 2010).  In the 25 patients in the MTD cohort of the initial phase 1 trial of copanlisib, 2 partial 
responses (PR), both with breast cancer, were observed, including 1 HR+/HER2-/PIK3CA WT 
and 1 HR+/HER2+/PIK3CA Mut (Patnaik et al., 2016).  One complete response (CR) occurred in 
a patient with endometrial cancer with mutations in both PIK3CA and PTEN.  Fifteen stable 
diseases (SDs), with 6 lasting 6 cycles, including 1 with PIK3CA WT/KRAS Mut endometrial 
cancer, 1 PTEN loss endometrial cancer, 1 PIK3CA Mut BC, were observed.  Interestingly, of 10 
patients without complete PTEN loss, none had objective response or SD for 4 cycles.  Among 
the 7 with complete PTEN loss, 3 (43%) had CR/PR/SD6 cycles.  Therefore, it appears that 
copanlisib may have enhanced activity among those with PTEN loss.  No clear relationship was 
observed with PIK3CA status.  Clearly, more in-depth biomarker studies are needed.  Therefore, 
we plan to compare PTEN IHC results between paired archival primary tumor versus baseline 
tumor biopsies to determine changes over time.  We also plan to compare the ORR, CBR, PFS of 
eribulin and eribulin plus copanlisib arms in patients with tumors harboring loss of PTEN 
expression by IHC in pre-treatment metastatic site (in patients with available tissue from 
metastatic site). 
 
Hypothesis:  
We hypothesize that tumors harboring PTEN loss could be more sensitive to the addition of 
copanlisib.  
 
2.5.3 Whole Exome Sequencing 
 
Biologic Rationale: 
Aberrant PI3K/AKT pathway signaling has been frequently observed in TNBC (Marty et al., 
2008; López-Knowles et al., 2010).  Per The Cancer Genome Atlas (TCGA) TNBC data set, 
activation of this key pathway occurs by various mechanisms, including PIK3CA mutations 
(7%), and more frequently, deficient or loss of tumor suppressor phosphatase and tensin 
homolog PTEN expression (35%) (Saal et al., 2005; Bose et al., 2006; Leary and Dowsett, 2006; 
Fedele et al., 2010; López-Knowles et al., 2010).  A significantly higher level of Akt 
phosphorylation has been observed in TNBC patient specimens compared with non–TNBC cases 
(Umemura et al., 2007; Marty et al., 2008).  In addition, PI3K pathway activation has been 

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linked to promotion of tumor cell growth and chemotherapy resistance (West et al., 2002).  
Various preclinical models have illustrated how inhibition of PI3K pathway signaling could 
enhance and synergize the cytotoxicity of a variety of chemotherapy agents (Shi et al., 1995; 
Geoerger et al., 2001; Xu et al., 2003).  Furthermore, increasing evidence indicates that 
activation of the PI3K/AKT pathway serves a role to maintain the stemness and chemoresistance 
of breast CSCs (Zhou et al., 2007; Hu et al., 2015).  Importantly, previous studies have shown 
that PI3K inhibition sensitizes these CSCs to chemotherapy and molecular targeted therapy in 
several cancers, including breast cancer (Zhang et al., 2012).  Manipulating this pathway via 
combination chemotherapy plus PI3K inhibitors thereby renders it an attractive therapeutic target 
in TNBC.   
At present, it remains unclear whether PIK3CA mutation status and/or PTEN mutation status in 
the tumor is predictive of response to PI3K alpha selective or pan-PI3K inhibitors.  To our 
knowledge, there is no data on efficacy of PI3K pathway inhibitor in combination with eribulin 
by PI3K pathway mutational alteration status in TNBC.  However, based on the previously noted  
PAKT and LOTUS trials investigating the effect of paclitaxel +/- AKT inhibitor, the PFS in both 
of these trials was similar regardless of PI3K pathway mutational status (wildtype versus altered) 
in the standard of care chemotherapy monotherapy arms.  Specifically, in the randomized phase 
2 LOTUS trial with advanced TNBC in the first line setting, PFS was equivalent with paclitaxel 
alone arm in both the ITT population and in patients with PIK3CA/AKT/PTEN altered advanced 
triple negative breast cancer at 4.9 months (Kim et al., 2017).  The addition of the oral highly 
selective AKT inhibitor ipatasertib to paclitaxel resulted in improved PFS of 6.2 months (HR 
0.6) in the ITT population and to 9.0 months (HR 0.44) in those with PIK3CA/AKT/PTEN 
altered tumors.  In patients with pathway unaltered tumors, the median PFS for the combination 
was 5.3 months as compared to 3.6 months with paclitaxel alone (HR 0.76).  Likewise, in the 
PAKT trial investigating the addition of AKT inhibitor AZD5363 to paclitaxel, the PFS was 
similar with paclitaxel alone in both the PIK3CA/AKT/PTEN pathway altered and unaltered 
cohorts (3.8 months and 4.4 months, altered and unaltered pathways, respectively).  In patients 
with pathway altered tumors, the combination resulted in median PFS of 9.3 versus 5.3 months 
in pathway unaltered tumors.  It remains unclear whether PIK3CA mutation status and/or PTEN 
mutation status in the tumor is predictive of response to PI3K alpha selective or pan-PI3K 
inhibitors.   
Hypothesis:  
Mutations in PIK3CA or PTEN or loss of PTEN protein expression activate PI3K signaling, 
therefore are potential predictive markers for PI3K inhibitors.  As a secondary objective, we will 
compare the ORR, CBR, PFS of eribulin and eribulin plus copanlisib arms in tumors harboring 
and lacking mutations in PIK3CA/PTEN per baseline tumor biopsy.  We hypothesize that the 
addition of copanlisib to eribulin has superior antitumor activity, in particular in the subset of 
patients with tumors harboring PIK3CA mutation or PTEN mutation/loss. 
 
2.5.4 RNA Sequencing (RNASeq) 
 
Biologic Rationale:  
As an exploratory objective, we will examine fresh tumor biopsies collected at baseline (pre-

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treatment), C2D1-2, and at disease progression by gene expression microarray to determine 
breast cancer gene signatures of PI3K and MAPK activation as well as other genes and gene 
signatures to correlate with treatment response.  In preclinical studies, a gene expression 
signature of PI3K activation is associated with response, while MAPK or RAS signatures are 
associated with resistance to PI3K inhibitors (Folkes et al., 2008; Kwei et al., 2012).  Candidate 
genes implicated in PI3K inhibitor activities will also be assessed.  We will assess treatment 
induced changes in other EMT markers and other potentially compensatory pathways (i.e. 
MAPK pathway) by comparing pre- and post-treatment biopsies.  
Hypothesis:  
We will assess baseline gene expression and treatment-induced gene expression changes. 
 
2.5.5 Tumor Proteomics (RPPA) 
 
Biologic rationale:  
We will examine fresh tumor biopsies collected at baseline (pre-treatment), C2D1-2, and at 
disease progression using reverse phase protein assay (RPPA) analysis to examine baseline and 
treatment-induced changes in various cancer associated pathways, including but not limited to 
PI3K, MAPK to correlate with treatment response.  Based on preclinical data (Folkes et al., 
2008; Muranen et al., 2016; Kwei et al., 2012), we hypothesize that tumors with increased PI3K 
pathway activity at baseline would benefit the most from adding copanlisib to eribulin.  
 
Hypothesis:  
The incorporation of tumor proteomics will allow for analysis of treatment-induced changes to 
understand tumor response to PI3K pathway inhibition. 
 
2.5.6 Circulating Tumor DNA (ctDNA) mutation profile 
 
Biologic Rationale:   
Plasma from patients with cancer often carries small amounts of fragmented cell-free DNA of 
160-180 base pairs, which are originated from the necrosis or apoptotic process of cancer cells 
(Jahr et al., 2001; Snyder et al., 2016; Stroun et al., 2001).  Compared to a single tumor biopsy, 
ctDNA mutations may represent genomic alterations of different tumor clones or deposits and 
better reflect the inter- and intra-tumor heterogeneity (De Mattos-Arruda et al., 2016; Murtaza et 
al., 2015).  In addition, with a half-life ranging from 16 minutes to a few hours (Yu et al., 2013; 
Lo et al., 1999), ctDNA provides real-time status of the tumor genome.  Advances in the NGS 
technology and digital genomic techniques support the clinical validity of cell-free ctDNA 
sequencing analysis to non-invasively identify actionable genomic alterations, monitor treatment 
response, and investigate resistance mechanisms (De Mattos-Arruda et al., 2016). 
ctDNA sequencing is particularly helpful in cases that tumor DNA sequencing is not possible 
due to insufficient quality or quantity of the tumor tissue.  In addition, changes in the variant 
allele frequencies (VAFs) of ctDNA mutations occur rapidly, prior to the detection of changes in 

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tumor size, upon treatment with cancer therapies including those that target the PI3K pathway 
(Ma et al., 2017b; Hyman et al., 2017) and serial monitoring of ctDNA mutation profile allows 
the identification of treatment emergent resistant mechanisms (Ma et al., 2017b; Hanker et al., 
2017; Ahronian et al., 2017; Diaz et al., 2012).  Multiple studies have demonstrated the ability of 
ctDNA analysis in the detection of PIK3CA mutation, PTEN mutations, ESR1, TP53, and others, 
which may be better than tumor DNA sequencing (De Mattos-Arruda et al., 2016; Juric et al., 
2017; Ma et al., 2017c).  In this trial, as part of correlative studies, we will examine baseline 
ctDNA mutations, including PIK3CA, PTEN, ESR1, and others, with treatment response, 
examine the dynamics of ctDNA mutation profile over time for early tumor response and 
treatment-emergent resistant mechanisms. 
 
Hypothesis:  
The incorporation of ctDNA mutation profile over the course of study treatment will allow for 
detection of treatment-emergent genomics alterations which may highlight potential resistant 
mechanisms. 
 
2.5.7 Plasma and serum proteomics and metabolomics 
 
Biologic Rationale:   
As part of the exploratory objectives, serum and plasma samples at baseline, on therapy and at 
disease progression are collected for circulating markers that reflect changes due to treatment.  In 
addition to regulating cell proliferation, PI3K pathway is important in regulating glucose and 
lipid metabolism (Engelman et al., 2006), and circulating markers of metabolism before and after 
PI3K inhibitor therapy may predict treatment response and resistance mechanisms.  Inhibition of 
PI3K pathway reduces glucose uptake in the cancer cells (Maynard et al., 2017; Maynard et al., 
2016; Maynard et al., 2013).  PI3K inhibitors reduce glycolysis, affect the nonoxidative pentose 
phosphate pathway that delivers the Ribose-5-phosphate required for base ribosylation, therefore 
suppressing nucleotide synthesis and inducing replication stress and DNA damage (Juvekar et 
al., 2016).  In addition, there is evidence of reduction of enzymes involved in cholesterol 
biosynthesis upon PI3K inhibition, which leads to changes in levels of critical metabolites such 
as deoxyribonucleotide triphosphates (dNTPs), driving a cellular stress phenotype (Lynch et al., 
2017).  Proteomic technology, such as mass spectrometry and SOMAscan technology, allows 
systematic profiling of cellular metabolites and metabolic enzymes in the serum or plasma in a 
parallel and multiplexed high-throughput manner (Gold et al., 2010; Mehan et al., 2014).  We 
are particularly interested in members of the glycolytic pathway, both the enzymes as well as the 
metabolic intermediates, as these are expected to be sensitive to PI3K-inhibition (Juvekar et al., 
2016).  Some of these studies will be performed at the Beth Isreal Deaconess Medical Center 
Proteomics Core, in collaboration with Dr. Gerburg Wulf. 
 
Hypothesis:  
The analysis of plasma and serum proteomics and metabolomics over the course of study 
treatment will allow for detection of treatment-emergent alterations which may highlight 
potential resistant mechanisms. 
 

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2.6 
Rationale for Protocol Amendment #4a and Study Closure 
 
Bayer announced in November 2023 that they were voluntarily withdrawing their New Drug 
Application (NDA) for copanlisib due to failure to meet their primary endpoint in the 
CHRONOS-4 study for patients with relapsed follicular lymphoma. Therefore, this study is 
closing to any new patient enrollments. Patients currently on study who are incurring clinical 
and/or radiographic benefit may be allowed to continue on study treatment at the discretion of 
their treating physician, and if the patient consents. 
 
 
3. 
PATIENT SELECTION 
 
3.1 
Eligibility Criteria  
 
3.1.1 Male or Female patients must have metastatic or unresectable carcinoma of the breast 
that is estrogen receptor (ER) negative (less than 10%), progesterone receptor (PR) 
negative (less than 10%), and HER2 negative/unamplified. 
  
3.1.2 Patients must have had prior treatment with an anthracycline and taxane in the 
neoadjuvant, adjuvant, or metastatic setting, unless contraindicated or deemed to be 
suboptimal therapy per the treating physician. 
 
3.1.3 Patients must have progressed on at least one and not more than five prior chemotherapy 
regimens, including in the neoadjuvant, adjuvant, and metastatic settings. Prior 
chemotherapy in the neoadjuvant and/or adjuvant setting counts as one prior line. Prior 
endocrine therapy, anti-HER2 directed therapies, PARP inhibitors, immunotherapy alone, 
or other targeted therapy will not count as a prior therapy line, as long as the patient 
meets the eligibility criteria in 3.1.1 prior to enrollment. Immunotherapy combined with 
chemotherapy will be considered one line. 
 
3.1.4 All patients must agree to provide archival tumor material (most recent archival tumor 
tissue immediately prior to enrollment is strongly preferred) for research and must agree 
to undergo research tumor biopsy before treatment if presence of easily accessible lesions 
(judged by the treating physician).  For patients with bone only disease, or patients 
without easily accessible lesions for the baseline research biopsy, availability of archival 
tumor material (2 x 4-5 micron section unstained slides, plus 15-20 x 10 micron section 
unstained slides or a tumor rich block, see Section 5.1 for details) from previous breast 
cancer diagnosis or treatment is required for PTEN and PIK3CA analysis. 
 
3.1.5 Age ≥18 years.  Because no dosing or adverse event data are currently available on the 
use of copanlisib in combination with eribulin in patients <18 years of age, children are 
excluded from this study, but will be eligible for future pediatric trials.   
 
3.1.6 ECOG performance status ≤1 (Karnofsky ≥70%, see Appendix A). 
 

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3.1.7 Patients must have adequate organ and marrow function as defined below: 
 
− 
leukocytes  
 
≥3,000/mcL 
− 
absolute neutrophil count 
 
≥1,500/mcL 
− 
platelets  
 
≥100,000/mcL 
− 
hemoglobin 
 
≥ 8.0 g/dL 
− 
total bilirubin 
 
≤ 1.5 × institutional upper limit of normal (ULN) 
(≤3 × institutional ULN for patients with Gilbert 
syndrome)  
− 
AST(SGOT)/ALT(SGPT) 
 
≤3 × institutional ULN  
− 
lipase  
  
 
 
 
 
≤1.5 × ULN 
− 
creatinine  
 
<1.5 mg/dL 
AND 
− 
glomerular filtration rate (GFR) ≥50 mL/min/1.73 m2 (see Appendix B) 
− 
international normalized ratio (INR) 
≤1.5 x ULN 
− 
partial thromboplastin time (PTT) 
 ≤1.5 x ULN 
 
3.1.8 Patients with history of known Type I or Type II diabetes must have a fasting glucose 
level of <120 mg/dL on at least 2 separate occasions or HbA1c <8.5% at screening within 
14 days prior to registration. 
 
3.1.9 Patients who are therapeutically treated with an agent such as warfarin or heparin will be 
allowed to participate provided that their medication dose and INR/PTT is stable. 
 
3.1.10 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, as long as QTc interval on 
baseline ECG < 480 msec.  The use of corticosteroids as antiemetics prior to copanlisib 
administration will not be allowed.  
 
3.1.11 For patients with evidence of chronic hepatitis B virus (HBV) infection, the HBV viral 
load must be undetectable on suppressive therapy, if indicated. 
 
3.1.12 Human immunodeficiency virus (HIV)-infected patients on effective anti-retroviral 
therapy with undetectable viral load within 6 months are eligible for this trial provided 
they are on a stable regimen of anti-retroviral therapy (ART) with no medications 
otherwise prohibited by this protocol (e.g. drug-drug interactions). 
 
3.1.13 Patients with a history of hepatitis C virus (HCV) infection must have been treated and 
cured.  For patients with HCV infection who are currently on treatment, they are eligible 
if they have an undetectable HCV viral load. 
 
3.1.14 Patients with treated brain metastases are eligible if follow-up brain imaging after 
central nervous system (CNS)-directed therapy shows no evidence of progression.  For 
patients with history of treated brain metastases, brain scans will be performed within 6 
weeks of study enrollment.  During study enrollment in the phase 2 portion of the study, 

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brain MRI will be performed every 12 weeks or sooner if clinically-indicated in all 
patients with history of known brain metastases 
  
3.1.15 For Phase 1 portion of the study only: Patients with new or progressive brain 
metastases (active brain metastases) or leptomeningeal disease are eligible if the 
treating physician determines that immediate CNS specific treatment is not required and 
is unlikely to be required during the first cycle of therapy.  This is not allowed for Phase 
2 portion of the study. 
 
3.1.16 Patients with a prior or concurrent malignancy whose natural history or treatment does 
not have the potential to interfere with the safety or efficacy assessment of the 
investigational regimen are eligible for this trial. 
 
3.1.17 Patients with known history or current symptoms of cardiac disease, or history of 
treatment with cardiotoxic agents, should have a clinical risk assessment of cardiac 
function using the New York Heart Association Functional Classification.  To be eligible 
for this trial, patients should be class 2B or better.  Patients with history of known 
congestive heart failure (left ventricular ejection fraction (LVEF) <50%) must have 
documented LVEF ≥50% within 12 months of study enrollment. 
 
3.1.18 Known mutation status for PIK3CA and PTEN from archival tumor tissue analysis. 
 
3.1.19 The effects of copanlisib on the developing human fetus are unknown.  For this reason 
and because maternal toxicity, developmental toxicity and teratogenic effects have been 
observed in nonclinical studies and PI3K inhibitors as well as other therapeutic agents 
used in this trial are known to be teratogenic, women of child-bearing potential must 
agree to use adequate contraception (hormonal or barrier method of birth control; 
abstinence) prior to study entry and for the duration of study participation, and for 1 
month after the last dose of study medication.  Should a woman become pregnant or 
suspect she is pregnant while she or her partner is participating in this study, she should 
inform her treating physician immediately.  Men treated or enrolled on this protocol must 
also agree to use adequate contraception prior to the study, for the duration of study 
participation, and 3.5 months after completion of study treatment. 
 
3.1.20 Ability to understand and the willingness to sign a written informed consent document.  
Participants with impaired decision-making capacity (IDMC) who have a legally-
authorized representative (LAR) and/or family member available will also be eligible. 
 
 
3.2 
Exclusion Criteria 
 
3.2.1 Patients who have had chemotherapy or radiotherapy within 3 weeks of treatment start 
(C1D1).  
 
3.2.2 Patients who have had prior treatment with nitrosoureas or mitomycin C. 
 

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3.2.3 Patients who have had prior treatment with eribulin. 
 
3.2.4 Patients who have had prior treatment with PI3K/mTOR/AKT pathway inhibitor. 
 
3.2.5 Clinically significant ECG abnormality, including prolonged corrected QT (QTc) interval 
>480 msec or history of risk factors for Torsades de Pointes (TdP) (i.e. congestive heart 
failure, hypokalemia, hypomagnesemia, bradyarrhythmias, family history of long QT 
syndrome). 
 
3.2.6 Patients with pre-existing neuropathy of grade 2 or higher. 
 
3.2.7 Myeloid growth factors within 7 days prior to treatment start. 
 
3.2.8 Platelet transfusion within 7 days prior to treatment start. 
 
3.2.9 Patients who have not recovered from adverse events due to prior anti-cancer therapy 
(i.e., have residual toxicities > Grade 1), with the exception of alopecia.   
 
3.2.10 Patients who are receiving any other investigational agents. 
 
3.2.11 Immunosuppressive therapy is not allowed while on study. 
 
3.2.12 Known tumor AKT mutation from archival tumor tissue analysis. 
 
3.2.13 History of allergic reactions attributed to compounds of similar chemical or biologic 
composition to copanlisib, PI3K inhibitors, or other agents used in study. 
 
3.2.14 Copanlisib is primarily metabolized by CYP3A4.  Therefore, the concomitant use of 
strong inhibitors of CYP3A4 (e.g., ketoconazole, itraconazole, clarithromycin, ritonavir, 
indinavir, nelfinavir and saquinavir), and strong inducers of CYP3A4 (e.g. rifampin, 
phenytoin, carbamazepine, phenobarbital, St. John’s Wort) are not permitted from 14 
days prior to enrollment until the end of the study.   
 
Other medications that are prohibited while on copanlisib treatment:  
• Herbal medications/preparations (except for vitamins) 
• Anti-arrhythmic therapy other than beta blockers or digoxin 
 
For the list of specific medications prohibited while on copanlisib treatment refer to 
Appendix C.  Because the lists of these agents are constantly changing, it is important to 
regularly consult a frequently-updated medical reference.   
 
Appendix D (Patient Clinical Trial Wallet Card) should be provided to patients.  As part 
of the enrollment/informed consent procedures, the patient will be counseled on the risk 
of interactions with other agents, and what to do if new medications need to be prescribed 
or if the patient is considering a new over-the-counter medicine or herbal product.  

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3.2.15 Systemic corticosteroid therapy at a daily dose higher than 15 mg prednisone or 
equivalent is not permitted while on study.  Previous corticosteroid therapy must be 
stopped or reduced to the allowed dose at least 7 days prior to the CT/MRI screening.  If 
a patient is on chronic corticosteroid therapy, corticosteroids should be de-escalated to 
the maximum allowed dose before the screening.  Patients may be using topical or 
inhaled corticosteroids.  Short-term (up to 7 days) systemic corticosteroids above 15 mg 
prednisolone or equivalent will be allowed for the management of acute conditions (e.g., 
treatment non-infectious pneumonitis).  The use of corticosteroids as antiemetics prior to 
copanlisib administration will not be allowed. 
 
3.2.16 Patients with uncontrolled intercurrent illness. 
 
3.2.17 Patients with psychiatric illness/social situations that would limit compliance with study 
requirements. 
 
3.2.18 Patients with non-healing wound, ulcer, or bone fracture. Patients with compression or 
pathologic fractures that are stable in the opinion of the investigator may be enrolled, as 
long as the bone fracture is not felt to pose a high likelihood of treatment delay or 
difficulties in treatment adherence as per the judgement of the investigator.  
 
3.2.19 Patients with active, clinically serious infections > Grade 2 (CTCAEv5.0) (viral, bacterial 
or fungal infection).  
 
3.2.20 History of known Pneumocystis jiroveci pneumonia (PJP) infection. 
 
3.2.21 Patients with arterial or venous thrombotic or embolic events such as cerebrovascular 
accident (including transient ischemic attacks), deep vein thrombosis or pulmonary 
embolism within 3 months before the start of study medication. 
 
3.2.22 Concurrent diagnosis of pheochromocytoma due to risk of hypertension with copanlisib. 
 
3.2.23 Uncontrolled hypertension (defined as blood pressure ≥150/90 mm/Hg) despite optimal 
medical management (per investigator’s opinion).  
 
3.2.24 Proteinuria as estimated by urine protein/creatinine ratio >3.5 g/g on random urine 
sample or grade ≥3 as assessed by 24-hour urine protein collection. 
 
3.2.25 Patients with history of, or current uncontrolled autoimmune disease. Patients who have 
adrenal or pituitary insufficiency who are stable on replacement therapy (i.e. thyroxine or 
physiologic corticosteroid replacement therapy that meets concomitant medication 
restrictions in Section 6.3) are allowed. Limited exceptions may be made to this after 
discussion with the study PI. 
 
3.2.26 Patients with congenital QT prolongation. 
 

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34 
3.2.27 The patient has a personal history of any of the following conditions: syncope of 
cardiovascular etiology, ventricular arrhythmia of pathological origin (including, but not 
limited to, ventricular tachycardia and ventricular fibrillation), or sudden cardiac arrest. 
 
3.2.28 Pregnant women are excluded from this study because copanlisib is a PI3K inhibitor 
agent and eribulin is an anti-tubulin agent with the potential for teratogenic or 
abortifacient effects.  Because there is an unknown but potential risk for adverse events in 
nursing infants secondary to treatment of the mother with copanlisib and eribulin, 
breastfeeding should be discontinued if the mother is treated with copanlisib and/or 
eribulin.  These potential risks may also apply to other agents used in this study. 
 
3.3 
Inclusion of Women and Minorities 
 
NIH policy requires that women and members of minority groups and their subpopulations be 
included in all NIH-supported biomedical and behavioral research projects involving NIH-
defined clinical research unless a clear and compelling rationale and justification establishes to 
the satisfaction of the funding Institute & Center (IC) Director that inclusion is inappropriate 
with respect to the health of the subjects or the purpose of the research.  Exclusion under other 
circumstances must be designated by the Director, NIH, upon the recommendation of an IC 
Director based on a compelling rationale and justification.  Cost is not an acceptable reason for 
exclusion except when the study would duplicate data from other sources.  Women of 
childbearing potential should not be routinely excluded from participation in clinical research.  
Please see http://grants.nih.gov/grants/funding/phs398/phs398.pdf. 
 
4. 
REGISTRATION PROCEDURES 
 
4.1 
Investigator and Research Associate Registration with CTEP 
 
Food and Drug Administration (FDA) regulations require sponsors to select qualified 
investigators.  National Cancer Institute (NCI) policy requires all individuals contributing to 
NCI-sponsored trials to register with their qualifications and credentials and to renew their 
registration annually.  To register, all individuals must obtain Cancer Therapy Evaluation 
Program (CTEP) credentials necessary to access secure NCI Clinical Oncology Research 
Enterprise (CORE) systems.  Investigators and clinical site staff who are significant contributors 
to research must register in the Registration and Credential Repository (RCR) at 
https://ctepcore.nci.nih.gov/rcr/. The RCR is a self-service online person registration application 
with electronic signature and document submission capability. 
 
RCR utilizes four person registration types that are applicable to ETCTN trials. 
• Investigator (IVR):  MD, DO, or international equivalent, 
• Non Physician Investigator (NPIVR):  advanced practice providers (e.g., NP or PA) or 
graduate level researchers (e.g., PhD), 
• Associate Plus (AP):  clinical site staff (e.g., RN or CRA) with data entry access to CTSU 
applications such as the Roster Update Management System (RUMS), OPEN, Rave, 
acting as a primary site contact, or with consenting privileges, 
Associate (A):  other clinical site staff involved in the conduct of NCI-sponsored trials,  

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36 
Sites participating through the NCI Central Institutional Review Board (NCI CIRB) must submit 
the Study Specific Worksheet (SSW) for Local Context to the CIRB using IRBManager to 
indicate their intent to open the study locally.  The NCI CIRB’s approval of the SSW is 
automatically communicated to the CTSU Regulatory Office, but sites are required to contact the 
CTSU Regulatory Office at CTSURegPref@ctsu.coccg.org to establish site preferences for 
applying NCI CIRB approvals across their Signatory Network.  Site preferences can be set at the 
network or protocol level.  Questions about establishing site preferences can be addressed to the 
CTSU Regulatory Office by email or by calling 1-888-651-CTSU (2878). 
 
In addition, the Site-Protocol PI (i.e., the investigator on the IRB/REB approval) must meet the 
following criteria for the site to be able to have an Approved status following processing of the 
IRB/REB approval record: 
• Have an active CTEP status, 
• Have an active status at the site(s) on the IRB/REB approval (applies to US and Canadian 
sites only) on at least one participating organization’s roster, 
• If using NCI CIRB, be active on the NCI CIRB roster under the applicable CIRB 
Signatory Institution(s) record, 
• Include the IRB number of the IRB providing approval in the Form FDA 1572 in the RCR 
profile, 
• List all sites on the IRB/REB approval as Practice Sites in the Form FDA 1572 in the 
RCR profile; and 
• Have the appropriate CTEP registration type for the protocol.  
 
Additional Requirements 
 
Additional site requirements to obtain an approved site registration status include: 
• An active Federal Wide Assurance (FWA) number, 
• An active roster affiliation with the Lead Protocol Organization (LPO) or a Participating 
Organization (PO),  
• An active roster affiliation with the NCI CIRB roster under at least one CIRB Signatory 
Institution (US sites only); and 
• Compliance with all applicable protocol-specific requirements (PSRs). 
 
4.2.1 Downloading Site Registration Documents 
 
Download the site registration forms from the protocol-specific page located on the CTSU 
members’ website.  Permission to view and download this protocol and its supporting documents 
is restricted to institutions and their associated investigators and staff on a participating roster.  
To view/download site registration forms:   
 
• Log in to the CTSU members’ website (https://www.ctsu.org), 
• Click on Protocols in the upper left of the screen 
o Enter the protocol number in the search field at the top of the protocol tree, or 
o Click on the By Lead Organization folder to expand, then select LAO-CT018, and 
protocol number 10382, 

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37 
• Click on Documents, Protocol Related Documents, and use the Document Type filter and 
select Site Registration to download and complete the forms provided.  (Note:  For sites 
under the CIRB, IRB data will load automatically to the CTSU.)  
 
4.2.2 Protocol Specific Requirements For 10382 Site Registration 
 
• Site Initiation Meeting (SIM) by the Study Chair/Lead Principal Investigator (Prior to the 
start of subject enrollment, participating sites must contact the Study Chair/Study 
Coordinator to schedule a SIM.) 
 
•  Specimen Tracking System Training Requirement: 
o All data entry users (Clinical Research Associate role) at each participating site will 
need to complete the Theradex-led training. 
o Theradex will provide a certificate of completion, which will need to be submitted to 
the CTSU through the Regulatory Submission Portal. 
o The training is a one-time only requirement per individual.  If an individual has 
previously completed the training for another ETCTN study, the training does not 
need to be completed again nor does the certificate of completion need to be 
resubmitted to the CTSU.  Users are strongly encouraged to take a refresher of the 
training if they have not entered specimen data for an extended period of time. 
o This training will need to be completed before the first patient enrollment at a given 
site. 
o Please contact STS Support at Theradex for the training 
(STS.Support@theradex.com). 
 
4.2.3 Submitting Regulatory Documents 
 
Submit required forms and documents to the CTSU Regulatory Office via the Regulatory 
Submission Portal on the CTSU members’ website.  
 
To access the Regulatory Submission Portal, log on to the CTSU members’ website, go to the 
Regulatory section, and select Regulatory Submission. 
 
Institutions with patients waiting that are unable to use the Regulatory Submission Portal should 
alert the CTSU Regulatory Office immediately by phone or email: 1-866-651-CTSU (2878), or 
CTSURegHelp@coccg.org in order to receive further instruction and support. 
 
Delegation of Tasks Log (DTL) 
 
Each site must complete a protocol-specific DTL using the DTL application in the Delegation 
Log section on the CTSU members’ website.  The Clinical Investigator (CI) is required to review 
and electronically sign the DTL prior to the site receiving an Approved site registration status 
and enrolling patients to the study.  To maintain an approved site registration status the CI must 
re-sign the DTL at least annually and when a new version of the DTL is released; and activate 
new task assignments requiring CI sign-off.  Any individual at the enrolling site on a 
participating roster may initiate the site DTL.  Once the DTL is submitted for CI approval, only 

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38 
the designated DTL Administrators or the CI may update the DTL.  Instructions on completing 
the DTL are available in the Help Topics button in the DTL application and describes DTL task 
assignments, CI signature, and CTEP registration requirements, as well as includes a Master 
Task List. 
 
4.2.4 Checking Site Registration Status 
 
Site’s registration status may be verified on the CTSU members’ website.  
 
• Click on Regulatory at the top of the screen, 
• Click on Site Registration, and  
• Enter the site’s 5-character CTEP Institution Code and click on Go. 
o Additional filters are available to sort by Protocol, Registration Status, Protocol 
Status, and/or IRB Type. 
Note:  The status shown only reflects institutional compliance with site registration requirements 
as outlined within the protocol.  It does not reflect compliance with protocol requirements for 
individuals participating on the protocol or the enrolling investigator’s status with NCI or their 
affiliated networks. 
 
4.3 
Patient Registration 
 
4.3.1 OPEN / IWRS 
 
The Oncology Patient Enrollment Network (OPEN) is a web-based registration system available 
on a 24/7 basis.  OPEN is integrated with CTSU regulatory and roster data and with the Lead 
Protocol Organization (LPOs) registration/randomization systems or Theradex Interactive Web 
Response System (IWRS) for retrieval of patient registration/randomization assignment.  OPEN 
will populate the patient enrollment data in NCI’s clinical data management system, Medidata 
Rave. 
 
Requirements for OPEN access:   
 
• Active CTEP registration with the credentials necessary to access secure NCI/CTSU IT 
systems. 
• To perform enrollments or request slot reservations:  Must be on an LPO roster, ETCTN 
Corresponding roster, or Participating Organization roster with the role of Registrar.  
Registrars must hold a minimum of an AP registration type. 
• If a DTL is required for the study, the registrar(s) must hold the OPEN Registrar task on 
the DTL for the site. 
• Have an approved site registration for a protocol prior to patient enrollment. 
 
To assign an Investigator (IVR) or Non-Physician Investigator (NPIVR) as the treating, 
crediting, consenting, or receiving investigator for a patient transfer in OPEN, the IVR or NPIVR 
must list the Institutional Review Board’s (IRB) number used on the site’s IRB approval on their 
Form Food and Drug Administration (FDA) 1572 in Registration and Credential Repository 
(RCR).  If a DTL is required for the study, the IVR or NPIVR must be assigned the appropriate 

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39 
OPEN-related tasks on the DTL. 
 
Prior to accessing OPEN, site staff should verify the following: 
 
• Patient has met all eligibility criteria within the protocol stated timeframes, and  
• All patients have signed an appropriate consent form and Health Insurance Portability 
and Accountability Act (HIPAA) authorization form (if applicable). 
 
Note:  The OPEN system will provide the site with a printable confirmation of registration and 
treatment information.  Please print this confirmation for your records.  
 
Access OPEN at https://open.ctsu.org or from the OPEN link on the CTSU members’ website.  
Further instructional information is in the OPEN section of the CTSU website at 
https://www.ctsu.org or https://open.ctsu.org.  For any additional questions, contact the CTSU 
Help Desk at 1-888-823-5923 or ctsucontact@westat.com. 
 
Patient enrollment for this study will be facilitated using the Slot Reservation System in 
conjunction with patient enrollment in OPEN.  Prior to discussing protocol entry with the patient, 
all site staff must use the CTSU OPEN Slot Reservation System to ensure that a slot on the 
protocol is available to the patient.  Once a slot reservation confirmation is obtained, site staff 
may then proceed to enroll the patient to this study. Step 0 registration of patient in CTSU OPEN 
should occur within 1 business day of patient’s obtained informed consent signature. 
 
4.3.2 Special Instructions for Patient Enrollment 
 
This Study will use the ETCTN Specimen Tracking System (STS).  
 
• 
All biospecimens collected for this trial must be submitted using the ETCTN Specimen 
Tracking System (STS) unless otherwise noted.   
• 
Important:  Failure to complete required fields in STS may result in a delay in 
sample processing.  Any case reimbursements associated with sample submissions will 
not be credited if samples requiring STS submission are not logged into STS. 
• 
The system is accessed through Rave user roles:  “Rave CRA” and “Rave CRA 
(Labadmin)” for data entry at the treating institutions and “Biorepository” for users 
receiving the specimens for processing and storage at reference labs and the 
Biorepository.   
• 
Please refer to the Medidata Account Activation and Study Invitation Acceptance link on 
the CTSU website in the Data Management section  under the Rave Home tab and then 
under Rave Resource Materials. 
 
Detailed instructions can be found in Section 5.4. 
 
Patient Registration Process:  
 
1. Site confirms slot availability and reserves slot in Theradex IWRS prior to consenting 
patient. 

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2. Site enters first step data into OPEN.  
3. IWRS received data from OPEN, generates the Patient Study ID and the Universal 
Patient ID, both of which are sent back to OPEN.  
4. IWRS send first step registration data, including the IDs and a TAC of “NOT REG” 
directly to Rave.  
5. The specimen tracking system in Rave is utilized for submission of baseline samples if 
collected prior to C1D1 (specimen tracking role required). 
6. When eligibility is confirmed at the site, Step 2 registration is completed in 
OPEN.  IWRS receives all data from OPEN, then sends it to Rave with the assigned 
TAC. 
 
Patient Randomization for Phase 2: 
 
Prior to accessing OPEN/IWRS to register/randomize patient, site staff should verify the 
following: 
• All eligibility criteria have been met within the protocol stated timeframes.   
• If applicable, all patients have signed an appropriate consent form and HIPAA 
authorization form. 
 
A stratified randomization for the phase 2 portion of the study will be conducted to assign 
patients in a 1:1 ratio to Eribulin alone group or Eribulin and Copanlisib group.  The 
stratification factor will be by PTEN/PIK3CA mutation status per archival tumor tissue analysis 
(altered or not). 
 
The OPEN system will provide the site with a printable confirmation of registration and 
treatment information.  Please print this confirmation for your records.  
 
4.3.3 OPEN/IWRS Questions? 
 
Further instructional information on OPEN is provided on the OPEN link of the CTSU website 
at https://www.ctsu.org or at https://open.ctsu.org.  For any additional questions contact the 
CTSU Help Desk at 1-888-823-5923 or ctsucontact@westat.com.  
 
Theradex has developed a Slot Reservations and Cohort Management User Guide, which is 
available on the Theradex website:  http://www.theradex.com/clinicalTechnologies/?National-
Cancer-Institute-NCI-11. This link to the Theradex website is also on the CTSU website OPEN 
tab. For questions about the use of IWRS for slot reservations, contact the Theradex Helpdesk at 
855-828-6113 or Theradex main number 609-799-7580; CTMSSupport@theradex.com. 
 
4.4 
General Guidelines 
 
Following registration, patients should begin protocol treatment within 14 days.  Issues that 
would cause treatment delays should be discussed with the Principal Investigator.  If a patient 
does not receive protocol therapy following registration, the patient’s registration on the study 
may be canceled.  The Study Coordinator should be notified of cancellations as soon as possible. 
 

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• 10 mL blood clot -tube (red top) processed for 
serum (Mandatory) 
1For archival tissue, a copy of the corresponding anatomic pathology report must be sent with the 
tissue and uploaded to Rave.  If submitting slides, then slides must be processed in order, and 
numbered sequentially. Clearly label the section thickness on slides. 
2For new biopsies, the Tissue Biopsy Verification Form (Appendix H), a copy of the radiology 
and/or operative reports from the tissue removal procedure and the diagnostic anatomic pathology 
report must be sent with the tissue to the EET Biobank.   
3Blood collections will occur at C2D1. 
4Disease progression specimens should be collected prior to beginning any additional therapies.  
 
 
5.2 
Summary Table(s) for Research Biopsies 
 
Biopsy #:  1 
Trial Time Point:  Baseline 
Biopsy Definition:  Research – No Clinical Impact  
Core 
Priority 
Use in the 
Trial 
Biomarker 
Name(s) 
Tumor 
Content 
Required 
Post-Biopsy Processing 
1 
Integrated 
PTEN IHC 
At least 50 
evaluable 
tumor cells 
Formalin 
2 
Integrated  
RPPA 
>60%  
Snap-frozen 
3 
Exploratory 
WES/RNASeq 
>50%  
Snap-frozen 
 
Biopsy #:  2 
Trial Time Point:  Cycle 2 Day1-2 
Biopsy Definition:  Research – No Clinical Impact  
Core 
Priority 
Use in the 
Trial 
Biomarker 
Name(s) 
Tumor 
Content 
Required 
Post-Biopsy Processing 
1 
Integrated 
RPPA 
 
>60% 
Snap-frozen 
2 
Exploratory 
RNASeq 
>50%  
Snap-frozen 
3 
Exploratory 
RNASeq 
>50%  
Snap-frozen 
 
 
Biopsy #:  3 
Trial Time Point:  Disease Progression 
Biopsy Definition:  Research – No Clinical Impact  
Core 
Priority 
Use in the 
Trial 
Biomarker 
Name(s) 
Tumor 
Content 
Required 
Post-Biopsy Processing 
1 
Integrated 
RPPA 
>60%  
Snap-frozen 

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2 
Integrated 
PTEN IHC 
At least 50 
evaluable 
tumor cells 
Formalin 
3 
Exploratory 
WES/RNASeq 
>50%  
Snap-frozen 
 
 
5.3 
Specimen Procurement Kits and Scheduling 
 
5.3.1 Specimen Procurement Kits  
 
Kits for the collection and shipment of tissue in formalin, snap frozen tissue cores, and blood in 
cfDNA Streck tubes to the EET Biobank can be ordered online via the Kit Management system: 
(https://kits.bpc-apps.nchri.org/Auth/Login?ReturnUrl=%2fKitOrders%2fCreate).  
 
Users at the clinical sites will need to set up an account in the Kit Management system and select 
a specific clinical trial protocol to request a kit.  Please note that protocol may include more than 
one type of kit.  Each user may order two kits per kit type per protocol per day (daily max = 6 
kits).  Kits are shipped ground, so please allow 5-7 days for receipt.  A complete list of kit 
contents for each kit type is located on the Kit Management system website. 
 
Note:  Kits or supplies are only provided for specimens shipped to the Biorepository. 
Institutional supplies must be used for all other specimen collection and processing.  
 
5.3.2 Scheduling of Specimen Collections 
 
Please adhere to the following guidelines when scheduling procedures to collect tissue:  
• Tumor tissue specimens collected during biopsy procedures and fixed in formalin must 
be shipped on the same day of collection. 
• Tissue in formalin can be collected Monday through Wednesday and shipped overnight 
for arrival on Tuesday through Thursday at the EET Biobank at Nationwide Children’s 
Hospital. 
• 
Tissue submitted as FFPE (blocks or slides) can be collected on any day but must be 
shipped to the EET Biobank on Monday through Thursday.  
• Specimens submitted frozen including tumor cores, plasma, and serum can be collected 
on any day but must be stored frozen and shipped to the EET Biobank on Monday 
through Thursday.  In the event that frozen specimens cannot be shipped immediately, 
they must be maintained in a -70°C to -80°C freezer. 
 
• Fresh blood specimens may be collected and shipped Monday through Friday.  
 
5.4 
Specimen Tracking System Instructions 
 
5.4.1 Specimen Tracking System Overview and Enrollment Instructions 
 
For the ETCTN STS, the following information will be requested: 

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• Protocol Number 
• Investigator Identification  
o Institution and affiliate name 
o Investigator’s name 
• Eligibility Verification:  Patients must meet all the eligibility requirements listed in 
Section 3. 
• Additional Requirements: 
o Patients must provide a signed and dated, written informed consent form. 
 
Upon enrolling a patient, IWRS will communicate with OPEN, assigning two separate and 
unique identification numbers to the patient, a Universal patient ID (UPID) and a Treatment 
patient ID.  The UPID is associated with the patient and used each and every time the patient 
engages with the portion of this protocol that uses the ETCTN Specimen Tracking System.  The 
UPID contains no information or link to the treatment protocol.  IWRS will maintain an 
association between the UPID for ETCTN biobanking and molecular characterization and any 
treatment protocols the patient participates in, thereby allowing analysis of the molecular 
characterization results with the clinical data.   
 
Immediately following enrollment, the institutional anatomical pathology report for the diagnosis 
under which the patient is being enrolled must be uploaded into Rave.  The report must include 
the surgical pathology ID (SPID), collection date, block number, and the IWRS-assigned UPID 
and patient study ID for this trial.  For newly acquired biopsies without a corresponding 
pathology report, the radiology and operative report(s) must also be uploaded into Rave, when 
available.  Important:  Remove any personally identifying information, including, but not 
limited to, the patient’s name, date of birth, initials, medical record number, and patient 
contact information from the institutional pathology report prior to submission. 
 
Additionally, please note that the STS software creates pop-up windows when reports are 
generated, so you will need to enable pop-ups within your web browser while using the software.   
 
For questions regarding the Specimen Tracking System, please contact the STS Support at 
STS.Support@theradex.com. 
 
The Shipping List report must be included with all sample submissions. 
 
5.4.2 Specimen Labeling 
 
5.4.2.1 Blood Specimen Labels  
 
Include the following on blood specimens (including whole blood and frozen, processed blood 
products – like serum and plasma): 
• Patient Study ID 
• Universal Patient ID (UPID) 
• Specimen ID (automatically generated by Rave) 
• Time point 
• Specimen type (e.g., blood, serum) 

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• Collection date  (to be added by hand) 
 
5.4.2.2 Tissue Specimen Labels  
 
Include the following on all tissue specimens or containers (e.g., formalin jar):  
• Patient Study ID 
• Universal Patient ID (UPID) 
• Specimen ID (automatically generated by Rave) 
• Time point 
• Specimen type (e.g., formalin-fixed paraffin-embedded [FFPE] Block, Formalin 
Fixed Tissue, Frozen Tissue, etc.) 
• Tissue type (P for primary, M for metastatic or N for normal) 
• Surgical pathology ID (SPID) number (when applicable)  
• Block number from the corresponding pathology report (archival only) 
• Collection date  (to be added by hand) 
• Slide section number (only if archival tissue is submitted as slides) (to be added by 
hand) 
• Core number (only for new tissue biopsy cores) (to be added by hand) 
 
 
5.4.2.3 
    Example of Specimen Label Generated by STS 
 
STS includes a label printing facility, accessed via the Print Label CRF in the All Specimens 
folder. A generated PDF is emailed to the user as a result of saving that form.  
 
The following image is an example of a tissue specimen label printed on a label that is 0.5” high 
and 1.28” wide. 
The QR code in the above example 
is for the Specimen ID shown on the second line.   
 
Labels may be printed on a special purpose label printer, one label at a time, or on a standard 
laser printer, multiple labels per page. Theradex recommends the use of these low temperature 
waterproof labels for standard laser printers: https://www.labtag.com/shop/product/cryo-laser-
labels-1-28-x-0-5-cl-23-colors-available/ 
 
 

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The last line item on the label includes the following data points joined together: 
1. Tissue only: Primary (P), Metastatic (M), Normal (N) tissue indicated at the 
beginning of the specimen ID; this field is blank if not relevant (e.g., for blood) 
2. Block ID or blank if not relevant 
3. SPID (Surgical Pathology ID) or blank if none 
4. An optional alpha-numeric code that is protocol specific and is only included if the 
protocol requires an additional special code classification 
 
Space is provided at the bottom of the label for the handwritten date and optional time.  
The last line on the example label is for the handwritten date and optional time. 
 
5.4.3 Overview of Process at Treating Site 
 
5.4.3.1 OPEN Registration 
 
All registrations will be performed using the Oncology Patient Enrollment Network (OPEN) 
system.  OPEN communicates automatically with the Interactive Web Response System (IWRS) 
which handles identifier assignments, any study randomization, and any prescribed slot 
assignments.  If specimen analysis is required to determine eligibility, the protocol will be setup 
with multi-step registration. 
 
Registration without eligibility specimen analysis:  
 
1. Site enters registration data into OPEN during one or more steps. 
2. IWRS receives data from OPEN, generates the Patient Study ID and the Universal Patient 
ID, both of which are sent back to OPEN. 
3. IWRS sends all applicable registration data directly to Rave at the end of the final 
registration step. 
 
Any data entry errors made during enrollment should be corrected in Rave. 
 
5.4.3.2 Rave Specimen Tracking Process Steps 
 
Step 0: Log into Rave via your CTEP-IAM account, then navigate to the appropriate participant. 
Step 1:  Complete the Histology and Disease form (but do not upload reports until a specimen 
label can be applied to them) and the Baseline forms regarding Prior Therapies.  Enter the 
initial clinical specimen data:  
• Specimen Tracking Enrollment CRF:  Enter Time Point, Specimen Category, 
Specimen Type, Block number, Tissue type, Surgical Path ID, and number of labels 
needed (include extra labels to apply to reports to be uploaded).  CRF generates unique 
Specimen ID.  
 
Step 2:  Print labels using the Print Labels CRF located in the All Specimens folder, then 
collect specimen. 
• Label specimen containers and write collection date on each label.   

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• After collection, store labeled specimens as described in Section 5.4.2. 
• Apply an extra specimen label to each report before scanning.  Return to the Histology 
and Disease form to upload any initial Pathology, Radiology, Molecular Reports (up to 
4), Surgical (or Operative) reports. Return to Specimen Tracking Enrollment CRF to 
upload any molecular report (one per specimen) and/or specimen specific pathology or 
related report (one per specimen) and/or the Tissue Biopsy Verification form (Appendix 
H).  Uploaded reports should have protected health information (PHI) data, like name, 
date of birth, mailing address, medical record number or social security number (SSN), 
redacted.  Do not redact SPID, block number, diagnosis or relevant dates (such as 
collection date), and include the UPID and patient study ID on each document 
(either by adding a label or hand writing).  
 
Step 3:  Complete specimen data entry. 
• Specimen Transmittal Form:  Enter collection date and time and other required 
specimen details. 
 
Step 4:  When ready to ship, enter shipment information. 
• Shipping Status CRF:  Enter tracking number, your contact information, recipient, 
number of sample containers and ship date once for the first specimen in a shipment. 
Copy Shipping CRF:  In the specimen folders for additional specimens (if any) that will 
be shipped with the initial specimen, please use the Copy Shipping form to derive 
common data into additional Shipping Status forms. A few unique fields will still need 
to be entered in Shipping Status.   
 
Step 5:  Print shipping list report and prepare to ship.  
• Shipping List report is available at the site level. 
• Print two copies of the shipping list, one to provide in the box, the other for your own 
records. 
• Print pathology or other required reports to include in the box.  Be sure the printed copy 
includes the specimen label. 
 
Step 6:  Send email notification.  
• For only one of the specimens in the shipment, click “Send Email Alert” checkbox on the 
Shipping Status CRF to email recipient. 
 
Step 7:  Ship the specimen(s). 
Step 8: Monitor the Receiving Status form located in each specimen folder for acknowledgment 
of receipt and adequacy. 
 
5.5 
Specimen Collection  
 
5.5.1 Archival Tumor (Required)  
 
If previously-collected FFPE tissue will be submitted, then the following criteria must be met: 
 

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• Tissue from previous diagnostic or therapeutic procedures of the primary breast cancer or 
metastatic site is required for all patients.  (There is no time limit for this specimen; any 
previously collected specimen is accepted, but when available it is preferred to submit the 
most immediate tissue prior to study enrollment.)   
• Tumor rich FFPE tumor tissue block(s) is preferred.  The optimal block is at least 70% 
tumor.  Specimen size requirement is as follows: 
o Surface area:  25 mm2 is optimal.  Minimum is 5 mm2. 
o Volume:  1 mm3 optimal.  Minimum volume is 0.2 mm3, however the success of 
DNA extraction decreases at suboptimal tissue volume. 
 
If an existing tumor tissue block cannot be submitted, the following are requested: 
• Fifteen to twenty (15-20) 10 µm unstained, uncharged, air dried slides  
• Two (2) 4-5 µm unstained charged slides  
• One (1) 3-5 μm H&E stained slide 
 
Process and number slides sequentially (e.g., H&E stained slide should be created first and 
labeled with “1,” and additional unstained slides should be processed next and be labeled 2 – n). 
Clearly label section thickness on slides. 
 
See Section 5.4.2.2 for labeling instructions. 
 
5.5.2 Biopsy Collection Procedure - Tumor Specimen Allocation and Prioritization 
 
Baseline (Required) 
Tumor biopsy is required for all patients with accessible tumors that could be safely biopsied as 
determined by the site investigator.  This will serve as additional tumor material to analyze in 
cases of insufficient quantity, or quality, archival tumor material for sequencing studies. 
• Biopsy Core Collection:  Either skin punches (in cases of skin metastasis) or core 
biopsies (in the clinic or by radiology guidance) will be performed according to the 
sequence of priority listed below.  If feasible, up to 3 cores (or punches) will be taken at 
each time point.  Punches could be divided to smaller pieces to make up the 3 cores.   
o Core (punch) #1:  Place in the formalin jar provided in the biopsy kit at room 
temperature (for PTEN IHC) 
o Core (punch) #2:  Place in a cryovial, snap freeze on dry ice then put in a Ziploc 
bag (for RPPA), vapor phase liquid nitrogen be preferred, if available 
o Core (punch) #3:  Place in a cryovial, snap freeze on dry ice then put in a Ziploc 
bag, vapor phase liquid nitrogen be preferred, if available (for RNA Seq and 
Whole Exome Seq) 
 
For cores 2 and 3, if immediate bedside freezing is not possible, place samples on ice for a 
maximum of 2 h before freezing procedure to avoid protein and RNA degradation.  
 
C2D1-2 (Required)  
▪ Collect biopsy within 2-8 h post the administration of copanlisib, for scheduling issues, 
up to 24 h following the copanlisib is acceptable. 
▪ Biopsy core collection:  Either skin punches (in cases of skin metastasis) or core biopsies 

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(in the clinic or by radiology guidance) will be performed according to the sequence of 
priority listed below.  If feasible, up to 3 cores (or punches) will be taken at each time 
point.  Punches could be divided to smaller pieces to make up the 3 cores.  (Note that 
frozen cores are priorities at these time points rather than formalin fixation which was 
the priority at Baseline collection) 
o Core (punch) #1:  Place in a cryovial and snap freeze on vapor phase liquid 
nitrogen (preferred, if available) or dry ice, wrap in foil then put in a Ziploc bag 
(for RPPA) 
o Core (punch) #2 and #3:  Place in a cryovial, Snap freeze on dry ice then put in a 
Ziploc bag (for RNA Seq); vapor phase liquid nitrogen be preferred, if available  
 
For cores 1, 2 and 3, if immediate bedside freezing is not possible, place samples on ice 
for a maximum of 2 h before freezing procedure to avoid protein and RNA degradation.  
 
Disease Progression (Optional)  
▪ Biopsy core collection:  Either skin punches (in cases of skin metastasis) or core biopsies 
(in the clinic or by radiology guidance) will be performed according to the sequence of 
priority listed below.  If feasible, up to 3 cores (or punches) will be taken at each time 
point.  Punches could be divided to smaller pieces to make up the 3 cores.  (Note that 
frozen cores are priorities at these time points rather than formalin fixation which was 
the priority at Baseline collection) 
o Core (punch) #1:  Place in a cryovial and snap freeze on vapor phase liquid 
nitrogen (preferred, if available) or dry ice, wrap in foil then put in a Ziploc bag 
(for RPPA)  
o Core (punch) #2:  Place in the formalin jar provided in the biopsy kit at room 
temperature (for PTEN IHC) 
o Core (punch) #3:  Place in a cryovial, Snap freeze on dry ice then put in a Ziploc 
bag (for RNA Seq and Whole Exome Seq); vapor phase liquid nitrogen be 
preferred, if available   
 
For cores 1, and 3, if immediate bedside freezing is not possible, place samples on ice for 
a maximum of 2 h before freezing procedure to avoid protein and RNA degradation.  
 
 
5.5.3 Collection of formalin tissue specimen using kits  
 
Pre-label each formalin jar (See Specimen Tracking instructions in Section 5.4.2.2 for labeling 
requirements). 
 
5.5.3.1 
Reagents, supplies, and equipment 
 
• 
Pre-filled formalin jars (provided in kit) 
• 
Mesh cassettes (provided in kit) 
• 
Autoclaved forceps 
 

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5.5.3.2 
Procedures 
 
1. Immediately transfer each biopsy specimen into a tissue cassette to prevent specimen 
damage.  Place cassette in the pre-filled formalin jar.  
2. Perform fixation at room temperature (20-25°C).  Record the time of fixation and enter 
into the Sample Tracking System (Rave) for all submitted specimens.  The optimal 
duration of fixation should be 16-24 h by the time it is received at the EET Biobank. 
3. Ship the specimen to the EET Biobank (FedEx Priority Overnight strongly preferred) for 
processing the day of collection to allow for paraffin embedding within 48 h. 
4. See Section 5.6 for instructions for shipping to the EET Biobank at Nationwide 
Children’s Hospital. 
 
5.5.4 Collection of Biopsy to Snap-Freeze 
 
Pre-label each cryovial (See Specimen Tracking instructions in Section 5.4.2.2 for labeling 
requirements). 
 
5.5.4.1 
Reagents, supplies and equipment 
 
• Autoclaved forceps 
• Cryovials (provided in kit) 
• Dry ice or liquid nitrogen 
• -80°C freezer  
 
5.5.4.2 
Procedures 
 
1. Tissue should be frozen as soon as possible.  Optimally, freeze within 30 minutes from 
resection.  If immediate bedside freezing is not possible, place samples on ice for a 
maximum of 2 hours before freezing procedure to avoid protein and RNA degradation. 
2. Label cryovial(s) according to instructions in Section 5.4.2.2.  
3. Using clean forceps place the tissue in a pre-chilled cryovial and freeze the tube in either 
vapor phase liquid nitrogen (preferred), on dry ice, or by immediate placement in a -70 to 
-80°C freezer.  Keep frozen until shipment to the EET Biobank. 
 
5.5.5 Blood Samples 
 
5.5.5.1 
Whole blood collection in red-top tubes for serum processing 
 
Blood in redtop tubes will be collected at the following time points: 
• Baseline 
• C2D1 
• Each tumor restaging assessment (every 9 weeks +/- 7 days)  
• Disease Progression 
 
1) Label one 10 mL red-top tube. Refer to section 5.4.2.1 for labeling requirements. 
2) Collect 10 mL of whole blood in the red-top tube.  

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3) Allow blood to clot upright at room temperature for at least 30 minutes (maximum 60 
minutes) prior to processing.  If the blood is not immediately processed after the clotting 
period, then tubes should be stored (after the 30-60 minutes of clotting time) at 4°C for no 
longer than 4 h.  Process serum from red top tubes by centrifuging at 1,200 x g at 4°C for 10 
minutes. 
4) Using a clean transfer pipette, aliquot serum into pre-labeled cryovials at an aliquot volume 
of 1 mL per tube.  Do not disturb the red blood cells when aliquoting.  This can be done by 
keeping the pipet above the red blood cell layer and leaving a small amount of serum in the 
tube.  Tightly secure the cap of the vials before storage.  Aliquoting and freezing of serum 
specimens should be completed within 1 h of centrifugation.  
5) Store serum cryovials upright in a specimen box or rack in an -70°C to -90°C or colder 
freezer prior to shipping.  Do not allow specimens to thaw after freezing.  
 
See Section 5.6 for instructions for shipping to the EET Biobank at Nationwide Children’s 
Hospital. 
 
5.5.5.2 
Whole blood collection in purple-top (EDTA) tubes for plasma processing 
 
Blood in EDTA at the following time point: 
• Baseline 
• C2D1 
• Each tumor restaging assessment (every 9 weeks +/- 7 days) 
• Disease Progression 
 
1) Label 10 mL purple-top (EDTA) tube(s). Refer to section 5.4.2.1 for labeling requirements. 
2) Collect 10 mL of whole blood in purple-top (EDTA) tube(s). 
3) After collection, gently invert tube(s) 5-10 times to ensure adequate mixing of anticoagulant.  
4) Process plasma from EDTA tube at all time points by centrifuging at 1,200 x g at 4°C for 10 
minutes. 
5) Using a clean transfer pipette, aliquot plasma into pre-labeled cryovials at a volume of 1 mL 
per tube.  Do not disturb the buffy coat or red blood cells when aliquoting.  This can be done 
by keeping the pipet above these layers and leaving a small amount of plasma above the 
buffy coat.  
6) Tightly secure the caps of the vials before storage.  Aliquoting and freezing of plasma 
specimens should be completed within 1 h of centrifugation.  
7) Store plasma cryovials upright in a specimen box or rack in an -70°C to -90°C or colder 
freezer prior to shipping.  Do not allow specimens to thaw after freezing.  
 
See Section 5.6 for instructions for shipping to the EET Biobank at Nationwide Children’s 
Hospital. 
 
5.5.5.3 
Whole blood collection in cfDNA Streck tubes 
 
Blood in cfDNA tubes will be collected at the following time points: 
• Baseline 
• C2D1 

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• Each tumor restaging assessment (every 9 weeks +/- 7 days) 
• Disease Progression 
 
• Label two cfDNA Streck tubes.  Refer to section 5.4.2.1 for labeling requirements. 
• After collection, blood in cfDNA Streck tubes should never be refrigerated, as this may 
compromise the specimen.  Blood collected in cfDNA Streck tubes is stable at room 
temperature.  
 
See Section 5.6 for instructions for shipping to the EET Biobank at Nationwide Children’s 
Hospital. 
 
5.6 
Shipping Specimens from Clinical Site to the EET Biobank  
 
5.6.1 General Shipping Information 
 
Core biopsies that are fixed in formalin and fresh blood should be shipped as one shipment at 
ambient temperature, whenever possible.  The shipping container sent with kit contents should 
be used to ship specimens to the EET Biobank.  In winter months, please include extra 
insulation, such as bubble wrap, inside the shipping container. 
 
For formalin-fixed biopsies, if the corresponding anatomical pathology report is not available at 
the time of shipment, then the Tissue Biopsy Verification form, operative and/or radiology 
report, and diagnostic pathology report must be uploaded to the ETCTN specimen tracking 
system and included in the package, or the specimen will not be processed.  
  
For all archival tissue, the corresponding anatomical clinical pathology report is required both in 
the package and uploaded in the ETCTN specimen tracking system.  If this is not available at the 
time of shipment, then it must be uploaded to the ETCTN specimen tracking system, or the 
specimen will not be processed.  The pathology report must state the disease diagnosis made by 
the reviewing pathologist. 
 
5.6.1.1 Required Forms for Specimen Submissions 
 
Each document submitted with the specimen must be labeled with a label printed from the 
STS, or the Universal ID and Patient Study ID.  
 
Tissue  
Required Forms 
Archival 
1. Shipping List 
2. Corresponding Pathology Report 
Formalin-fixed biopsy 
 
1. Shipping List 
2. Tissue Biopsy Verification Form (Appendix H) 
3. Diagnostic Pathology Report  
4. Operative and/or Radiology Report 
 

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Tissue  
Required Forms 
Blood 
1. Shipping List 
 
 
 
5.6.2 Specimen Shipping Instructions 
 
Tissue in formalin must be shipped on the day of collection.  Collect and ship on Monday 
through Wednesday. 
 
Frozen specimens and archival (FFPE) tissue may be shipped on Monday through Thursday.  
 
Fresh blood may be shipped on Monday through Friday.  Please select “Saturday Delivery” 
when shipping fresh blood on a Friday.  
 
5.6.2.1 
Shipping FFPE Blocks and Glass Slides  
 
1. Before packaging blocks or slides, verify that each specimen is labeled according to 
Section 5.4.2.2. 
2. Blocks should be placed in a hard-sided container, preferably a special block holder, to 
protect the specimen.  Glass slides are to be placed in plastic slide holders.  Place tissue 
paper on top of the separated slides prior to closing the slide holder to reduce slide 
movement during shipment. 
3. Place the blocks or slides in a reinforced cardboard shipping box with appropriate 
packaging filler to minimize movement of specimens within the shipping box. 
4. Include a copy of the forms listed above and a shipping manifest from the Specimen 
Tracking System with each shipment.  
5. Please include a cold pack when shipping on hot days and extra insulation on cold days. 
6. Ship specimens to the address listed below.  FedEx Priority Overnight is strongly 
recommended to prevent delays in package receipt.  
 
5.6.2.2 
Shipping Frozen Tissue Cores (Cycle 2 Day 1-2) in a Single-Chamber Kit 
 
1. Before packaging specimens, verify that each specimen is labeled according to the 
instructions above and that lids of all primary receptacles containing liquid are tightly 
sealed.  
2. Place the specimens in zip-lock bags.  Use a separate zip-lock bag for each specimen type 
and time point.  
3. Place the zip-lock bags in the biohazard envelope containing absorbent material.  Expel 
as much air as possible and seal securely.  
4. Put the secondary envelope into a Tyvek envelope.  Expel as much air as possible and 
seal securely.  
5. Place frozen specimens in the kit compartment with dry ice.  Layer the bottom of the 
compartment with dry ice until it is approximately one-third full.  Place the frozen 
specimens on top of the dry ice.  Cover the specimens with the dry ice until the 
compartment is almost completely full.  When packaging specimens, ensure that you 

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leave enough room to include at least 5 pounds of dry ice in the shipment.  
6. Insert a copy of the required forms into a plastic bag and place in the kit chamber. 
7. Place the Styrofoam lid on top to secure specimens during shipment.  Do not tape the 
inner chamber shut. 
8. Close the outer lid of the Specimen Procurement Kit and tape it shut with durable sealing 
tape.  Do not completely seal the container. 
9. Complete a FedEx air bill and attach to top of shipping container. 
10. Complete a dry ice label. 
11. Attach the dry ice label and an Exempt Human Specimen sticker to the side of the 
shipping container. 
12. Ship specimens via overnight courier to the address below.  FedEx Priority Overnight is 
strongly recommended to prevent delays in package receipt.  
 
5.6.2.3 
Shipping Frozen and Ambient Specimens in a Dual-Chamber Kit  
 
The Dual Chambered Specimen Procurement Kit is constructed to allow the shipment of frozen 
(on dry ice) and ambient (room temperature) specimens in the same container.  Dry ice may be 
placed in either compartment of the kit but should not be put in both.  The dual chambered 
kit provided for 10382 is only used for shipments of tissue in formalin and snap frozen tissue 
cores collected at Baseline and Progression. If formalin-fixed tissue is shipped separately (not in 
the same shipment as frozen specimens), then it must be shipped using institutional shipping 
supplies.    
 
1. Before packaging specimens, verify that each specimen is labeled according to the 
instructions above and that lids of all primary receptacles containing liquid are tightly 
sealed.  
2. Pre-fill one of the kit chambers about 1/3 with dry ice. 
3. Prepare the frozen specimens for shipment: 
a. Place the specimens into zip-lock bags.  
b. Place the zip-lock bags into a biohazard envelope containing absorbent material.  
Expel as much air as possible before sealing the biohazard envelope. 
c. Put each biohazard envelope into a Tyvek envelope.  Expel as much air as possible 
and then seal the Tyvek envelope. 
4. Quickly place the Tyvek envelope containing frozen specimens in the kit compartment 
that is pre-filled with dry ice.  Place the Tyvek envelope on top of the dry ice.  Cover the 
specimens with additional dry ice until the compartment is almost completely full.   
5. Place the Styrofoam lid on top to secure specimens during shipment.  Do not tape the 
inner chamber shut. 
6. Prepare the ambient specimens for shipment: 
a. Seal the lids of the formalin jars with parafilm.  Place absorbent material around 
the primary container of each liquid specimen.  Place the specimens into zip-lock 
bags. 
b. Place specimens inside the secondary pressure vessel with bubble wrap.  
c. Secure the lid on the secondary pressure vessel and set it inside the kit chamber. 
7. Insert a copy of the required forms in the kit chamber with the ambient specimens. 

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8. Place the Styrofoam lid on top of the kit compartment to secure specimens during 
shipment.  Do not tape the inner chamber shut. 
9. Close the outer lid of the Specimen Procurement Kit and tape it shut with durable sealing 
tape.  Do not completely seal the container. 
10. Complete a FedEx air bill and attach to top of shipping container. 
11. Complete a dry ice label. 
12. Attach the dry ice label and an Exempt Human Specimen sticker to the side of the 
shipping container. 
13. Ship specimens via overnight courier to the address below.  FedEx Priority Overnight is 
strongly recommended to prevent delays in package receipt.  
 
5.6.2.4 
Shipping Blood cfDNA Streck Tubes in an Ambient Shipper 
 
1. Before packaging specimens, verify that each specimen is labeled according to the 
instructions above and that the lids of all primary receptacles containing liquid are tightly 
sealed.   
2. Prepare the SAF-T-TEMP Gel Pak for shipment.  Note: If contents of the Pak are 
crunchy, place Pak in a warm water bath until gel is smooth.  Do not refrigerate, freeze, 
or microwave.  
3. Place the SAF-T-TEMP Pak in bottom of insulated chest.  Note:  The insulated chest 
must be shipped inside the provided cardboard box(es).  
4. Place the blood collection tubes in zip-lock bags.   
5. Next, place blood into a biohazard envelope with absorbent material.  Expel as much air 
as possible and seal the envelope securely.  
6. Place the biohazard envelope into a Tyvek envelope.  Expel as much air as possible and 
seal securely. 
7. Place packaged blood collection tube(s) and a copy of the shipping manifest from the 
Sample Tracking System on top of SAF-T-TEMP Pak.  
8.  Place the lid on the insulated chest.  
9. Close the outer flaps of the shipping box and tape shut. 
10. Attach a shipping label to the top of the shipping container.  
11. Attach an Exempt Human Specimen sticker to the side of the box. 
12. Ship specimens via overnight courier to the address below.  FedEx Priority Overnight is 
strongly recommended to prevent delays in package receipt.  
 
5.6.3 Shipping Address 
 
Ship to the address below.  Ship formalin-fixed and fresh blood specimens the same day of 
specimen collection.  Do not ship specimens the day before a holiday. 
 
EET Biobank 
2200 International Street 
Columbus, Ohio 43228 
PH: (614) 722-2865 
FAX: (614) 722-2897 
Email: BPCBank@nationwidechildrens.org 

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FedEx Priority Overnight service is very strongly preferred.   
 
NOTE:  The EET Biobank FedEx Account will not be provided to submitting institutions. 
 
5.6.4 Contact Information for Assistance 
 
For all queries, please use the contact information below: 
 
EET Biobank  
Phone:  (614) 722-2865 
E-mail:  BPCBank@nationwidechildrens.org 
 
5.7 
Biomarker Plan  
 
(see next page) 

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5.8 
Integral Correlative Studies 
 
5.8.1 Tumor DNA Sequencing 
 
5.8.1.1 Specimen Receipt and Processing at Local Labs 
 
Local labs should process these samples per institutional standard operating procedures (SOPs) 
as part of standard of care. 
 
5.8.1.2 Sites Performing Correlative Study 
 
This study will be conducted at local labs. 
 
5.9 
Integrated Correlative Studies 
 
5.9.1 PTEN Immunohistochemistry 
 
5.9.1.1 
Specimens Receipt and Processing at the EET Biobank 
 
Specimens to be shipped to EET Biobank for centralized processing and storage, rather than ship 
directly to lab of Dr Wang directly from individual study sites to streamline the process.  
Following processing at the EET Biobank, two (2) unstained slides (4-5 microns) for each 
specified time point (baseline and at time of disease progression) will be sent from the 
biorepository to Dr Wei-Lien Billy Wang, MD, Co-Director of the Immunohistochemistry 
Laboratory, MD Anderson Cancer Center, Houston, TX. 
 
5.9.1.2 
Sites Performing Correlative Study 
 
PTEN IHC will be performed under the CLIA CAP provision at MD Anderson Clinical 
Immunohistochemistry Laboratory. 
 
5.9.1.3 Shipment of Specimens from the EET Biobank to Site Performing Correlative Study 
 
Specimens will be shipped from the EET Biobank to: 
Wei-Lien Wang, M.D. 
Department of Pathology 
The University of Texas MD Anderson Cancer Center 
1515 Holcombe Blvd Unit 085 
Room B3.4611 
Houston, TX 77030 
 
5.9.1.4 Contact Information for Notification of Specimen Shipment 
 
wlwang@mdanderson.org 
 

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5.9.2 RPPA  
 
5.9.2.1 
Specimens Receipt and Processing at the EET Biobank 
 
Specimens to be shipped to the EET Biobank for storage.  Snap-frozen cores will be stored in a 
vapor phase liquid nitrogen freezer.  One whole frozen core from each patient per timepoint will 
be sent by the biorepository to the MD Anderson RPPA core. 
 
5.9.2.2 
Site Performing Correlative Study 
 
This correlative study will be performed by Dr Yiling Lu, MD, Director of RPPA Core, MD 
Anderson Cancer Center, Houston, TX. 
 
5.9.2.3 Shipment of Specimens from the EET Biobank to Site Performing Correlative Study 
 
Specimens will be shipped from the EET Biobank to: 
Yiling Lu, M.D. 
Professor 
Director of RPPA Core 
IPCT / Dept. Genomic Medicine 
Z4.2038 
UT MD Anderson Cancer Center 
6565 MD Anderson Blvd. 
(713)563-4218 
 
5.9.2.4 Contact Information for Notification of Specimen Shipment 
 
yilinglu@mdanderson.org  
 
5.10 
Exploratory/Ancillary Correlative Studies 
 
5.10.1 Whole exome sequencing 
 
5.10.1.1 
Specimens Receipt and Processing at the EET Biobank 
 
Archival FFPE tissue blocks and snap-frozen tissues will be sectioned to generate an initial 
hematoxylin and eosin (H&E)-stained slide, and for nucleic acid extractions, additional RNase-
free slides. 
DNA will be co-extracted from archival FFPE or frozen tumor tissue.  Germline DNA will be 
extracted from the blood collected in the cfDNA Streck tube at Baseline, following plasma 
processing. The nucleic acids will be analyzed to determine concentration and quality. Aliquots 
of DNA will be shipped to the central sequencing laboratory for analysis. 
 
5.10.1.2 
Site Performing Correlative Study 
 
WES will be performed at the MoCha, Frederick National Laboratory for Cancer Research 

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(FNLCR) under the supervision of Dr. Chris Karlovich. 
 
5.10.1.3 Shipment of Specimens from the EET Biobank to Site Performing Correlative Study 
  
Specimens will be shipped from the EET Biobank to: 
MoCha Lab, Frederick National Laboratory for Cancer Research (FNLCR) 
1050 Boyles St. 
Bldg. 459, Rm. 125 
Frederick, MD 21702 
Attn: Alyssa Chapman or Ruth Thornton 
 
5.10.1.4   Contact Information for Notification of Specimen Shipment 
 
Thomas Forbes (mochasamplereceiving@nih.gov) 
 
5.10.2 RNA Seq 
 
5.10.2.1 
Specimens Receipt and Processing at the EET Biobank 
 
Archival FFPE tissue blocks and snap-frozen tissue will be sectioned to generate an initial 
hematoxylin and eosin (H&E)-stained slide, and for nucleic acid extractions, additional RNase-
free slides. 
 
RNA will be co-extracted from tumor tissue. The nucleic acids will be analyzed to determine 
concentration and quality. Aliquots of RNA will be shipped to the central sequencing laboratory 
for analysis. 
 
5.10.2.2 
Site Performing Correlative Study 
 
WES will be performed at the MoCha, Frederick National Laboratory for Cancer Research 
(FNLCR) under the supervision of Dr. Chris Karlovich. 
 
5.10.2.3 Shipment of Specimens from the EET Biobank to Site Performing Correlative Study  
 
Specimens will be shipped from the EET Biobank to: 
MoCha Lab, Frederick National Laboratory for Cancer Research (FNLCR) 
1050 Boyles St. 
Bldg. 459, Rm. 125 
Frederick, MD 21702 
Attn: Alyssa Chapman or Ruth Thornton 
 
5.10.2.4   Contact Information for Notification of Specimen Shipment 
 
Thomas Forbes (mochasamplereceiving@nih.gov) 
 

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5.10.3 ctDNA sequencing 
 
5.10.3.1 
Specimens Receipt and Processing at the EET Biobank 
 
Specimens to be shipped to the EET Biobank for centralized processing and storage.   
 
Whole blood collected in cfDNA Streck tubes will be centrifuged to separate plasma at all time 
points.  Note that at baseline, residual blood will be processed for DNA and buffy coat will be 
isolated for germline DNA.  At C2D1 and progression, buffy coat will be processed and banked. 
Plasma and buffy coat aliquots will be stored in a -80°C freezer. 
 
5.10.3.2 
Site Performing Correlative Study   
 
ctDNA will be performed on baseline and progression specimens at the MoCha, Frederick 
National Laboratory for Cancer Research (FNLCR) under the supervision of Dr. Chris 
Karlovich. 
 
5.3.10.3 
Shipment of Specimens from the EET Biobank to Site Performing Correlative Study 
 
Specimens will be shipped from the EET Biobank to: 
MoCha Lab, Frederick National Laboratory for Cancer Research (FNLCR) 
1050 Boyles St. 
Bldg. 459, Rm. 125 
Frederick, MD 21702 
Attn: Alyssa Chapman or Ruth Thornton 
 
 
5.3.10.4 
Contact Information for Notification of Specimen Shipment 
 
Thomas Forbes (mochasamplereceiving@nih.gov)  
 
5.10.4 Plasma and serum proteomics and metabolomics 
 
5.10.4.1 
Specimens Receipt and Processing at the EET Biobank 
 
The cryovials of serum, and plasma will be stored at -80ºC until sent to the laboratory for 
analysis. 
 
5.10.4.2 
Site Performing Correlative Study   
 
At the end of the study, the EET Biobank will distribute serum processed from red-top tubes, and 
plasma processed from EDTA and redtop tubes.  This correlative study will be performed at the 
Broad Institute and other laboratories if needed. 
 
5.10.4.3 
Shipment of Specimens from the EET Biobank to Site Performing Correlative Study 
 

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TBD 
 
5.10.4.4 
Contact Information for Notification of Specimen Shipment 
 
TBD 
 
5.10.5 Banking 
 
5.10.5.1 
Specimens Receipt and Processing at the EET Biobank 
 
Specimens to be shipped to the EET Biobank for centralized processing and storage.   
 
Whole blood collected in cfDNA Streck tubes will be centrifuged to separate plasma.  At all time 
points, buffy coat will be processed and banked. Plasma and buffy coat aliquots will be stored in 
a -80°C freezer. 
 
5.10.5.2 
Site Performing Correlative Study 
 
TBD 
 
5.10.5.3 
Shipment of Specimens from the EET Biobank to Site Performing Correlative Study 
 
Specimens will be shipped from the EET Biobank to: 
TBD 
 
5.10.5.4 
Contact information for notification of specimen shipment 
 
TBD 
 
6. 
TREATMENT PLAN 
 
6.1 
Agent Administration 
 
Treatment will be administered on an outpatient basis.  Reported adverse events and potential 
risks are described in Section 10.  Appropriate dose modifications are described in Section 7.  No 
investigational or commercial agents or therapies other than those described below may be 
administered with the intent to treat the patient's malignancy. 
 
Phase 1: 
Dose Escalation Schedule 
Dose Level 
Dose 
Copanlisib 
Eribulin** 
Schedule*** 
Cycle Length 
Level -1 
45 mg IV 
1.1 mg/m2 IV 
Days 1 and 15 
28 days 
Level 1* 
45 mg IV 
1.1 mg/m2 IV 
Days 1 and 8 
21 days 
Level 2 
45 mg IV 
1.4 mg/m2 IV 
Days 1 and 8 
21 days 
Level 3 
60 mg IV 
1.4 mg/m2 IV 
Days 1 and 8 
21 days 

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*Starting Dose Level 
**Eribulin doses are based on actual body weight. Baseline weight on cycle 1, day 1 should be 
used for eribulin dosing. Weight must be obtained on each day of treatment. Dose 
recalculation must occur only if weight changes greater than or equal to 10% from baseline 
weight. 
***Treatment window +/- 2 days.  Ensure minimum of 7 days between any two consecutive 
infusions within a cycle. Ensure minimum of 14 days between cycles, prior to day 1 of next 
treatment cycle. 
 
Before initiating treatment with copanlisib, consider Pneumocystis jiroveci pneumonia 
prophylaxis per treating physician assessment of patient risk. 
 
Before initiating treatment with copanlisib, patients must initiate oral anti-histamine 
prophylaxis (i.e cetirizine) daily for rash prophylaxis to be continued throughout the course of 
protocol therapy. It is highly recommended that anti-histamine prophylaxis be initiated 2 to 3 
days prior to Cycle 1 Day 1, but it may be initiated on Cycle 1 Day 1. 
 
 
Phase 2: 
 
Group 1 (Eribulin Only) 
Dose 
Eribulin* 
Schedule** 
Cycle Length 
1.4 mg/m2 IV 
Days 1 and 8 
21 days 
* Eribulin doses are based on actual body weight.  Baseline weight on cycle 1, day 1 should 
be used for eribulin dosing. Weight must be obtained on each day of treatment. Dose 
recalculation must occur only if weight changes greater than or equal to 10% from baseline 
weight. 
**Treatment window +/- 2 days.  Ensure minimum of 7 days between any two consecutive 
infusions within a cycle. Ensure minimum of 14 days between cycles, prior to day 1 of next 
treatment cycle. 
 
Group 2 (Eribulin + Copanlisib) 
 
Dose 
Copanlisib 
Eribulin* 
Schedule** 
Cycle Length 
45 mg IV 
1.1 mg/m2 IV 
Days 1 and 8  
21 days 
* Eribulin doses are based on actual body weight. Baseline weight on Cycle 1, Day 1 should 
be used for eribulin dosing. Weight must be obtained on each day of treatment. Dose 
recalculation must occur only if weight changes greater than or equal to 10% from baseline 
weight. Eribulin should be administered before copanlisib when both drugs are given. 
 
**Treatment window +/- 2 days.  Ensure minimum of 7 days between any two consecutive 
infusions within a cycle. Ensure minimum of 14 days between cycles, prior to day 1 of next 
treatment cycle. 
 

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Before initiating treatment with copanlisib, consider Pneumocystis jiroveci pneumonia 
prophylaxis per treating physician assessment of patient risk. 
 
 
Before initiating treatment with copanlisib, patients must initiate oral anti-histamine 
prophylaxis (i.e cetirizine) daily for rash prophylaxis to be continued throughout the course 
of protocol therapy. It is highly recommended that anti-histamine prophylaxis be initiated 2 
to 3 days prior to Cycle 1 Day 1, but it may be initiated on Cycle 1 Day 1. 
 
 
 
Regimen Description 
Agent 
Premedications; 
Precautions 
Dose 
Route 
Schedule 
Eribulin* 
N/A 
** 
IV over 2 to 5 
minutes 
** 
Copanlisib  
No IV glucose 
preparations should be 
administered on the days 
of infusion. 
** in 50-
200 mL 
NSS 
IV over 60 
minutes (+/- 10 
minutes) 
** 
* Eribulin should be administered before copanlisib when both drugs are given. 
** Doses and Schedule as appropriate for assigned arm 
 
6.1.1 Copanlisib 
 
Based on the company-sponsored studies with copanlisib in patients with oncologic 
malignancies, the historical RP2D of copanlisib monotherapy has been established as 60 mg 
administered IV (over 1 hour) once weekly for 3 weeks (days 1, 8, and 15) on a 28-day cycle.  A 
copanlisib dose reduction to 45 mg and 30 mg has been allowed for toxicities (Investigator’s 
Brochure, 2019).  
 
The dosage of copanlisib in the Phase 1 portion of this study was determined by the assigned 
dose level.   
 
The dosage of copanlisib for patients randomized to Group 2 (Eribulin + Copanlisib) in the 
phase 2 portion of this study will be the RP2D of 45 mg IV on days 1 and 8 of a 21-day 
cycle (when given with eribulin 1.1 mg/m2) as determined by the Phase 1 portion of the 
study. 
 
6.1.1.1 
Copanlisib Administration 
 
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, as long as QTc interval on baseline ECG < 480 msec.  
The use of corticosteroids as antiemetics prior to copanlisib administration will not be allowed.  

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Administer copanlisib as an IV infusion over one hour.  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.   
 
Before initiating treatment with copanlisib, consider Pneumocystis jiroveci pneumonia 
prophylaxis per treating physician assessment of patient risk. 
 
Before initiating treatment with copanlisib, patients must initiate oral anti-histamine prophylaxis 
(i.e cetirizine) daily for rash prophylaxis to be continued throughout the course of protocol 
therapy. It is highly recommended that anti-histamine prophylaxis be initiated 2 to 3 days prior to 
Cycle 1 Day 1, but it may be initiated on Cycle 1 Day 1. 
 
Recommendations on meal timing on copanlisib infusion days 
 
Because of an inhibitory effect on the PI3Kα-isoform, which is implicated in insulin metabolism, 
copanlisib infusions could be associated with temporarily increase in blood glucose. Blood 
glucose levels typically peak 5 to 8 hours post-infusion and subsequently decline to baseline 
levels for a majority of patients, but hyperglycemia has been seen to persist for approximately 1 
to 3 days after study drug administration. Consuming a meal in close proximity to copanlisib 
infusion may exacerbate a glucose level increase. On infusion days, administration while fasting 
is preferred, but if not possible, then consumption of a low glycemic/carbohydrate meal at least 
4h prior to the start of copanlisib is recommended and patients should be encouraged to stay 
hydrated.  The timing and content of meal intake, and additional glucose testing (if clinically 
indicated), should be managed and monitored by the investigators based on glucose response 
patterns during prior treatment days.   
 
NOTE: If patient needs to take a meal, then glucose testing should be taken prior to meal intake.  
All glucose measurements, oral glucose lowering medication and/or insulin administration, if 
applicable, pre-dose fasting/non-fasting status, and meal intake timing on infusion days will be 
collected as part of the clinical source documentation.  
 
NOTE: Caloric intake and timing recommendations for diabetic patients who require insulin 
treatment prior to the infusion at any cycle visit should be managed by the investigator based on 
consultation with treating physician or diabetes/endocrinologist physician. 
 

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Pre-dose glucose levels 
Period 
     Pre-dose glucose levels  
(first glucose measurement) 
Day 1 of 
cycle 1 
<160 mg/dL (fasting*) 
 < 200 mg/dL (non-fasting**)  
Subsequent infusions 
after Cycle 1 Day 1 
 <160 mg/dL (fasting*) 
 < 200 mg/dL (non-fasting**)  
*Fasting refers to a ≥ 8 h fast. 
**Non-fasting status includes any caloric intake such as meals and also 
juice, snacks, and other caloric intake not consistently called a meal. 
 
NOTE: If patient needs to take a meal, then glucose testing should be taken prior to meal intake. 
Glucose monitoring is required before and after each copanlisib infusion.  The glucose testing is 
scheduled as follows:   
On Cycle 1 Day 1:  Glucose test is performed before starting copanlisib IV infusion at time 0 
hour (pre-dose), at the end of the infusion (1 hour after starting infusion), 1 hour after completing 
the infusion, and 2 hours after completing the infusion (a window of ± 10 minutes is allowed 
except for pre-dose measurement).   
All subsequent visits:  Glucose test is performed before starting copanlisib IV infusion at time 0 
hour.  Additional measurements are to be performed at the clinic as clinically indicated at the 
investigator’s discretion.  Review blood glucose measurements/meal timing/insulin 
administration/oral glucose lowering medication, if applicable. 
 
6.1.2 Eribulin 
 
The dosage of eribulin in the Phase 1 portion of this study will be determined by the assigned 
dose level.  
 
The recommended starting dose of eribulin in the phase 2 portion of the study for patients 
randomized to Group 1 (Eribulin only) is 1.4 mg/m2 administered intravenously over 2 to 5 
minutes on Days 1 and 8 of a 21-day cycle, as per standard of care.   
 
The dosage of eribulin for patients randomized to Group 2 (Eribulin + Copanlisib) in the phase 2 
portion of the study will be the RP2D of 1.1 mg/m2 IV on days 1 and 8 of a 21-day cycle (when 
given with copanlisib 45 mg IV) as determined by the Phase 1 portion of the study. Treatment 
window +/- 2 days.  Ensure minimum of 7 days between any two consecutive infusions within a 
cycle. Ensure minimum of 14 days between cycles, prior to day 1 of next treatment cycle. 
 
Eribulin doses are based on actual body weight. Baseline weight on cycle 1, day 1 should be 
used for eribulin dosing. Weight must be obtained on each day of treatment. Dose recalculation 
must occur only if weight changes by greater than or equal to 10% from baseline weight. 
 

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Eribulin mesylate may be administered without further dilution or diluted in up to 100 mL 0.9% 
Sodium Chloride Injection, USP.  Do not dilute in or administer through an intravenous line 
containing solutions with dextrose.  Do not administer in the same intravenous line concurrent 
with the other medicinal products. 
 
 
6.2 
Definition of Dose-Limiting Toxicity 
 
The DLT observation window for the phase 1 portion of this study will be 1 treatment cycle, based 
on the dose level assignment.  Patients assigned to dose level -1 will have a treatment cycle and 
DLT window of 28 days.  Patients assigned to all other dose levels will have a treatment cycle and 
DLT window of 21 days.  Any patient receiving a single dose of therapy will be evaluable for 
toxicity. 
 
 
Dose limiting toxicity (DLT) is defined as adverse events at least possibly related to treatment 
using NCI-CTCAE v5.0 that meet the following criteria: 
• Any death not clearly due to the underlying disease or extraneous causes. 
• Hematology: 
o Febrile neutropenia 
o Grade ≥3 thrombocytopenia with bleeding requiring transfusion. 
o Grade 4 thrombocytopenia 
o Grade 4 neutropenia lasting more than 7 days 
• Non-Hematology: 
o Hy’s law 
o For patients with hepatic metastases, AST or ALT >5xULN or AST or ALT >3X 
ULN for ≥14 days 
o Grade 3 nausea/vomiting lasting >7 days with adequate anti-emetic and other 
supportive care 
o Grade 4 nausea/vomiting. 
o Grade ≥3 diarrhea that persists more than 7 days despite optimal supportive care. 
o Asymptomatic Grade ≥3 electrolyte abnormality lasting >72 hours. 
o Symptomatic Grade >3 electrolyte abnormality. 
o Post-infusion blood glucose > 400 mg/dL not responsive to glucose lowering 
therapy that persists longer than 24 hours. 
o Grade >4 hypertension 
o Grade ≥3 peripheral neuropathy. 
o Recurrence of Grade 2 non-infectious pneumonitis despite initial recovery post 
treatment following resumption of study therapy with copanlisib. 
• Grade ≥3 non-hematologic toxicity with the following exceptions:   
o Transient infusion-related hyperglycemia as indicated per hyperglycemia 
management/dosing table in Section 7.2.1 and Appendix E and F. 

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o Transient infusion-related hypertension responsive to intervention.  As indicated 
in Section 7.2.2 and Appendix G. 
o Grade 3 diarrhea that responds to standard-of-care supportive therapy 
o Grade 3 nausea or vomiting, in the absence of premedication, that responds to 
standard-of-care supportive therapy 
o Grade ≥3 amylase or lipase elevation NOT associated with symptoms or clinical 
manifestation of pancreatitis does not need to be counted as a DLT. 
 
The treating physician should exercise his or her judgement in the application of DLT criteria. 
 
Management and dose modifications associated with the above adverse events are outlined in 
Section 7. 
 
Dose escalation will proceed within each cohort according to the following schema.  DLT is 
defined above.   
 
Number of Patients with DLT at a 
Given Dose Level 
Escalation Decision Rule 
0 out of 3 
Enter 3 patients at the next dose level. 
≥2 
Dose escalation will be stopped.  This dose level will be 
declared the maximally administered dose (highest dose 
administered).  Three (3) additional patients will be 
entered at the next lowest dose level if only 3 patients 
were treated previously at that dose. 
1 out of 3 
Enter at least 3 more patients at this dose level. 
• If 0 of these 3 patients experience DLT, proceed to 
the next dose level. 
• If 1 or more of this group suffer DLT, then dose 
escalation is stopped, and this dose is declared the 
maximally administered dose.  Three (3) additional 
patients will be entered at the next lowest dose level 
if only 3 patients were treated previously at that dose. 
≤1 out of 6 at highest dose level 
below the maximally administered 
dose 
This is generally the recommended phase 2 dose. At 
least 6 patients must be entered at the recommended 
phase 2 dose. 
 
6.3 
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 

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taking any agent known to affect or with the potential for drug interactions.  The known potential 
targets for drug interaction with copanlisib are CYP3A4 inducers or inhibitors, as well as drugs 
modulating P-gp, BCRP, and MATE2K function.  Concomitant use of medications listed in 
Appendix C is prohibited while on copanlisib.  The study team should check a frequently-
updated medical reference for a list of drugs to avoid or minimize use of.  Appendix D (Patient 
Clinical Trial Wallet Card) should be provided to patients. 
 
6.3.1 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.  
Please see prescribing information for further information. 
 
6.3.2 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. 
 
6.3.3 Systemic corticosteroid therapy at a daily dose higher than 15 mg prednisone or 
equivalent is not permitted while on study.  Previous corticosteroid therapy must be 
stopped or reduced to the allowed dose at least 7 days prior to the CT/MRI screening.  If 
a patient is on chronic corticosteroid therapy, corticosteroids should be de-escalated to 
the maximum allowed dose before the screening.  Patients may be using topical or 
inhaled corticosteroids.  Short-term (up to 7 days) systemic corticosteroids above 15 mg 
prednisolone or equivalent will be allowed for the management of acute conditions (e.g., 
treatment non-infectious pneumonitis).  The use of corticosteroids as antiemetics prior to 
copanlisib administration will not be allowed. 
 
6.3.4 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.   
 
6.3.5 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, as long as QTc interval on 
baseline ECG < 480 msec.   
 
6.3.6 Prophylactic use of oral anti-histamine (i.e. cetirizine) daily for rash prophylaxis is 
required throughout the course of protocol therapy. It is highly recommended that anti-
histamine prophylaxis be initiated 2 to 3 days prior to Cycle 1 Day 1, but it may be 
initiated on Cycle 1 Day 1. Use is only required for patients receiving copanlisib. 
 
6.3.7 Palliative radiation for pain control is not advised concurrently with eribulin to minimize 
risk of cytopenias.  
 
 

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6.4 
Duration of Therapy 
 
In the absence of treatment delays due to adverse event(s), treatment may continue until one of 
the following criteria applies: 
 
• 
Disease progression 
 
• 
Intercurrent illness that prevents further administration of treatment 
 
• 
Unacceptable adverse event(s) 
 
• 
Patient decides to withdraw from the study 
 
• 
General or specific changes in the patient's condition render the patient unacceptable for 
further treatment in the judgment of the investigator 
 
• 
Clinical progression 
 
• 
Patient non-compliance 
 
• 
Pregnancy 
 
o All women of child bearing potential should be instructed to contact the investigator 
immediately if they suspect they might be pregnant (e.g., missed or late menstrual 
period) at any time during study participation. 
 
o The investigator must immediately notify CTEP in the event of a confirmed 
pregnancy in a patient participating in the study. 
 
• 
Termination of the study by sponsor 
 
• 
The drug manufacturer can no longer provide the study agent 
 
The reason(s) for protocol therapy discontinuation, the reason(s) for study removal, and the 
corresponding dates must be documented in the Case Report Form (CRF). 
 
6.5 
Duration of Follow-Up 
 
All patients will be followed every 3 months for up to 36 months after removal from study or 
until death, whichever occurs first.  The follow-up will be through review of the charts and 
phone calls.  For patients who discontinue study therapy due to progression of disease, follow-up 
will be for survival only. For patients who discontinue study therapy for reasons other than 
progression of disease, follow-up will consist of imaging, concomitant medication review, and 
AEs until progression, after which follow-up will be for survival only. Patients removed from 
study for unacceptable adverse event(s) will be followed until resolution or stabilization, in the 

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judgement of the treating physician, of the adverse event.  The first contact in this case must be 
performed within 3 days of the adverse event. 
 
 
7. 
DOSING DELAYS/DOSE MODIFICATIONS 
 
7.1 
Dose Modification Schemas 
 
General Guidance:  Doses omitted for toxicity within a cycle are to be replaced within stated 
parameters within the same cycle once toxicity is resolved as per dose modification guidelines.  
Instructions for dose delays and dose modifications for specific toxicities are summarized in dose 
modification tables.  If treatment is delayed due to pre-dose copanlisib related toxicity of 
hyperglycemia or hypertension, then a maximum hold of 2 days of both copanlisib and eribulin 
is permitted.  If these copanlisib specified toxicities persist within 2 days, then eribulin must be 
given without copanlisib as stated in copanlisib-related toxicity dose modification tables.  
 
Regardless of whether there is delay for toxicity of the day 8 dose (or day 15 dose if treating on 
dose level -1 dosing schedule in phase 1 portion of the study), there should be minimum of 14 
days between the day 8 infusion and the day 1 infusion of the next treatment cycle.  
 
Treatment delays lasting >21 days without recovery will require permanent discontinuation of 
protocol treatment, except for copanlisib-related severe cutaneous reactions, where patients 
requiring >14 day delay without recovery and despite dose reduction to copanlisib 30 mg should 
discontinue copanlisib protocol therapy but may continue receiving eribulin monotherapy on 
study per treating MD discretion. No other treatment interruptions are permitted aside from that 
stated in dose modification guidelines.  
 
7.1.1 Phase 1 Dose Modification Schema 
 
In Phase 1, the starting dose will be per the assigned dose level in Section 6.1.  Any dose 
modifications due to toxicity will follow the table below.  The frequency of eribulin and 
copanlisib and cycle length for any dose modifications will be based on the dose level to which 
the patient is enrolled.  For patients enrolled in Dose Level -1 (Day 1 and Day 15 dosing 
frequency), recovery will be based on a 28 day cycle. 
 
Dose Levels for Dose 
Modification  
Eribulin* 
Copanlisib** 
Starting dose 
Assigned dose level 
 
Assigned dose level 
Dose Reduction 1 
Reduce from assigned dose level 
by 0.3 mg/m2  
Reduce from assigned dose level 
by 15 mg 
Dose Reduction 2 
Reduce from assigned dose level 
by 0.6 mg/m2 
Reduce from assigned dose level 
by 30 mg 
*Lowest permitted eribulin dose is 0.7 mg/m2 
**Lowest permitted copanlisib dose is 30 mg 
 

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Treatment window +/- 2 days.  Ensure minimum of 7 days between any two consecutive 
infusions within a cycle. Ensure minimum of 14 days between cycles, prior to day 1 of next 
treatment cycle. 
 
Assess for peripheral neuropathy and obtain complete blood cell counts prior to each dose.  
 
Dose of eribulin and copanlisib must not be re-escalated following a dose reduction. 
 
In case of toxicity requiring dose reductions specific to copanlisib below 30 mg at start of cycle 
or within a cycle, the patient will discontinue copanlisib, but may continue eribulin on study. 
 
In case of toxicity requiring dose reductions in eribulin below dose reduction 2 at start of cycle 
or within a cycle, the patient will discontinue eribulin and come off study protocol.  The lowest 
permitted dose for eribulin will be 0.7 mg/m2. 
 
 
7.1.2 Phase 2: Group 1 (Eribulin Only) Dose Modification Schema 
 
Dose Levels for Dose Modification  
Eribulin* 
Starting dose 
1.4 mg/m2 
Dose Reduction 1 
1.1 mg/m2  
Dose Reduction 2 
0.7 mg/m2 
*Eribulin given on Day 1 and Day 8 dosing schedule in Group 1 (Eribulin Only) group in the 
Phase 2 portion of the study.   
 
Treatment window +/- 2 days.  Ensure minimum of 7 days between any two consecutive 
infusions within a cycle. Ensure minimum of 14 days between cycles, prior to day 1 of next 
treatment cycle. 
 
Assess for peripheral neuropathy and obtain complete blood cell counts prior to each dose.  
 
Dose of eribulin must not be re-escalated following a dose reduction. 
 
In case of toxicity requiring dose reduction below dose reduction 2 at start of cycle or within a 
cycle, the patient will discontinue eribulin and come off study protocol. 
 
7.1.3 Phase 2: Group 2 (Eribulin + Copanlisib) Dose Modification Schema 
 
The frequency of eribulin and copanlisib and cycle length for any dose modifications will be 
based on the frequency for the RP2D of 45 mg IV copanlisib and 1.1 mg/m2 IV eribulin on days 
1 and 8 of a 21-day cycle. 
 
Dose Levels for Dose 
Modification  
Eribulin* 
Copanlisib** 
Starting dose 
1.1 mg/m2 IV 
45 mg IV 
Dose Reduction 1 
Reduce to 0.9 mg/m2 IV 
Reduce to 30 mg IV 

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Dose Reduction 2 
Reduce to 0.7 mg/m2 IV 
No further dose reduction 
permitted*** 
*Lowest permitted eribulin dose is 0.7 mg/m2 
**Lowest permitted copanlisib dose is 30 mg 
***In case of toxicity requiring dose reductions specific to copanlisib below 30 mg at start of cycle or 
within a cycle, the patient will discontinue copanlisib, but may continue eribulin on study. 
 
Treatment window +/- 2 days.  Ensure minimum of 7 days between any two consecutive 
infusions within a cycle. Ensure minimum of 14 days between cycles, prior to day 1 of next 
treatment cycle. 
 
Assess for peripheral neuropathy and obtain complete blood cell counts prior to each dose.  
 
Dose of eribulin and copanlisib must not be re-escalated following a dose reduction. 
 
In case of toxicity requiring dose reductions specific to copanlisib below 30 mg at start of cycle 
or within a cycle, the patient will discontinue copanlisib, but may continue eribulin on study. 
 
In case of toxicity requiring dose reductions in eribulin below dose reduction 2 at start of cycle 
or within a cycle, the patient will discontinue eribulin and come off study protocol.  The lowest 
permitted dose for eribulin will be 0.7 mg/m2. 
 
7.2 
Copanlisib 
 
This section contains guidance for specific copanlisib-associated toxicities, and is applicable to 
all patients receiving copanlisib in this study. Section 7.4 contains guidance for toxicities 
associated with both copanlisib and eribulin. For patients on combination therapy, both this 
section and Section 7.4 should be used for guidance. 
 
7.2.1 Dose Modification Rules for Copanlisib for Transient Post-Infusion Hyperglycemia 
 
Patients who develop transient post-infusion glucose >250 mg/dL after study drug administration 
may continue treatment (see table below for guidance).  However, the next infusion must be 
delayed until the patient’s pre-infusion glucose levels return to <160 mg/dL (fasting) or 
<200 mg/dL (non-fasting).  Guidelines for the management of transient glucose increases are 
given in Appendix E and Appendix F.  Continuing occurrence of post-infusion blood glucose 
≥400 mg/dL, based on repeated laboratory analysis despite optimal glucose lowering therapy 
after 2 infusions of copanlisib, will require dose reduction by one dose level (see table below for 
guidance). 
• 
Further dose reduction (where appropriate per study design/population) is allowed as 
long as discontinuation criteria was not met. 
• 
Persistent occurrence of post-infusion blood glucose ≥400 mg/dL based on laboratory 
analysis which occurred at the lowest dose level despite optimal glucose lowering therapy 
(after at least one cycle of treatment) with consultation of a diabetes specialist requires 
permanent discontinuation of copanlisib. 

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Hyperglycemia 
Management/Next Dose for Copanlisib 
Pre-dose fasting 
blood glucose ≥ 160 
mg/dL or non-fasting 
glucose ≥ 200 mg/dL 
 
Withhold copanlisib until fasting blood glucose < 160 mg/dL, or non-
fasting blood glucose < 200 mg/dL.  
 
Eribulin and copanlisib should be given on the same day.  Copanlisib 
can be held for a maximum of 2 days for pre-dose hyperglycemia.  If 
copanlisib is held for hyperglycemia, eribulin must also be held.  If 
hyperglycemia resolves within 2 days, copanlisib will be given along 
with eribulin (within 2 days).**  
 
If hyperglycemia persists within 2 days, copanlisib dose will be 
omitted and eribulin must be given (if meets criteria for eribulin 
administration so as to limit dose interruption of eribulin).*** 
 
 
 
Pre-dose or post-dose 
blood glucose ≥ 400 
mg/dL  
On first occurrence, withhold copanlisib until fasting blood glucose 
<160 mg/dL, or non-fasting blood glucose < 200 mg/dL, then reduce 
copanlisib by one dose reduction and resume. 
 
On subsequent occurrences, withhold copanlisib until fasting blood 
glucose < 160 mg/dL, or non-fasting blood glucose < 200 mg/dL. 
Then reduce copanlisib by an additional dose level.  If persistent 
beyond 2 dose reductions*, permanently discontinue copanlisib. 
 
Eribulin and copanlisib should be given on the same day.  Copanlisib 
can be held for a maximum of 2 days for pre-dose hyperglycemia.  If 
copanlisib is held for hyperglycemia, eribulin must also be held.  If 
hyperglycemia resolves within 2 days, copanlisib will be given as 
above along with eribulin (within 2 days).**  
 
If hyperglycemia persists within 2 days, copanlisib dose will be 
omitted and eribulin must be given (if meets criteria for eribulin 
administration so as to limit dose interruption of eribulin).*** 
 
 
*Patients requiring more than two dose reductions (or a dose below 30 mg even if less than 2 
dose reductions) should permanently discontinue copanlisib and may continue eribulin on 
study. 
**Eribulin should be given before copanlisib when both drugs are given.  
***Ensure minimum of 7 days between any two consecutive infusions within a cycle. Ensure 
minimum of 14 days between cycles, prior to day 1 of next treatment cycle. 
 
Recommended management:  Guidelines for the management of transient glucose increases 

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Hyperglycemia 
Management/Next Dose for Copanlisib 
are given in Appendix E and Appendix F. 
 
7.2.2 Copanlisib Dose Modifications Rules and Treatment of Blood Pressure Increases 
Associated with Copanlisib 
 
It is important that patients with pre-existing arterial hypertension adhere to their regular 
medication schedule and take their usual doses on the days of study drug infusion.  
The management of acute blood pressure (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).  Topical nitrates should also be considered.  Verapamil and diltiazem 
(non-dihydropyridine calcium channel blockers and moderate inhibitors of CYP3A4) should be 
used with caution due to a potential CYP3A4 interaction.  In general, it is advisable for sites to 
be prepared, so that 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 G.  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 in 
Appendix G 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 every 5-10 min prior to each copanlisib dose (no more than 4 
measurements) until there are two consecutive results <150/90 mmHg.  If blood pressure is ≥ 
150/90 mmHg, the investigator can consider a medical intervention or delaying the infusion of 
study drug. The patient should rest for 5-10 min before blood pressure is recorded. 
On infusion days, blood pressure will be measured at 0 hour (pre-dose), 30 min (mid-infusion), 
60 min (end of infusion), and 1 hour and 2 hours after the end of infusion  
NOTE: A window of ±10 min is allowed for all BP measurements, except for pre-dose (0 hour) 
measurement. 
 
7.2.3 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 (NIP)  

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Suspected or confirmed 
NIP per CTCAE 
Action Taken 
Re-treatment dose after 
recovery 
Grade 1 
No Change 
NA 
Grade 2 
Withhold copanlisib and treat 
NIP until recovery to ≤grade 
1 
Decrease dose to the next 
lowest dose level a 
Grade 2 second re-occurrence If Grade 2 NIP recurs, 
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 if receiving treatment at lowest allowed dose level of copanlisib (30 mg).  No re-escalation is 
allowed after the dose reduction.  Patients with recurrence of grade 2 NIP after initial recovery post therapy should 
go off protocol therapy.  Patients requiring more than  two dose reductions should go off protocol therapy. 
 
7.2.4 Other severe toxicities  
 
Also refer to Section 7.4. 
 
Severe Cutaneous 
Reaction 
Management/Next Dose for Copanlisib 
Grade 3 
Hold* copanlisib until ≤ Grade 2and not considered a safety risk per 
treating physician.  Resume copanlisib at one dose level lower upon 
recovery, if indicated.** 
Grade 4 
Permanent discontinuation of copanlisib. 
* Treatment delays lasting >21 days without recovery will require permanent discontinuation 
of protocol treatment, except for copanlisib-related severe cutaneous reactions, where patients 
requiring >14 day delay without recovery and despite dose reduction to copanlisib 30 mg 
should discontinue copanlisib, but may continue receiving eribulin monotherapy on study per 
treating physician discretion. No other treatment interruptions are permitted aside from that 
stated in dose modification guidelines.  
** The lowest permitted copanlisib dose is 30 mg. Patients requiring > 1 dose reduction should 
go off protocol therapy as above. 
Reported events included dermatitis exfoliative, exfoliative rash, pruritis and rash (including 
maculo-papular rash).  
Recommended management:  Consider referral to dermatologist for assistance in 
management of severe cutaneous reaction. 
 
 

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Suspected 
Pneumocystis 
jiroveci pneumonia 
(PCP) infection 
Management/Next Dose for Copanlisib 
Any Grade 
 
Withhold study treatment immediately.  
 
If infection is confirmed, treat infection until resolution, and 
permanently discontinue copanlisib. Patient may continue receiving 
eribulin monotherapy on study per treating physician discretion. 
 
Treat PCP infection immediately until resolution. Recommend consultation with infectious 
disease specialist. 
 
 
7.2.5 Retreatment Criteria for Copanlisib 
 
A new cycle of treatment with copanlisib may start cycle only if: 
 
• 
ANC ≥1000/mm3 
• 
Platelet count ≥75,000/mm3 
• 
Fasting pre-dose glucose  < 160 mg/dL (or non-fasting pre-dose glucose < 200 mg/dL.  
• 
Arterial blood pressure <150/90 mmHg (Both systolic of less than 150 mmHg and 
diastolic of less than 90 mmHg are required.) 
• 
Total bilirubin 1.5 × institutional upper limit of normal (IULN) 
• 
Aspartate aminotransferase/alanine transaminase 3 × IULN 
• 
Copanlisib related non-hematologic toxicities have returned to baseline or grade ≤1 
severity, unless otherwise specified, or if not specified grade ≤2 if not considered a safety 
risk for the patient at the investigator’s discretion. 
 
Criteria for dose interruption for copanlisib within a cycle:  
 
• 
Pre-dose glucose level: Fasting ≥160 mg/dL or non-fasting  ≥200 mg/dL.  May start if 
controlled on the day or the day after. Refer to Section 7.2.1 for further management 
guidance. 
• 
BP ≥150/90 mmHg.  May start if controlled with use of anti-hypertensive agents if BP < 
150/90 mmHg. 
• 
Copanlisib related non-hematologic toxicities have returned to baseline or grade ≤1 
severity, unless otherwise specified, or if not specified, grade ≤2 if not considered a 
safety risk for the patient at the investigator’s discretion. 
 
7.3 
Eribulin 
 
7.3.1 Recommended dose delays and modifications for Phase 2 Group 1 (Eribulin Only): 
 
Do not administer eribulin Day 1 or Day 8 for any of the following:  

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• ANC <1,000/mm3  
• Platelets <75,000/mm3  
• Grade 3 or 4 non-hematological toxicities.  
• Withhold eribulin in patients with Grade ≥3 peripheral neuropathy until resolution to 
≤ Grade 2.  If Grade ≥3 peripheral neuropathy lasts >21 days without recovery, 
permanently discontinue study treatment. 
 
The Day 8 dose may be delayed for a maximum of 7 days.  
• If toxicities do not resolve or improve to Grade ≤2 severity by Day 15, omit the dose.  
• If toxicities resolve or improve to Grade ≤2 severity by Day 15, administer eribulin at a 
reduced dose and initiate the next cycle no sooner than 2 weeks later. 
 
Recommended dose reductions 
• If a dose has been delayed for toxicity and toxicities have recovered to Grade ≤2 severity, 
resume eribulin at a reduced dose as set out in the table below and Section 7.1.2. 
• Do not re-escalate eribulin dose after it has been reduced. 
 
7.3.1.1 
Recommended Supportive Care and Management of Toxicities 
 
Management of anemia (red blood cell transfusion, erythropoietin, etc.) need not delay treatment 
at the discretion of the treating physician.   
 
Use of colony-stimulating growth factor for neutropenia management is permitted after 
completion of Cycle 1 per investigator discretion in patients enrolling to the Phase I portion of 
the study, and is permitted at any time while on treatment in patients enrolling to the Phase II 
portion of the study as per discretion of treating MD.  
 
QT interval monitoring. 
ECG is required at screening to assess eligibility prior to enrollment and Day 1 of Cycle 2.  
Abnormal findings should be evaluated as clinically indicated, including repeat ECGs.  ECGs 
may be done at other study time points if clinically indicated.  Correct hypokalemia and 
hypomagnesemia prior to initiating eribulin and monitor these electrolytes during therapy.  
 
 
Recommended Dose Reductions for Phase 2 Group 1 (Eribulin Only): 
 
Event Description  
Recommended Eribulin Dose  
Permanently reduce the 1.4 mg/m2 eribulin dose for any 
of the following:  
1.1 mg/m2  
• 
ANC <500/mm3 for >7 days  
• 
ANC <1,000/mm3 with fever or infection  
• 
Platelets <25,000/mm3  
• 
Platelets <50,000/mm3 requiring transfusion  
• 
Non-hematologic grade 3 or 4 toxicities*  
• 
Omission or delay of Day 8 eribulin dose in 
previous cycle for toxicity  

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Occurrence of any event requiring permanent dose 
reduction while receiving 1.1 mg/m2  
0.7 mg/m2  
Occurrence of any event requiring permanent dose 
reduction while receiving 0.7 mg/m2  
Discontinue eribulin 
ANC = absolute neutrophil count.   
Toxicities graded in accordance with National Cancer Institute (NCI) Common Terminology 
Criteria for Adverse Events (CTCAE) version 5.0.  
* See below for extra guidance on select non-hematologic toxicities, including dosing for renal 
and hepatic impairment. 
 
 
 
Neuropathy 
Management/ Next Dose for Eribulin 
 
 
Grade ≥3 
 
Withhold eribulin until toxicity is recovered to  ≤ Grade 
2 and deemed safe per treating physician, then reduce by 
1 dose level and resume as long as recovers within 21 
days**. 
 
 
**If grade ≥3 peripheral neuropathy lasts >21 days without recovery, permanently discontinue 
study treatment. 
 
 
 
Hypokalemia/Hypomagnesemia  
Management/Next Dose for Eribulin 
 
 
Grade ≤2 
No change in dose.  
 
Appropriate supplementation should be provided 
immediately. 
 
Grade ≥3 
Withhold eribulin dose until Grade ≤ 2 and deemed 
safe per treating physician. 
 
Appropriate supplementation should be provided 
immediately.  
 
Resume same dose if recovers Grade ≤ 2.  
 
 
 
Additional Eribulin Guidance for Hepatic and Renal Toxicity for Phase 2 Group 1 (Eribulin 
Only): 

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The recommended dose of eribulin in patients enrolled to Phase 2 Group 1 (Eribulin Only) with 
normal hepatic and renal function is 1.4 mg/m2.  
 
Renal Impairment 
Management/Next Dose for Eribulin 
CrCl 15-49 mL/min 
No dosage adjustment is required for CrCl alone, unless dose delay or 
modification is required for another adverse event as determined by dosing 
modifications guidelines.  
CrCl < 15 mL/min 
Eribulin should be held in patients who develop severe renal impairment 
(CrCl < 15 mL/min) during the course of study treatment. Use is not 
recommended in patients with end stage renal disease.  
 
Resumption of eribulin is permitted at the 1.1 mg/m2 dose for renal function 
recovering to a CrCl of >15 mL/min, if deemed safe and in the patient’s best 
interest by treating physician.  
 
Subsequent infusions may be continued with appropriate supportive care. 
 
For new onset renal insufficiency, patient should be evaluated to determine etiology of renal impairment, 
and prompt initiation of appropriate management and supportive care is advised.  
 
Consultation with a nephrologist for new onset renal impairment is recommended. 
 
Any contributing factors for renal impairment (i.e. dehydration, nausea/emesis, diarrhea) must be 
adequately treated and resolved per investigator judgement prior to treatment resumption. Instructions for 
dosing and therapy resumption for concomitant adverse events/toxicities will be dictated by dosing 
modification guidelines for the concomitant adverse events. 
 
 
Hepatic Impairment 
Management/Next Dose for Eribulin 
Mild hepatic impairment  
(Child-Pugh A) 
No dosage adjustment is required for eribulin at this level of hepatic 
impairment alone, unless dose delay or modification is required for another 
adverse event/toxicity as determined by the appropriate dosing modifications 
guidelines.  
Moderate hepatic 
impairment  
(Child-Pugh B) 
Eribulin should be reduced to 0.7 mg/m2 in patients who develop 
moderate hepatic impairment during the course of study treatment. 
Severe hepatic 
impairment  
(Child-Pugh C) 
Eribulin should be held in patients who develop severe hepatic 
impairment during the course of study treatment. Use is not 
recommended.  
For new onset hepatic impairment, the patient should be evaluated to determine etiology of hepatic 
impairment, including disease progression and biliary obstruction, and prompt initiation of appropriate 
management and supportive care is advised.  
 
Consultation with a hepatologist for new onset hepatic impairment is recommended. 
 
Any contributing factors for hepatic impairment must be adequately treated and resolved per investigator 

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Hepatic Impairment 
Management/Next Dose for Eribulin 
judgement prior to treatment resumption. Instructions for dosing and therapy resumption for concomitant 
adverse events/toxicities will be dictated by dosing modification guidelines for the concomitant AEs. 
 
 
 
7.4 
Eribulin + Copanlisib 
 
7.4.1 Recommended dose delays for Phase 1 and Phase 2 Group 2 (Eribulin + Copanlisib): 
 
Do not administer eribulin or copanlisib at start of cycle (Day 1) or within a cycle for any of the 
following:  
• ANC <1,000/mm3  
• Platelets <75,000/mm3  
• Total bilirubin ≥1.5 × institutional upper limit of normal (IULN) 
• Aspartate aminotransferase/alanine transaminase  ≥3 × IULN 
• Grade ≥2 diarrhea. 
• Grade 3 or 4 non-hematological toxicities, unless otherwise stated.   
• Withhold eribulin in patients with grade ≥3 peripheral neuropathy until resolution to 
≤Grade 2.  If grade ≥3 peripheral neuropathy lasts >21 days without recovery, 
permanently discontinue study treatment.  When eribulin is withheld, copanlisib is also 
withheld. 
 
The dose within a cycle may be delayed for a maximum of 7 days.  
• If toxicities do not resolve or improve to meet the retreatment parameters listed above by 
Day 15, omit the dose. 
•         If toxicities resolve or improve to meet the retreatment parameters listed above by Day 
15, administer eribulin following the dose modification guidelines in 7.4.1.1 and initiate 
the next cycle no sooner than 2 weeks later. 
 
Recommended dose reductions 
• If a dose has been delayed for toxicity and toxicities resolve to meet the retreatment 
parameters listed above, resume eribulin following the dose modification guidelines in 
7.4.1.1.  See Section 7.1 for the phase 1 and phase 2 dose modification tables. 
• Do not re-escalate eribulin dose after it has been reduced. 
 
 
7.4.1.1 
Recommended Supportive Care and Management of Toxicities 
 
Management of anemia (red blood cell transfusion, erythropoietin, etc.) need not delay treatment 
at the discretion of the treating physician.   
 
Use of colony-stimulating growth factor for neutropenia management is permitted after 
completion of Cycle 1 per investigator discretion in patients enrolling to the Phase I portion of 
the study, and is permitted at any time while on treatment in patients enrolling to the Phase II 
portion of the study as per discretion of treating MD.  

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QT interval monitoring. 
ECG is required at screening to assess eligibility prior to enrollment and Day 1 of Cycle 2.  
Abnormal findings should be evaluated as clinically indicated, including repeat ECGs.  ECGs 
may be done at other study time points if clinically indicated.  Correct hypokalemia and 
hypomagnesemia prior to initiating eribulin and monitor these electrolytes during therapy.  
 
Hypokalemia/Hypomagnesemia  
Management/Next Dose for Eribulin/Copanlisib 
 
 
Grade ≤2 
No change in dose.  
 
Appropriate supplementation should be provided 
immediately. 
 
Grade ≥3 
Withhold* dose until Grade ≤ 2. 
 
 
Appropriate supplementation should be provided 
immediately.  
 
Resume same dose if recovers Grade ≤ 2 and deemed 
safe per treating physician.  
 
 
* When eribulin is withheld, copanlisib is also withheld. 
In case of toxicity requiring dose reductions specific to copanlisib below 30 mg at start of 
cycle or within a cycle, the patient will discontinue copanlisib, but may continue eribulin 
on study 
 
Neutropenia 
Management/Next Dose for 
Copanlisib 
Management/Next Dose for 
Eribulin 
≤ Grade 1 
(neutrophils ≥ 
1500/mm3) 
No change in dose. 
 
No change in dose. 
Grade 2 
(neutrophils 1000-
1500/mm3) 
No change in dose. 
  
No change in dose. 
Grade 3  
(neutrophils 500-
<1000/mm3) 
Hold * copanlisib, until ANC 
recovers to ≤Grade 2.  Resume at 
one dose level lower.** 
 
If Grade 3 neutropenia is 
associated with fever (febrile 
Hold* eribulin until ≤ Grade 2, 
resume at same dose.   
 
If Grade 3 neutropenia is 
associated with fever (febrile 
neutropenia) or infection, resume 

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Neutropenia 
Management/Next Dose for 
Copanlisib 
Management/Next Dose for 
Eribulin 
neutropenia) or infection, resume 
at one dose level lower once fever 
or infection have been adequately 
treated and resolved per treating 
investigator discretion. 
 
at one dose level lower once fever 
or infection have been adequately 
treated and resolved per treating 
investigator discretion.  
Grade 4  
(neutrophils 
<500/mm3) 
Withhold copanlisib until ≤Grade 
2. Resume at one dose level 
lower.** 
 
If Grade 4 neutropenia lasts >7 
days but ultimately recovers to 
≤Grade 2 within ≤21 days, resume 
at one dose level lower. 
 
Withhold eribulin until ≤Grade 2. 
Resume at one dose level lower.**   
 
If Grade 4 neutropenia lasts >7 
days but ultimately recovers to 
≤Grade 2 within ≤21 days, resume 
at one dose level lower. 
 
*Patients requiring a delay of >21 days should go off protocol therapy. 
**Patients requiring > two dose reductions of eribulin, or a dose below 30 mg copanlisib should 
go off protocol therapy. 
In case of toxicity requiring dose reductions specific to copanlisib below 30 mg at start of cycle 
or within a cycle, the patient will discontinue copanlisib, but may continue eribulin on study. 
Use of colony-stimulating growth factor for neutropenia management is permitted after 
completion of Cycle 1 per investigator discretion in patients enrolling to the Phase I portion of 
the study, and is permitted at any time while on treatment in patients enrolling to the Phase II 
portion of the study as per discretion of treating MD.  
 
 
 
Platelet Count 
Reduced 
(Thrombocytopenia) 
Management/Next Dose for 
Copanlisib 
Management/Next Dose for 
Eribulin 
≤ Grade 1 
(platelets ≥ 
75,000/mm3) 
No change in dose. 
  
No change in dose. 
Grade 2 
(platelets < 75,000 – 
50,000/mm3) 
Withhold* copanlisib until ≤ Grade 
1. Resume at same dose.   
  
Withhold* eribulin until ≤ Grade 1. 
Resume at same dose. 
  
Grade 3 not requiring 
transfusion 
(platelets < 50,000 – 
25,000/mm3) 
Withhold* copanlisib until ≤ Grade 
1.  Resume at one dose level 
lower.** 
1st occurrence: withhold* eribulin 
until ≤ Grade 1.  Resume at same 
dose. 
  
2nd occurrence: withhold* eribulin 
until ≤ Grade 1.  Resume at one 
does level lower.** 

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Platelet Count 
Reduced 
(Thrombocytopenia) 
Management/Next Dose for 
Copanlisib 
Management/Next Dose for 
Eribulin 
Grade 3 requiring 
transfusion 
(platelets < 50,000 – 
25,000/mm3) 
Withhold* copanlisib until ≤ Grade 
1, then resume one dose level 
lower.** 
Withhold* eribulin until ≤Grade 1, 
then resume one dose level 
lower.** 
Grade 4 
(platelets < 
25,000/mm3) 
Withhold copanlisib until ≤ Grade 
1. Resume at one dose level 
lower.** 
  
Withhold eribulin until ≤ Grade 1. 
Resume at one dose level lower.** 
  
*Patients requiring a delay of > 21 days should go off protocol therapy. 
**Patients requiring > two dose reductions of eribulin, or a dose below 30 mg copanlisib should 
go off protocol therapy.   
In case of toxicity requiring dose reductions specific to copanlisib below 30 mg at start of cycle 
or within a cycle, the patient will discontinue copanlisib, but may continue eribulin on study. 
  
 
 
Nausea 
Management/Next Dose for 
Copanlisib 
Management/Next Dose for 
Eribulin 
≤ Grade 1 
Manage with anti-emetics. No 
change in dose. 
 
Manage with anti-emetics. No 
change in dose. 
Grade 2 
Manage with anti-emetics. No 
change in dose. 
 
Manage with anti-emetics. No 
change in dose. 
Grade 3 
Withhold copanlisib* until ≤Grade 
2 and deemed safe per treating 
physician.  Resume at same dose. 
 
Manage with anti-emetics and 
supportive care.  
 
If grade 3 lasting > 7 days despite 
adequate anti-emetic use and other 
supportive care measures, resume 
at one dose level lower. ** 
 
Withhold* eribulin until ≤Grade 2 
and deemed safe per treating 
physician.  Resume at same dose. 
 
Manage with anti-emetics and 
supportive care.  
 
If grade 3 lasting > 7 days despite 
adequate anti-emetic use and other 
supportive care measures, resume 
at one dose level lower. ** 
 
 
Grade 4 
Withhold copanlisib until ≤Grade 2 
and deemed safe per treating 
physician. Resume at one dose 
level lower. ** 
 
Manage with anti-emetics and 
Withhold eribulin until ≤Grade 2 
and deemed safe per treating 
physician. Resume at one dose 
level lower. ** 
 
Manage with anti-emetics and 

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Nausea 
Management/Next Dose for 
Copanlisib 
Management/Next Dose for 
Eribulin 
supportive care.  
 
If grade 4 lasting > 72 hours 
despite adequate anti-emetic use 
and other supportive care 
measures, off protocol. 
 
supportive care.  
 
If grade 4 lasting > 72 hours 
despite adequate anti-emetic use 
and other supportive care 
measures, off protocol 
*Patients requiring a delay of > 21 days should go off protocol therapy. 
**Patients requiring > two dose reductions of eribulin, or a dose below 30 mg copanlisib) 
should go off protocol therapy.   
In case of toxicity requiring dose reductions specific to copanlisib below 30 mg at start of cycle 
or within a cycle, the patient will discontinue copanlisib, but may continue eribulin on study. 
Recommended management:  Use of antiemetics. Consider IV fluids if clinically indicated. 
 
 
Vomiting 
Management/Next Dose for 
Copanlisib 
Management/Next Dose for 
Eribulin 
≤ Grade 1 
Manage with anti-emetics.  
 
No change in dose. 
 
Manage with anti-emetics.  
 
No change in dose. 
 
Grade 2 
Manage with anti-emetics. No 
change in dose. 
 
Manage with anti-emetics. No 
change in dose. 
Grade 3 
Hold* until ≤ Grade 2 and deemed 
safe per treating physician.   
 
Manage with anti-emetics and 
supportive care. 
 
If grade 3 lasting > 7 days despite 
adequate anti-emetic use and other 
supportive care measures, resume 
at one dose level lower. 
 
Hold* until ≤Grade 2 and deemed 
safe per treating physician.   
 
Manage with anti-emetics and 
supportive care. 
 
If grade 3 lasting > 7 days despite 
adequate anti-emetic use and other 
supportive care measures, resume 
at one dose level lower. 
Grade 4 
Withhold copanlisib until ≤Grade 2 
and deemed safe per treating 
physician. Resume at one dose 
level lower.** 
 
Manage with anti-emetics and 
supportive care.  
 
If grade 4 lasting > 72 hours 
Withhold eribulin until ≤Grade 2 
and deemed safe per treating 
physician. Resume at one dose 
level lower.** 
 
Manage with anti-emetics and 
supportive care.  
 
If grade 4 lasting > 72 hours 

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Vomiting 
Management/Next Dose for 
Copanlisib 
Management/Next Dose for 
Eribulin 
despite adequate anti-emetic use 
and other supportive care 
measures, off protocol. 
 
despite adequate anti-emetic use 
and other supportive care 
measures, off protocol. 
*Patients requiring a delay of > 21 days should go off protocol therapy. 
**Patients requiring > two dose reductions of eribulin, or a dose below 30 mg copanlisib) 
should go off protocol therapy.   
In case of toxicity requiring dose reductions specific to copanlisib below 30 mg at start of cycle 
or within a cycle, the patient will discontinue copanlisib, but may continue eribulin on study 
Recommended management:  Use of antiemetics. Consider IV fluids if clinically indicated. 
 
 
Diarrhea 
Management/Next Dose for 
Copanlisib 
Management/Next Dose for 
Eribulin 
≤ Grade 1 
No change in dose.  
 
Manage with anti-diarrheal agents.  
 
No change in dose.  
 
Manage with anti-diarrheal agents.  
 
Grade 2 
Hold until ≤ Grade 1 and deemed 
safe per treating physician.  
Manage with anti-diarrheal agents.  
 
Resume at same dose level. 
 
 
Hold until ≤ Grade 1 and deemed 
safe per treating physician.  
Manage with anti-diarrheal agents.  
 
Resume at same dose level. 
Grade 3 
Hold* eribulin until ≤Grade 1 and 
deemed safe per treating physician.  
Resume at one dose level lower, if 
indicated.** 
 
 
Hold* eribulin until ≤Grade 1 and 
deemed safe per treating physician.  
Resume at one dose level lower, if 
indicated.** 
Grade 4 
Withhold copanlisib. Off protocol 
therapy. 
Withhold eribulin. Off protocol 
therapy. 
*Patients requiring a delay of > 21 days should go off protocol therapy. 
**Patients requiring > two dose reductions of eribulin, or a dose below 30 mg copanlisib should 
go off protocol therapy.   
In case of toxicity requiring dose reductions specific to copanlisib below 30 mg at start of cycle 
or within a cycle, the patient will discontinue copanlisib, but may continue eribulin on study 
Recommended management:  Loperamide antidiarrheal therapy 
Dosage schedule:  4 mg at first onset, followed by 2 mg with each loose motion until diarrhea-
free for 12 hours (maximum dosage:  16 mg/24 hours) 
Adjunct anti-diarrheal therapy is permitted and should be recorded when used. 
 
 

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Neuropathy 
Management/ Next Dose for Eribulin 
 
 
Grade ≥3 
 
Withhold eribulin* until toxicity is resolved to  ≤ Grade 2 
and deemed appropriate per treating physician, then reduce 
by 1 dose level** and resume as long as recovers within 21 
days***. 
 
 
*When eribulin is withheld, copanlisib is also withheld. 
**Patients requiring > two dose reductions of eribulin should go off protocol therapy. 
***If grade ≥3 peripheral neuropathy lasts >21 days without recovery, permanently discontinue 
study treatment. 
 
 
Renal Impairment 
Management/Next Dose for 
Copanlisib 
Management/Next Dose for 
Eribulin 
CrCl 15-49 mL/min 
No dosage adjustment is required for 
CrCl alone, unless dose delay or 
modification is required for another 
adverse event/toxicity as determined 
by dosing modifications guidelines.  
No dosage adjustment is required for 
CrCl alone, unless dose delay or 
modification is required for another 
adverse event as determined by dosing 
modifications guidelines.  
CrCl < 15 mL/min 
No dosage adjustment is required for 
CrCl alone, unless dose delay or 
modification is required for another 
adverse event/toxicity as determined 
by the appropriate dosing 
modifications guidelines.  
Eribulin should be held in patients 
who develop severe renal 
impairment (CrCl < 15 mL/min) 
during the course of study 
treatment. Use is not recommended 
in patients with end stage renal 
disease.  
 
Resumption of eribulin is permitted at 
the 1.1 mg/m2 dose for renal function 
recovering to a CrCl of >15 mL/min, 
if deemed safe and in the patient’s 
best interest by treating physician.  
 
Subsequent infusions may be 
continued with appropriate supportive 
care. 
For new onset renal insufficiency, patient should be evaluated to determine etiology of renal impairment, 
and prompt initiation of appropriate management and supportive care is advised.  
 
Consultation with a nephrologist for new onset renal impairment is recommended. 
 
Any contributing factors for renal impairment (i.e. dehydration, nausea/emesis, diarrhea) must be 
adequately treated and resolved per investigator judgement prior to treatment resumption. Instructions for 
dosing and therapy resumption for concomitant adverse events/toxicities will be dictated by dosing 
modification guidelines for the concomitant adverse events. 
 

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Hepatic Impairment 
Management/Next Dose for 
Copanlisib 
Management/Next Dose for 
Eribulin 
Mild hepatic impairment  
(Child-Pugh A) 
No dosage adjustment is required for 
copanlisib at this level of hepatic 
impairment alone, unless dose delay 
or modification is required for another 
adverse event/toxicity as determined 
by the appropriate dosing 
modifications guidelines.  
No dosage adjustment is required for 
eribulin at this level of hepatic 
impairment alone, unless dose delay 
or modification is required for another 
adverse event/toxicity as determined 
by the appropriate dosing 
modifications guidelines.  
Moderate hepatic 
impairment  
(Child-Pugh B) 
No dosage adjustment is required for 
copanlisib at this level of hepatic 
impairment alone, unless dose delay 
or modification is required for another 
adverse event/toxicity as determined 
by the appropriate dosing 
modifications guidelines.  
Eribulin should be reduced to 0.7 
mg/m2 in patients who develop 
moderate hepatic impairment 
during the course of study 
treatment. 
Severe hepatic 
impairment  
(Child-Pugh C) 
Copanlisib will not be dosed without 
eribulin. See Eribulin dosing 
recommendations. 
 
Eribulin should be held in patients 
who develop severe hepatic 
impairment during the course of 
study treatment. Use is not 
recommended.  
For new onset hepatic impairment, the patient should be evaluated to determine etiology of hepatic 
impairment, including disease progression and biliary obstruction, and prompt initiation of appropriate 
management and supportive care is advised.  
 
Consultation with a hepatologist for new onset hepatic impairment is recommended. 
 
Any contributing factors for hepatic impairment must be adequately treated and resolved per investigator 
judgement prior to treatment resumption. Instructions for dosing and therapy resumption for concomitant 
adverse events/toxicities will be dictated by dosing modification guidelines for the concomitant adverse 
events. 
 

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Toxicities 
Adverse 
Reaction 
Grade 
Management/Next Dose for 
Eribulin 
Management/Next Dose 
for Copanlisib 
 
Other severe and 
non-life-threatening 
toxicities (non-
hematologic) 
 
 
 
Grade >2 
Withhold eribulin* until 
toxicity is resolved to  
baseline or  Grade ≤1, then 
reduce by 1 dose level**, 
unless otherwise stated in 
toxicity management tables. 
 
For neuropathy, hold for grade 
≥3 toxicity, and refer to 
respective table for guidance. 
 
For severe and/or recurrent 
anorexia or fatigue, therapy 
interruption is permitted per 
MD discretion until deemed 
safe to resume per treating 
physician**. Therapy 
resumption with reduction by 
1 dose level of contributing 
agent per treating physician 
discretion is permitted. 
Withhold copanlisib* until 
toxicity is resolved to 
baseline or Grade ≤ 1 
severity (or at the 
investigator’s discretion, 
Grade ≤ 2, if not 
considered a safety risk for 
the patient), then reduce by 
1 dose level**, unless 
otherwise specified in 
toxicity table management. 
 
For severe and/or recurrent 
anorexia or fatigue, therapy 
interruption is permitted 
per MD discretion until 
deemed safe to resume per 
treating physician**. 
Therapy resumption with 
reduction by 1 dose level of 
contributing agent per 
treating physician 
discretion is permitted. 
*When eribulin is withheld, copanlisib is also withheld. 
**Patients requiring > two dose reductions of eribulin, or a dose below 30 mg copanlisib) should go 
off protocol therapy.  In case of toxicity requiring dose reductions specific to copanlisib below 30 mg 
at start of cycle or within a cycle, the patient will discontinue copanlisib, but may continue eribulin 
on study. 
 
Non-hematologic toxicity:  
• Withhold eribulin for Grade >2 until toxicity resolves to baseline or Grade ≤1, unless 
otherwise specified. Refer to individual toxicity management tables when specified for 
further details of management. 
• Refer to Section 7.2.1 and Appendix E and F for hyperglycemia related toxicity management 
and dose adjustments in patients also receiving copanlisib. 
• Refer to Section 7.2.2 and Appendix G for hypertension related toxicity management and 
dose adjustments in patients also receiving copanlisib. 
• Refer to Section 7.2.5 for management of copanlisib related severe cutaneous reactions. 
• Refer to Section 7.4 for management of dosing for new onset renal and hepatic impairment.  
 
 
 

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8. 
PHARMACEUTICAL INFORMATION 
 
A list of the adverse events and potential risks associated with the investigational or commercial 
agents administered in this study can be found in Section 10.1. 
 
8.1 
CTEP IND Agent 
 
8.1.1 Copanlisib (NSC 784727) 
 
Chemical Name or Amino Acid Sequence: 2-amino-N-[7-methoxy-8-(3-morpholin-4-
ylpropoxy)-2,3-dihydroimidazo[1,2-c]quinazolin-5-yl]pyrimidine-5-carboxamide 
dihydrochloride 
 
Other Names: BAY 80-6946 (free base); BAY 84-1236 (dihydrochloride salt) 
 
Classification: Pan class I PI3K inhibitor  
 
Molecular Formula: C23H28N8O4 2HCl  
M.W.: 553.45 g/mol 
 
Approximate Solubility: Freely soluble in water and 0.1 M hydrochloric acid (HCl) 
 
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. 
 
Description: The powder is white to yellow solid substance. 
 
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. 
 
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 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 sterile 0.9% sodium chloride bag. 
Mix well by inverting.  
 
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 

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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 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 4 hours after initial entry.  
 
Route of Administration: IV infusion  
 
Method of Administration:  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. 
 
Potential Drug Interactions:  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. 
 
Special Handling: Copanlisib is not genotoxic in vitro or in vivo.  Copanlisib is expected to 
adversely affect male and female reproduction. 
 
Patient Care Implications: Females of child-bearing potential and male patients must use adequate 
contraception while receiving copanlisib and for 1 month after last dose of copanlisib.  Do 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 protocol document for treatment and monitoring guidelines. 
 
Availability 

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Copanlisib is an investigational agent supplied to investigators by the Division of Cancer 
Treatment and Diagnosis (DCTD), NCI. 
 
If the study agent is provided by the NCI under a Collaborative Agreement with the agent 
manufacturer, the text below must be included in the protocol.  Information on the study agent’s 
Collaborative Agreement status will be provided in the approved LOI response letter.  
 
Copanlisib is provided to the NCI under a Collaborative Agreement between the Pharmaceutical 
Collaborator and the DCTD, NCI (see Section 13.5). 
 
8.1.2 Agent Ordering and Agent Accountability 
 
8.1.2.1 
NCI-supplied agents may be requested by eligible participating Investigators (or their 
authorized designee) at each participating institution.  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 participating investigator at that institution. 
 
No starter supplies are allowed. Agents may be ordered at the time of patient 
registration/randomization. 
 
Submit agent requests 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.  For questions 
about drug orders, transfers, returns, or accountability, call or email PMB any time.  
Refer to the PMB’s website for specific policies and guidelines related to agent 
management.   
 
8.1.2.2 
Agent Inventory Records – The investigator, or a responsible party designated by the 
investigator, must maintain a careful record of the receipt, dispensing and final 
disposition of all agents received from the PMB using the appropriate NCI 
Investigational Agent (Drug) Accountability Record (DARF) available on the CTEP 
forms page.  Store and maintain separate NCI Investigational Agent Accountability 
Records for each agent, strength, formulation and ordering investigator on this 
protocol. 
 
8.1.3 Investigator Brochure Availability 
 
The current versions of the IBs for the agents will be accessible to site investigators and research 
staff through the PMB OAOP application.  Access to OAOP requires the establishment of a 

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CTEP 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 via email. 
 
8.1.4 Useful Links and Contacts 
• CTEP Forms, Templates, Documents:  http://ctep.cancer.gov/forms/ 
• NCI CTEP Investigator Registration:  RCRHelpDesk@nih.gov 
• PMB policies and guidelines: 
http://ctep.cancer.gov/branches/pmb/agent management.htm  
• 
PMB Online Agent Order Processing (OAOP) application:  
https://ctepcore.nci.nih.gov/OAOP 
• CTEP Identity and Access Management (IAM) account: https://ctepcore.nci.nih.gov/iam/  
• CTEP IAM account help:  ctepreghelp@ctep.nci.nih.gov  
• IB Coordinator:  IBCoordinator@mail.nih.gov  
• PMB email:  PMBAfterHours@mail.nih.gov 
• PMB phone and hours of service: (240) 276-6575 Monday through Friday between 8:30 
am and 4:30 pm (ET) 
 
8.2 
Commercial Agent 
 
8.2.1 Eribulin Mesylate (NSC 707389) 
 
Chemical Name:
 
(2R,3R,3aS,7R,8aS,9S,10aR,11S,12R,13aR,13bS,15S,18S,21S,2
4S,26R,28R,29a S)-2-[(2S)-3- Amino-2-hydroxypropyl]-3-methoxy-26-
methyl-20,27-dimethylidenehexacosahydro-11,15:18,21:24,28-triepoxy-
7,9-ethano-12,15-methano-9H,15H-furo[3,2-i]furo[2',3':5,6]pyrano[4,3- 
b][1,4]dioxacyclopentacosin-5(4H)-one methanesulfonate (salt)  
 
Other Names: 
 
Eribulin mesilate, halichondrin B analog, E7389, Halaven® 
 
Classification: 
 
Antitubulin agent 
 
Molecular Formula: C41H63NO14S (C40H59NO11 ˑ CH4O3S) 
 
M.W.: 
826.00 
 
Approximate Solubility:   
o Freely soluble in water, methanol, ethanol, 1-octanol, benzyl alcohol, dimethylsufoxide, N-
methylpyrrolidone, dichloromethane and ethylacetate. 
o Soluble in acetone and sparingly soluble in acetonitrile. 
o Insoluble in tert-butylmethyl ether, n-heptane and n-pentane. 
 
Mode of Action: 
Tubulin-based antimitotic mechanism 
 
How Supplied: 
 
Eribulin mesylate is supplied by commercial sources as 1 mg/2mL 
vial (0.5 mg/mL). The clear, colorless, and sterile solution is packaged in glass 
vials with a Teflon®-coated, butyl rubber stopper and flip-off aluminum 

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overseal. 
 
 
 
  
  
Preparation:   Eribulin mesylate may be administered without further dilution or diluted in up to 100 
mL 0.9% Sodium Chloride Injection, USP. Do not dilute in or administer through an 
intravenous line containing solutions with dextrose.   
   
Storage: 
Supplies are labeled for room temperature storage (25°C).  Do not freeze.  Store the 
intact vials as directed by the product label.  Protection from light is not necessary. 
 
Stability: 
Refer to the product label.   
 
If not used immediately, eribulin mesylate as the undiluted solution in a syringe 
should not normally be stored longer than 4 hours at 25°C and ambient lighting, 
or 24 hours at 2 to 8°C.  
 
Diluted solutions of eribulin mesylate (0.02 mg/mL – 0.2 mg/mL in 0.9% Sodium 
Chloride solution for injection) should not be stored longer than 24 hours at 2 to 
8°C. 
 
Route and method of Administration:  
Intravenous; over 2 to 5 minutes 
 
Potential Drug Interactions: 
CYP3A4 appears to be the major enzyme responsible for eribulin 
mesylate metabolism in vitro but metabolism is a minor component in eribulin 
mesylate clearance.  It is not a substrate of BCRP, OAT1, OAT3, OATP1B1, 
OATP1B3, OCT1, OCT2, MATE1, BSEP, MRP2, or MRP4.  No drug-drug 
interactions are expected with CYP3A4 inhibitors, inducers, or P-gp inhibitors.  
Eribulin mesylate does not inhibit CYP1A2, 2B6, 2C8, 2C9, 2C19, 2D6, 2E1, 3A4, 
P-gp, BCRP, OCT1, OAT1, or OAT3.  Eribulin mesylate does not induce CYP1A2, 
2B6, 2C9, 2C19, or 3A4. 
 
Patient Care Implications: 
Females of childbearing potential should use effective 
contraception during and for at least 2 weeks after treatment.  Males with female 
partners of childbearing potential should use effective contraception during and for 
up to 3.5 months after treatment. 
 
 
 
Women should not breastfeed while receiving eribulin mesylate and for 2 
weeks after the final dose of eribulin mesylate.  
 
 
9. 
STATISTICAL CONSIDERATIONS 
 
9.1 
Study Design/Endpoints 
 
This is a phase 1/2 study in patients with metastatic triple negative breast cancer (TNBC).  The 
hypothesis is that the addition of copanlisib to eribulin in patients with metastatic TNBC is safe 

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and effective.  The phase I portion will consist of a standard 3+3 phase 1 dose escalation design to 
determine the MTD and RP2D.  In the phase 1 portion, patients will be treated with eribulin plus 
copanlisib at indicated dose levels below.  Eribulin will be administered IV on an outpatient basis 
at the assigned dose on days 1 and 8 of 21-day cycle.  Dose is assigned in mg/m2, and should be 
rounded to the nearest 5 mg increment.  Dose is assigned per dose level in the dose escalation 
portion, and as the RP2D in the dose expansion portion of the study.  Copanlisib will be 
administered IV on an outpatient basis at the assigned dose on days 1 and 8 of 21-day cycle.  Dose 
is assigned per dose level in the dose escalation portion, and at the RP2D in the Phase 2 portion of 
the study. 
 
Once the RP2D for eribulin plus copanlisib is determined, the randomized Phase 2 portion will 
begin.  The phase 2 portion will use a stratified randomized two-arm design on patients with 
metastatic TNBC, stratified by PTEN/PIK3CA mutation status per archival tumor tissue analysis. 
In this phase 2 portion of the study, patients will be randomized to be treated with either eribulin 
alone or with eribulin plus copanlisib at the RP2D.   
 
The primary endpoint of the phase 1 trial is dose limiting toxicity (DLT defined below).  A 3+3 
design will be used with the three dose levels planned.  If 0 or 1 out of 6 patients experiences a 
DLT at the starting dose level, then it will move to the subsequent dose level.  If ≥2 patients of a 
cohort out of 6 patients experience DLT during the first cycle, then treatment dose will de-
escalate to dose level -1.  MTD is defined as the highest dose level at which at most 1 of 6 
patients experience a DLT during the observation window, which will be the RP2D.  
 
A randomized two-arm phase 2 study will be conducted using a stratified complete block design 
(with varying block sizes), stratified by PTEN/PIK3CA mutation status.  Eligible patients with 
known PTEN/PIK3CA mutation status are randomized by stratification of PTEN/PIK3CA 
mutation status to receive the combination of eribulin and copanlisib versus eribulin alone.   
 
The primary endpoint of the phase 2 portion of the study is progression free survival (PFS), 
defined from date of treatment start to date of progression or death.  Patients who have not 
experienced progression or death will be censored at last follow up.  
 
The secondary endpoints of the Phase 2 portion of the study include ORR, CBR in each arm, in 
the overall population, and by PTEN/PIK3CA mutation status. 
 
9.1.1 Endpoints 
 
9.1.1.1 
Primary Endpoints 
 
1. Phase 1 portion: MTD, RP2D, toxicity profile  
2. Phase 2 portion: PFS in patients with metastatic TNBC treated with prior taxane and 
anthracycline 
 
9.1.1.2 
Secondary Endpoints 
 
1. Phase 1 portion: ORR, CBR, PFS  

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2. Phase 2 portion:  
• ORR, CBR, Toxicity profile in the overall population by treatment arm 
 
9.1.1.3 
Exploratory Endpoints 
 
1. Assess baseline (pre-treatment) tumor tissue mutation or gene expression profiles to 
correlate treatment response. 
2. Assess intrinsic and adaptive resistance mechanisms by analyzing pre and post treatment 
biopsies for gene expression and proteomic changes.  
3. Determine circulating tumor DNA (ctDNA) mutation profiles at baseline and changes in 
mutation profile and VAFs on C2D1 and at disease progression compared to baseline to 
correlate with treatment response. 
4. Assess circulating biomarkers predictive of treatment response.  
5. Assess plasma and serum proteomics and metabolomics predictive of treatment 
response. 
6. Compare the PTEN IHC results at disease progression compared to baseline. 
7. ORR, PFS, CBR by treatment arm in patients with TNBC harboring mutations in 
PIK3CA/ PTEN or loss of PTEN expression by IHC of baseline (pre-treatment) biopsy. 
8. Assess target inhibition of PI3K pathway (by phospho-AKT) and mitotic arrest (by 
phospho-histone H3) with eribulin plus copanlisib versus eribulin alone. 
9. ORR, PFS, CBR by treatment arm in patients with TNBC harboring mutations in 
PIK3CA/ PTEN by ctDNA at baseline (pre-treatment) biopsy and potential changes over 
time. 
 
9.1.2 Data Analysis 
 
All data analyses of the phase 1 portion of the study will be descriptive in nature. Demographic 
and clinical characteristics of the sample will be summarized using descriptive statistics.  
 
Demographics and Baseline Characteristics.  Frequency distributions of sex, race, ethnicity, 
target gene mutation and other categorical baseline characteristics will be tabulated.  Baseline 
body mass index (BMI) will be derived from measurements of baseline body weight and height.  
Summary statistics for age, body weight, height, and BMI will be provided using mean, median, 
standard deviation, inter-quartile range and range.  Baseline disease characteristics will be 
summarized overall and by arm, as appropriate 
 
Phase I toxicity analysis.  All data analyses of the phase 1 portion of the study will be descriptive 
in nature.  Demographic and clinical characteristics of the sample will be summarized using 
descriptive statistics.  The DLT observation window for the phase 1 portion of this study will be 
1 treatment cycle, based on the dose level assignment.  Patients assigned to dose level -1 will 
have a treatment cycle and DLT window of 28 days.  Patients assigned to all other dose levels 
will have a treatment cycle and DLT window of 21 days.  DLT will be determined based on the 
incidence, intensity and duration of AEs that are related to the drug combinations.  The severity 
of AEs will be graded according to NCI Common Terminology Criteria for Adverse Events 
(CTCAE) v5.0.  Toxicity will be listed by grade, relation to study drugs and by dose level.  For 
those patients treated at the RP2D, the overall response rate, clinical benefit rate, and the 

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corresponding 95% confidence intervals will be calculated.  
 
Phase II PFS analysis.  Due to early study closure as a result of the IND withdrawal for 
copanlisib, this endpoint ultimately had no statistical power. The original plan for analysis was as 
follows: The progression free survival (PFS) will be estimated using the Kaplan-Meier (KM) 
product limit estimator.  Median PFS and the 90% confidence interval will be estimated.  PFS 
probability at specified time points with 90% confidence interval will also be estimated.  Two 
sample log-rank test at a 0.1 alpha level will be conducted to compare the PFS difference 
between the two arms.  Cox proportional hazard model will be used to estimate hazard ratio 
(HR) with 95% confidence interval between the two arms overall and in the subset of patients of 
interest (e.g,.PIK3CA/PTEN mutant or with loss of PTEN).  The Cox model with the main 
effects of treatment arm and mutation and their interaction will be used to determine if treatment 
effect differs by mutational status. 
 
9.2 
Sample Size/Accrual Rate 
 
Sample Size:   
• Phase 1 portion: Minimum: 9  Maximum: 18 
• Phase 2 portion: Total: 88 
 
Accrual Rate:   
• Phase 1 portion: 2-4 patients/month 
• Phase 2 portion: 7-8 patients/month 
 
For the phase 1 portion of the study, a minimum of 9 patients and a maximum of 18 patients will 
be needed for the dose escalation portion of the study.  The MTD level with <2 DLTs out of 6 
patients will be identified. 
 
For the phase 2 portion of the study, a total of 88 evaluable patients will be enrolled.  The 
median PFS was estimated at 4 months for TNBC treated with eribulin (Twelves et al., 2014), 
and is expected to increase to approximately 7 months with the addition of copanlisib to eribulin.  
With an enrollment period of 12 months, an additional minimum follow-up of 12 months after 
the enrollment of the last patient, as well as to account for a 5% dropout rate, a total of 88 PFS-
evaluable patients will be required, 44 patients per study arm, to achieve 80% power to detect the 
overall PFS difference of median PFS of 6.95 vs. 4 months (corresponding to a hazard ratio of  
0.5755) between the two treatment arms, based on 1-sided two-sample log rank test at 0.1 alpha 
level.  Among a total of N=88 patients, approximately 60 total events are expected, specifically 
approximately 33 in the eribulin arm and 27 in the combination arm.   
 
PTEN/PIK3CA/AKT mutation and loss of PTEN expression occurs in ~50% patients.  In the 
combination arm, we estimate to have 22/22 PTEN/PIK3CA altered (mutated or with loss of 
PTEN)/not-altered patients.  Using the same sample size assumptions as above (assuming the 
not-altered patients with a median PFS of 4 months, 5% drop out), 44 patients (27 events) in the 

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baseline gene expression (or gene mutation) and potentially their interaction.  Odds ratio will be 
estimated with 95% confidence intervals. 
 
Additionally, exploratory endpoints will include ORR , CBR, and PFS by PTEN/PIK3CA 
mutation status based on archival tumor tissue NGS. Analysis of the exploratory endpoints will 
consist of ORR, CBR estimations with 95% Wilson confidence interval within subsets of 
interest.  PFS between the two arms within the PIK3CA/PTEN altered subset and the unaltered 
subset will be separately analyzed by KM method and log rank test. 
 
 
9.6 
For phase 2 portion: Reporting and Exclusions 
 
9.6.1 Evaluation of Toxicity 
 
All patients receiving a single dose of therapy will be evaluable for toxicity from the time of 
their first treatment with eribulin and copanlisib.  
 
9.6.2 Evaluation of Response 
 
All patients included in the study must be assessed for response to treatment, even if there are 
major protocol treatment deviations or if they are ineligible.  Each patient will be assigned one of 
the following categories:  1) complete response, 2) partial response, 3) stable disease, 4) 
progressive disease, 5) early death from malignant disease, 6) early death from toxicity, 7) early 
death because of other cause, or 9) unknown (not assessable, insufficient data).  [Note:  By 
arbitrary convention, category 9 usually designates the “unknown” status of any type of data in a 
clinical database.] 
 
All of the patients who met the eligibility criteria (with the possible exception of those who 
received no study medication) should be included in the main analysis of the response rate.  
Patients in response categories 4-9 should be considered to have a treatment failure (disease 
progression).  Thus, an incorrect treatment schedule or drug administration does not result in 
exclusion from the analysis of the response rate.  Precise definitions for categories 4-9 will be 
protocol specific.  
 
All conclusions should be based on all eligible patients.  Subanalyses may then be performed on 
the basis of a subset of patients, excluding those for whom major protocol deviations have been 
identified (e.g., early death due to other reasons, early discontinuation of treatment, major 
protocol violations, etc.).  However, these subanalyses may not serve as the basis for drawing 
conclusions concerning treatment efficacy, and the reasons for excluding patients from the 
analysis should be clearly reported.  The 95% confidence intervals should also be provided.  
 
9.7 
Data Safety Monitoring Board 
 
The Siteman Cancer Center independent standing Data and Safety Monitoring Board (DSMB) 
will review toxicity data for phase I of this trial.  The SCC standing DSMB includes clinical 
investigators and biostatisticians who are subject to the Washington University School of 

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Medicine policies regarding standards of conduct and who have disclosed any potential conflicts 
of interest in accordance with institution policies.  
 
The DSM report for the SCC standing DSMB will be prepared by the study team with assistance 
from the study statistician, will be reviewed by the DSMB, and will be submitted to institutional 
safety monitoring committees as required. The DSMB must review phase I data at least every six 
months beginning six months after study activation.  This report will include: 
 
• Study demographics (protocol number, protocol title, Principal Investigator name, 
data coordinator name, regulatory coordinator name, and statistician) 
• Date of initial IRB approval, date of most recent consent, date of most recent QA 
audit, study status, and phase of study 
• History of study including summary of substantive amendments; summary of accrual 
suspensions including start/stop dates and reason; and summary of protocol 
exceptions, error, or breach of confidentiality including start/stop dates and reason 
• Study-wide target accrual and study-wide actual accrual including numbers from 
participating sites 
• Protocol activation date at each participating site 
• Average rate of accrual observed in year 1, year 2, and subsequent years at each 
participating site 
• Expected accrual end date, accrual by site, and accrual by cohort 
• Objectives of protocol with supporting data and list the number of participants who 
have met each objective 
• Measures of efficacy 
• Early stopping rules with supporting data and list the number of participants who 
have met the early stopping rules 
• Summary of toxicities at all participating sites and separated by cohorts with the 
number of dose-limiting toxicities indicated 
• Abstract submissions/publications 
• Summary of any recent literature that may affect the safety or ethics of the study 
 
Further DSMB responsibilities are described in the DSMB charter. 
 
The study principal investigator and coordinator will monitor for serious toxicities on an ongoing 
basis. Once the principal investigator or coordinator becomes aware of an adverse event, the AE 
will be reported as described in the reporting requirements section 13.2. 
 
 The conduct of the phase 2 portion of this study will be overseen by the ETCTN DSMB. The 
DSMB will be responsible for recommendations to the Principal Investigator and NCI regarding 
possible trial closure and/or early reporting of the study. The study team (with the exception of 
the study statistician) will not have access to the summary outcome data until released by the 
DSMB. 
 
9.8 
Interim Futility Analysis 
 
An interim analysis for futility based on the Wieand rule is planned when approximately 50% of 

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mutant or loss tumors between the two arms, and 2) comparison between patients with PIK3CA 
mutation/PTEN mutant or loss patients and those with PIK3CA/PTEN WT patients within the 
eribulin + copanlisb arm.  Analyses on subsets will be similar to the above prescribed primary 
and secondary endpoint analysis.   
 
To investigate the predictive effect of PTEN/PIK3CA mutation, the treatment arms will be 
compared using the survival analysis methods previously described (KM method and Cox 
model) within the subset of patients with PIK3CA mutation or PTEN mutation, as well as in the 
subset of patients without these mutations, separately.  The interaction between the gene 
mutation and the treatment arm will be tested in a Cox proportional hazard model setting.  If the 
interaction effect is not statistically significant, we will continue to evaluate the prognostic effect 
of the PTEN/PIK3CA gene mutations for survival, PTEN/PIK3CA mutation will be associated 
with the survival endpoints by the KM method and Cox model among the control arm. 
 
9.11 
Population for Analysis 
 
• DLT-evaluable set:  This set will be used for the DLT assessment in the Phase 1 part.  
This analysis set refers to all subjects who receive at least 80% of the drug or (drug 
combinations) during Cycle 1 of 28 days of therapy from the time of their first treatment, 
or those who experience DLT within Cycle 1.  The patients who have no observed DLTs 
but drop out of the study before the completion of Cycle 1 due to reasons other than 
treatment-emergent toxicities, will be replaced.  
• Safety/toxicity evaluable analysis set:  this analysis set contains all subjects who receive 
any dose level of the drug combinations from the time of their first treatment.  The 
primary analysis set for the PFS is the intent-to-treat (ITT) population, referring to the 
patients who are randomized to the arms regardless of the actual treatment they receive, 
and receive at least one dose of the study drug.  
• The modified ITT analysis set restraint the IIT population to those who have no major 
violation of the study protocol.  
 
10. ADVERSE EVENTS:  LIST AND REPORTING REQUIREMENTS  
 
Adverse event (AE) monitoring and reporting is a routine part of every clinical trial.  The 
following list of AEs (Section 10.1) and the characteristics of an observed AE (Sections 10.2 and 
10.3) will determine whether the event requires expedited reporting via the CTEP-AERS in 
addition to routine reporting. 
 
10.1 
Comprehensive Adverse Events and Potential Risks List (CAEPR) 
 
 
10.1.1 CAEPRs for CTEP IND Agent 
 
10.1.1.1 
CAEPR for Copanlisib dihydrochloride (BAY 80-6946 dihydrochloride, NSC 
784727) 
 
The Comprehensive Adverse Events and Potential Risks list (CAEPR) provides a single list of reported 

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Blood bilirubin increased; Blood lactate dehydrogenase increased; Cholesterol high; CPK increased; 
Creatinine increased; GGT increased; INR increased; Investigations - Other (blood chloride decreased); 
Investigations - Other (breath sounds abnormal); Investigations - Other (c-reactive protein increased); 
Investigations - Other (neutrophil count increased); Lipase increased 
METABOLISM AND NUTRITION DISORDERS - Dehydration; Hypercalcemia; Hyperkalemia; 
Hypoalbuminemia; Hypocalcemia; Hypoglycemia; Hypokalemia; Hypomagnesemia; Hyponatremia; 
Hypophosphatemia; Metabolism and nutrition disorders - Other (failure to thrive) 
MUSCULOSKELETAL AND CONNECTIVE TISSUE DISORDERS - Flank pain; Muscle cramp; Muscle 
weakness3; Musculoskeletal and connective tissue disorder - Other (musculoskeletal stiffness) 
NEOPLASMS BENIGN, MALIGNANT AND UNSPECIFIED (INCL CYSTS AND POLYPS) - Leukemia 
secondary to oncology chemotherapy; Myelodysplastic syndrome; Treatment related secondary 
malignancy; Tumor hemorrhage; Tumor pain 
NERVOUS SYSTEM DISORDERS - Acoustic nerve disorder NOS; Ataxia; Depressed level of 
consciousness; Dysesthesia; Dysphasia; Edema cerebral; Encephalopathy; Hydrocephalus; Intracranial 
hemorrhage; Ischemia cerebrovascular; Lethargy; Memory impairment; Neuralgia; Recurrent laryngeal 
nerve palsy; Reversible posterior leukoencephalopathy syndrome; Seizure; Somnolence; Syncope; 
Transient ischemic attacks; Tremor 
PSYCHIATRIC DISORDERS - Anxiety; Confusion; Depression; Psychiatric disorders - Other (mental 
status changes) 
RENAL AND URINARY DISORDERS - Acute kidney injury; Hematuria; Proteinuria; Renal and urinary 
disorders - Other (hemorrhage urinary tract); Renal calculi; Urinary retention; Urinary tract obstruction; 
Urinary tract pain; Urine discoloration 
REPRODUCTIVE SYSTEM AND BREAST DISORDERS - Breast pain; Pelvic pain; Vaginal hemorrhage 
RESPIRATORY, THORACIC AND MEDIASTINAL DISORDERS - Adult respiratory distress syndrome; 
Atelectasis; Bronchopulmonary hemorrhage; Epistaxis; Hiccups; Hypoxia; Pharyngolaryngeal pain; 
Pleural effusion; Pneumonitis; Pneumothorax; Postnasal drip; Productive cough; Pulmonary fibrosis; 
Respiratory failure; Respiratory, thoracic and mediastinal disorders - Other (asthma); Respiratory, 
thoracic and mediastinal disorders - Other (chronic obstructive pulmonary disease); Sinus pain; Sore 
throat; Voice alteration; Wheezing 
SKIN AND SUBCUTANEOUS TISSUE DISORDERS - Dry skin; Hyperhidrosis; Nail loss; Palmar-plantar 
erythrodysesthesia syndrome; Pruritus; Skin and subcutaneous tissue disorders - Other (angioedema); 
Skin and subcutaneous tissue disorders - Other (skin exfoliation) 
VASCULAR DISORDERS - Capillary leak syndrome; Hypertension; Hypotension; Lymphocele; Phlebitis; 
Superior vena cava syndrome; Thromboembolic event 
 
 
Note: Eribulin Mesylate (E7389; Halichondrin B Analog) 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. 
 
10.2 
Adverse Event Characteristics  
 
• CTCAE term (AE description) and grade:  The descriptions and grading scales found 
in the revised NCI Common Terminology Criteria for Adverse Events (CTCAE) version 
5.0 will be utilized for AE reporting.  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. 
 
• For expedited reporting purposes only:   
- 
AEs for the agent that are bold and italicized in the CAEPR (i.e., those listed in the 
SPEER column, Section 10.1) should be reported through CTEP-AERS only if the 
grade is above the grade provided in the SPEER. 

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• Attribution of the AE: 
- 
Definite – The AE is clearly related to the study treatment. 
- 
Probable – The AE is likely related to the study treatment. 
- 
Possible – The AE may be related to the study treatment. 
- 
Unlikely – The AE is doubtfully related to the study treatment. 
- 
Unrelated – The AE is clearly NOT related to the study treatment. 
 
10.3 
Expedited Adverse Event Reporting 
 
10.3.1 Rave-CTEP-AERS Integration 
 
The Rave Cancer Therapy Evaluation Program Adverse Event Reporting System (CTEP-
AERS) integration enables evaluation of Adverse Events (AEs) entered in Rave to 
determine whether they require expedited reporting and facilitates entry in CTEP-AERS 
for those AEs requiring expedited reporting.  Sites must initiate all AEs for this study in 
Medidata Rave. 
 
Pre-treatment AEs:  AEs that occur after informed consent is signed and prior to start of 
treatment are collected in Medidata Rave using the Pre-treatment Adverse Event form.  
 
Pre-existing medical conditions (formerly referred to as baseline AEs) identified during 
baseline assessment are not considered AEs and therefore should not be reported on the 
Pre-treatment Adverse Event form. If these pre-existing conditions worsen in severity, 
the investigator must reassess the event to determine if an expedited report is required. 
Whether or not an expedited report is required, the worsened condition should be 
reported in Rave as a routine AE. 
 
Treatment-emergent AEs:  All AEs that occur after start of treatment are collected in 
Medidata Rave using the Adverse Event form, which is available for entry at each 
treatment course or reporting period and is used to collect AEs that start during the period 
or persist from the previous reporting period.  AEs that occur 30 days after the last 
administration of the investigational agent/intervention are collected using the Late 
Adverse Event form. 
Prior to sending AEs through the rules evaluation process, site staff should verify the 
following on the Adverse Event form in Rave: 
 
• The reporting period (course/cycle) is correct, and 
• AEs are recorded and complete (no missing fields) and the form is query free.  
 
The CRA reports AEs in Rave at the time the Investigator learns of the event.  If the CRA 
modifies an AE, it must be re-submitted for rules evaluation. 
 
Upon completion of AE entry in Medidata Rave, the CRA submits the AE for rules 
evaluation by completing the Expedited Reporting Evaluation form (i.e., checking the 
box Send All AEs for Evaluation and save the form).  Both NCI and protocol-specific 

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reporting rules evaluate the AEs submitted for expedited reporting.  A report is initiated 
in CTEP-AERS using information entered in Medidata Rave for AEs that meet reporting 
requirements.  The CRA completes the report by accessing CTEP-AERS via a direct link 
on the Medidata Rave Expedited Reporting Evaluation form.  Contact the CTSU Help 
Desk at 1-888-823-5923 or by email at ctsucontact@westat.com if you have any issues 
submitting an expedited report in CTEP-AERS. 
 
In the rare occurrence that internet connectivity is lost, a 24-hour notification is to be 
made to CTEP by telephone at 301-897-7497.  Once internet connectivity is restored, the 
24-hour notification that was phoned in must be entered immediately into CTEP-AERS 
using the direct link from Medidata Rave. 
 
Additional information about the CTEP-AERS integration is available on the CTSU 
members’ website: 
 
• Study specific documents:   Protocols > Documents> Protocol Related 
Documents> Adverse Event Reporting, and   
• Additional resources: Resources > CTSU Operations Information> User Guides 
& Help Topics. 
 
NCI requirements for SAE reporting are available on the CTEP website:  
 
• NCI Guidelines for Investigators:  Adverse Event Reporting Requirements is available at 
https://ctep.cancer.gov/protocolDevelopment/electronic applications/docs/aeguidelines.p
df. 
 
10.3.2 Distribution of Adverse Event Reports 
 
CTEP-AERS is programmed for automatic electronic distribution of reports to the following 
individuals:  Principal Investigator and Adverse Event Coordinator(s) (if applicable) of the 
Corresponding Organization or Lead Organization, the local treating physician, and the Reporter 
and Submitter.  CTEP-AERS provides a copy feature for other e-mail recipients.  
 
10.3.3 Expedited Reporting Guidelines 
 
Use the NCI protocol number and the protocol-specific patient ID assigned during trial 
registration on all reports. 
 
Note:  A death on study requires both routine and expedited reporting, regardless of 
causality as long as the death occurred within 30 days after the last administration of the 
investigational agent.  Attribution to treatment or other cause must be provided. 
 
Death due to progressive disease should be reported as Grade 5 “Disease progression” in the 
system organ class (SOC) “General disorders and administration site conditions.”  Evidence that 
the death was a manifestation of underlying disease (e.g., radiological changes suggesting tumor 
growth or progression: clinical deterioration associated with a disease process) should be 

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10 radioactive half-lives, rounded UP to the nearest whole day, after the agent/intervention was last administered.  Footnote “1” 
above applies after this reporting period. 
 
Effective Date: August 30, 2024 
 
10.3.4 Adverse Events of Special Safety Interest 
 
• Non-infectious pneumonitis 
 
Non-infectious pneumonitis has been observed in studies with copanlisib.  As soon as there is 
a reasonable suspicion of a patient experiencing non-infectious pneumonitis, the investigator 
should report it within 24 hours through CTEP-AERS in addition to routine reporting via 
Medidata Rave regardless of whether the event is assessed as causally related/not related to 
the study therapy, or as serious/non-serious by an investigator. 
 
• Torsades de Pointes 
 
Torsades de Pointes has been observed in studies with eribulin. As soon as there is a finding 
of patient experiencing Torsades de Pointes, the investigator should report it within 24 hours 
through CTEP-AERS in addition to routine reporting via Medidata Rave regardless of 
whether the event is assessed as causally related/not related to the study therapy, or as 
serious/non-serious by an investigator. 
 
10.4 
Routine Adverse Event Reporting 
 
All Adverse Events must be reported in routine study data submissions.  AEs reported 
expeditiously through CTEP-AERS must also be reported in routine study data 
submissions in Medidata Rave. 
 
Adverse event data collection and reporting, which are required as part of every clinical trial, are 
done to ensure the safety of patients enrolled in the studies as well as those who will enroll in 
future studies using similar agents.  AEs are reported in a routine manner at scheduled times 
during the trial using Medidata Rave.  For this trial the Adverse Event CRF is used for routine 
AE reporting in Rave. 
 
10.5 
Pregnancy 
 
Although not an adverse event in and of itself, pregnancy as well as its outcome must be 
documented via CTEP-AERS.  In addition, the Pregnancy Information Form included within 
the NCI Guidelines for Adverse Event Reporting Requirements must be completed and 
submitted to CTEP.  Any pregnancy occurring in a patient or patient’s partner from the time of 
consent to 90 days after the last dose of study drug must be reported and then followed for 
outcome.  Newborn infants should be followed until 30 days old.  Please see the “NCI 
Guidelines for Investigators: Adverse Event Reporting Requirements for DCTD (CTEP and CIP) 
and DCP INDs and IDEs” (at http://ctep.cancer.gov/protocolDevelopment/adverse effects.htm) 

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for more details on how to report pregnancy and its outcome to CTEP.  
 
10.6 
Secondary Malignancy 
 
A secondary malignancy is a cancer caused by treatment for a previous malignancy (e.g., 
treatment with investigational agent/intervention, radiation or chemotherapy). A secondary 
malignancy is not considered a metastasis of the initial neoplasm. 
 
CTEP requires all secondary malignancies that occur following treatment with an agent under an 
NCI IND/IDE be reported expeditiously via CTEP-AERS.  Three options are available to 
describe the event:  
 
• Leukemia secondary to oncology chemotherapy (e.g., acute myelocytic leukemia [AML])  
• Myelodysplastic syndrome (MDS)  
• Treatment-related secondary malignancy  
 
Any malignancy possibly related to cancer treatment (including AML/MDS) should also be 
reported via the routine reporting mechanisms outlined in each protocol.  
 
10.7 
Second Malignancy 
 
A second malignancy is one unrelated to the treatment of a prior malignancy (and is NOT a 
metastasis from the initial malignancy).  Second malignancies require ONLY routine AE 
reporting unless otherwise specified. 
 
 
11. STUDY CALENDAR 
 
Baseline evaluations are to be conducted within 2 weeks prior to start of protocol therapy.  Scans 
and x-rays must be done <4 weeks prior to the start of therapy.  In the event that the patient’s 
condition is deteriorating, laboratory evaluations should be repeated within 48 hours prior to 
initiation of the next cycle of therapy. 
 
 
 
Screening 
Baseline 
Cycle 119 
Cycle 219 
Cycle 3+19 
End of 
treatment14 
Follow up15 
D1 
D812 
D1 
D812 
D1 
D812 
Informed consent 
X 
 
 
 
 
 
 
 
 
 
Archival tumor tissue1 
X 
 
 
 
 
 
 
 
 
 
Fresh tumor biopsy2 
 
X 
 
 
X 
 
 
 
X11 
 
Physical exam w/ ECOG PS 
X 
 
X 
X 
X 
X 
X 
 
X 
 
Vital Signs (blood pressure, 
height, weight) 
X 
 
X 
X 
X 
X 
X 
X 
X 
 
Demographics 
X 
 
 
 
 
 
 
 
 
 
Concomitant medications 
X 
X -------------------------------------------------------------------------------------------------------------------------- X 

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Screening 
Baseline 
Cycle 119 
Cycle 219 
Cycle 3+19 
End of 
treatment14 
Follow up15 
D1 
D812 
D1 
D812 
D1 
D812 
Adverse event assessment 
 
X -------------------------------------------------------------------------------------------------------------------------- X 
CBC with diff 
X 
 
X 
X 
X 
X 
X 
X 
X 
 
Serum chemistry3, 18 
X 
 
X 
X 
X 
X 
X 
X 
X 
 
HbA1c 
X 
 
 
 
 
 
 
 
 
 
Glucose 
X 
 
X4 
X 
X 
X 
X 
X 
X 
 
Hepatitis panel5 
X 
 
 
 
 
 
 
 
 
 
Lipase, amylase 
X 
 
 
 
 
 
 
 
 
 
Lipid panel 
X 
 
 
 
 
 
Every 4 
cycles 
 
 
 
PT/INR and PTT 
X 
 
 
 
 
 
 
 
 
 
Phosphorus 
X 
 
X 
 
X 
 
X 
 
 
 
Magnesium18 
X 
 
X 
X 
X 
X 
X 
X 
 
 
ECG8 
X 
 
 
 
X 
 
 
 
 
 
Pregnancy Test 
X21 
 
 
 
 
 
X21 
 
 
 
Randomization16 
 
X 
 
 
 
 
 
 
 
 
Eribulin6 
 
 
X 
X 
X 
X 
X 
X 
 
 
Copanlisib7 
 
 
X 
X 
X 
X 
X 
X 
 
 
Tumor measurements13 
X 
 
 
 
 
 
X9 
 
 
X 
Whole Blood (cfDNA 
Streck)  
 
X 
 
 
X 
 
X10 
 
X 
 
Blood (EDTA) for plasma17 
 
X 
 
 
X 
 
X10 
 
X 
 
Blood (red top) for serum17 
 
X 
 
 
X 
 
X10 
 
X 
 
Urine protein/creatinine 
ratio20  
X 
 
 
 
 
 
 
 
 
 
1. 
Mandatory for correlative testing for all study phases if baseline research biopsy is not safely accessible per MD discretion.  For Phase 
2 portion: PIK3CA/PTEN tumor mutational status will be required for stratification purposes prior to screening and randomization. 
2. 
Mandatory, if tumor tissue is safely accessible as determined by study investigator.  Study biopsies will be performed at baseline and 
C2D1-2 (within 24 hours of study treatment).  
3. 
Serum chemistry is albumin, alkaline phosphatase, total bilirubin, bicarbonate BUN, calcium, chloride, creatinine, glucose, potassium, 
total protein, SGOT [AST], SGPT [ALT], sodium 
4. 
Cycle 1 Day 1 Only, if receiving copanlisib only: Glucose level will be tested before administration of copanlisib, 60 minutes after the 
start of the copanlisib infusion, 60 minutes after the end of the copanlisib infusion, and 2 hours after the end of the infusion. 
5. 
All patients must be screened for hepatitis B and C viral infection up to 28 days prior to study drug initiation using the routine hepatitis 
virus lab panel and include the following: Hepatitis B surface antigen (HbsAg), Hepatitis B core IgM antibody (anti-HBc IgM) and 
Hepatitis C antibody (anti-HCV). Patients positive for HBsAg and/or HBcAb will be eligible if they are negative for HBV DNA, these 
patients should receive prophylactic antiviral therapy. Patients positive for anti-HCV antibody will be eligible if they are negative for HCV 
RNA. Refer to Section 3.1.11 and 3.1.13. 
6. 
Eribulin: All patients in the Phase 1 portion of the study will receive eribulin in combination with copanlisib. All patients in the Phase 2 
portion of the study will receive eribulin, either alone or in combination with copanlisib. Treatment window ± 2 days permitted. 
7. 
Copanlisib: All patients in the Phase 1 portion of the study will receive copanlisib in combination with eribulin. Only patients randomized 
to the combination group in the Phase 2 portion of the study will receive both copanlisib and eribulin. Treatment window ± 2 days 
permitted. 
8. 
ECG will be performed at baseline and Day 1 of Cycle 2. Abnormal findings should be evaluated as clinically indicated, including repeat 
ECGs. ECGs may be done at other study time points if clinically indicated. 
9. 
Tumor assessment will be performed Q 9 weeks. Tumor assessment window ±7 days.. 
10. Every 9 weeks ±7 days with tumor imaging reassessment  
11. Optional Fresh biopsy if tissue safely accessible as determined by study investigator at disease progression (prior to subsequent line of 
therapy). 

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Screening 
Baseline 
Cycle 119 
Cycle 219 
Cycle 3+19 
End of 
treatment14 
Follow up15 
D1 
D812 
D1 
D812 
D1 
D812 
12. D8 will be D15 in Phase 1 dose level -1 with treatment dosing interval at Day 1 and Day 15. 
13. Tumor measurements are determined by radiologic evaluation at baseline and every 9 weeks ±7 days from C1D1.  Confirmatory scans 
are done 6 weeks after initial documentation of a response.  The same imaging modality should be utilized at screening and throughout 
duration of study.  During study enrollment in the phase 2 portion of the study, brain MRI will be performed every 12 weeks at minimum 
(or sooner if clinically-indicated) in all patients with history of known brain metastases. 
14. End of treatment assessment and procedures is required for all study patients within 30 days of the last dose of study drug, and prior to 
initiation of subsequent line of therapy. 
15. Refer to Section 6.5. Follow up for survival status occurs every 3 months for 36 months after removal from the study or until death, 
whichever occurs first. In addition, patients removed from study due to unacceptable adverse event(s) will be followed until resolution or 
stabilization of the adverse event.  First contact will occur within 3 days of adverse event(s). For pts that come off treatment for reasons 
other than PD, please continue to check imaging, AEs and Conmeds every 3 months. Follow up for survival only post progressive 
disease. No imaging, AEs, or Conmeds needed post PD, with exception of following for resolution or stabilization of an AE as noted 
above. 
16. Randomization for phase 2 only 
17. Mandatory 
18. Correct hypokalemia and hypomagnesemia prior to initiating eribulin and monitor electrolytes during therapy.  Refer to toxicity 
management table for instructions on management of hypokalemia and hypomagnesemia, and potential clinical need for additional 
ECG monitoring. 
19. All treatments, measurements and assessments should occur within ±2 days from the stated protocol day unless stated otherwise. 
20. Random urine sample for urine protein/creatinine ratio at screening.  Patients with urine protein/creatinine>3.5 g/g on random urine 
sample will be excluded from the study. If 24-hour urine protein collection is obtained per MD discretion, patients with grade ≥3 
proteinuria will be excluded from the study. 
21. Pregnancy testing is to be performed at screening and at every 3 treatment cycles in all women of child bearing potential (WOCBP), 
either using serum or urine βhCG testing. 
 
 
 

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12. MEASUREMENT OF EFFECT 
 
For phase 1 only:  Although the clinical benefit of these drugs has not yet been established, the 
intent of offering this treatment is to provide a possible therapeutic benefit, and thus the patient 
will be carefully monitored for tumor response and symptom relief in addition to safety and 
tolerability.  Patients with measurable disease will be assessed by standard criteria.  For the 
purposes of this study, patients should be re-evaluated every 9 weeks ±7 days.  In addition to a 
baseline scan, confirmatory scans will also be obtained 6 weeks following initial documentation 
of an objective response. 
 
12.1 
Antitumor Effect – Solid Tumors 
 
For the purposes of this study, patients should be re-evaluated for response every 9 weeks ±7 
days.  In addition to a baseline scan, confirmatory scans should also be obtained 6 weeks 
following initial documentation of objective response. 
 
Response and progression will be evaluated in this study using the new international criteria 
proposed by the revised Response Evaluation Criteria in Solid Tumors (RECIST) guideline 
(version 1.1) [Eur J Ca 45:228-247, 2009].  Changes in the largest diameter (unidimensional 
measurement) of the tumor lesions and the shortest diameter in the case of malignant lymph 
nodes are used in the RECIST criteria. 
 
12.1.1 Definitions 
 
Evaluable for toxicity.  All patients will be evaluable for toxicity from the time of their first 
treatment with copanlisib. 
 
Evaluable for objective response.  Only those patients who have measurable disease present at 
baseline, have received at least one cycle of therapy, and have had their disease re-evaluated will 
be considered evaluable for response.  These patients will have their response classified 
according to the definitions stated below.  (Note:  Patients who exhibit objective disease 
progression prior to the end of cycle 1 will also be considered evaluable.) 
 
Evaluable Non-Target Disease Response.  Patients who have lesions present at baseline that are 
evaluable but do not meet the definitions of measurable disease, have received at least one cycle 
of therapy, and have had their disease re-evaluated will be considered evaluable for non-target 
disease.  The response assessment is based on the presence, absence, or unequivocal progression 
of the lesions.  
 
12.1.2 Disease Parameters 
 
Measurable disease.  Measurable lesions are defined as those that can be accurately measured in 
at least one dimension (longest diameter to be recorded) as ≥20 mm (≥2 cm) by chest x-ray or as 
≥10 mm (≥1 cm) with CT scan, MRI, or calipers by clinical exam.  All tumor measurements 
must be recorded in millimeters (or decimal fractions of centimeters). 
 

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Note:  Tumor lesions that are situated in a previously irradiated area might or might not be 
considered measurable.   
 
Malignant lymph nodes.  To be considered pathologically enlarged and measurable, a lymph 
node must be ≥15 mm (≥1.5 cm) in short axis when assessed by CT scan (CT scan slice 
thickness recommended to be no greater than 5 mm [0.5 cm]).  At baseline and in follow-up, 
only the short axis will be measured and followed. 
 
Non-measurable disease.  All other lesions (or sites of disease), including small lesions (longest 
diameter <10 mm [<1 cm] or pathological lymph nodes with ≥10 to <15 mm [≥1 to <1.5 cm] 
short axis), are considered non-measurable disease.  Bone lesions, leptomeningeal disease, 
ascites, pleural/pericardial effusions, lymphangitis cutis/pulmonitis, inflammatory breast disease, 
and abdominal masses (not followed by CT or MRI), are considered as non-measurable. 
 
Note:  Cystic lesions that meet the criteria for radiographically defined simple cysts should not 
be considered as malignant lesions (neither measurable nor non-measurable) since they are, by 
definition, simple cysts. 
 
‘Cystic lesions’ thought to represent cystic metastases can be considered as measurable lesions, 
if they meet the definition of measurability described above. However, if non-cystic lesions are 
present in the same patient, these are preferred for selection as target lesions. 
 
Target lesions.  All measurable lesions up to a maximum of 2 lesions per organ and 5 lesions in 
total, representative of all involved organs, should be identified as target lesions and recorded 
and measured at baseline.  Target lesions should be selected on the basis of their size (lesions 
with the longest diameter), be representative of all involved organs, but in addition should be 
those that lend themselves to reproducible repeated measurements.  It may be the case that, on 
occasion, the largest lesion does not lend itself to reproducible measurement in which 
circumstance the next largest lesion which can be measured reproducibly should be selected.  A 
sum of the diameters (longest for non-nodal lesions, short axis for nodal lesions) for all target 
lesions will be calculated and reported as the baseline sum diameters.  If lymph nodes are to be 
included in the sum, then only the short axis is added into the sum.  The baseline sum diameters 
will be used as reference to further characterize any objective tumor regression in the measurable 
dimension of the disease. 
 
Non-target lesions.  All other lesions (or sites of disease) including any measurable lesions over 
and above the 5 target lesions should be identified as non-target lesions and should also be 
recorded at baseline.  Measurements of these lesions are not required, but the presence, absence, 
or in rare cases unequivocal progression of each should be noted throughout follow-up.  
 
12.1.3 Methods for Evaluation of Measurable Disease 
 
All measurements should be taken and recorded in metric notation using a ruler or calipers.  All 
baseline evaluations should be performed as closely as possible to the beginning of treatment and 
never more than 4 weeks before the beginning of the treatment. 
 

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The same method of assessment and the same technique should be used to characterize each 
identified and reported lesion at baseline and during follow-up. Imaging-based evaluation is 
preferred to evaluation by clinical examination unless the lesion(s) being followed cannot be 
imaged but are assessable by clinical exam. 
 
Clinical lesions.  Clinical lesions will only be considered measurable when they are superficial 
(e.g., skin nodules and palpable lymph nodes) and ≥10 mm (≥1 cm) diameter as assessed using 
calipers (e.g., skin nodules).  In the case of skin lesions, documentation by color photography, 
including a ruler to estimate the size of the lesion, is recommended.  
 
Chest x-ray.  Lesions on chest x-ray are acceptable as measurable lesions when they are clearly 
defined and surrounded by aerated lung.  However, CT is preferable.  
 
Conventional CT and MRI.  This guideline has defined measurability of lesions on CT scan 
based on the assumption that CT slice thickness is 5 mm (0.5 cm) or less.  If CT scans have slice 
thickness greater than 5 mm (0.5 cm), the minimum size for a measurable lesion should be twice 
the slice thickness.  MRI is also acceptable in certain situations (e.g. for body scans).   
 
Use of MRI remains a complex issue.  MRI has excellent contrast, spatial, and temporal 
resolution; however, there are many image acquisition variables involved in MRI, which greatly 
impact image quality, lesion conspicuity, and measurement.  Furthermore, the availability of 
MRI is variable globally.  As with CT, if an MRI is performed, the technical specifications of the 
scanning sequences used should be optimized for the evaluation of the type and site of disease.  
Furthermore, as with CT, the modality used at follow-up should be the same as was used at 
baseline and the lesions should be measured/assessed on the same pulse sequence.  It is beyond 
the scope of the RECIST guidelines to prescribe specific MRI pulse sequence parameters for all 
scanners, body parts, and diseases.  Ideally, the same type of scanner should be used and the 
image acquisition protocol should be followed as closely as possible to prior scans.  Body scans 
should be performed with breath-hold scanning techniques, if possible. 
 
PET-CT.  At present, the low dose or attenuation correction CT portion of a combined PET-CT 
is not always of optimal diagnostic CT quality for use with RECIST measurements.  However, if 
the site can document that the CT performed as part of a PET-CT is of identical diagnostic 
quality to a diagnostic CT (with IV and oral contrast), then the CT portion of the PET-CT can be 
used for RECIST measurements and can be used interchangeably with conventional CT in 
accurately measuring cancer lesions over time.  Note, however, that the PET portion of the CT 
introduces additional data which may bias an investigator if it is not routinely or serially 
performed.   
 
Ultrasound.  Ultrasound is not useful in assessment of lesion size and should not be used as a 
method of measurement.  Ultrasound examinations cannot be reproduced in their entirety for 
independent review at a later date and, because they are operator dependent, it cannot be 
guaranteed that the same technique and measurements will be taken from one assessment to the 
next.  If new lesions are identified by ultrasound in the course of the study, confirmation by CT 
or MRI is advised.  If there is concern about radiation exposure at CT, MRI may be used instead 
of CT in selected instances. 

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Endoscopy, Laparoscopy.  The utilization of these techniques for objective tumor evaluation is 
not advised.  However, such techniques may be useful to confirm complete pathological 
response when biopsies are obtained or to determine relapse in trials where recurrence following 
complete response (CR) or surgical resection is an endpoint. 
 
Tumor markers.  Tumor markers alone cannot be used to assess response.  If markers are initially 
above the upper normal limit, they must normalize for a patient to be considered in complete 
clinical response.  Specific guidelines for both CA-125 response (in recurrent ovarian cancer) 
and PSA response (in recurrent prostate cancer) have been published [JNCI 96:487-488, 2004; J 
Clin Oncol 17, 3461-3467, 1999; J Clin Oncol 26:1148-1159, 2008].  In addition, the 
Gynecologic Cancer Intergroup has developed CA-125 progression criteria which are to be 
integrated with objective tumor assessment for use in first-line trials in ovarian cancer [JNCI 
92:1534-1535, 2000]. 
 
Cytology, Histology.  These techniques can be used to differentiate between partial responses 
(PR) and complete responses (CR) in rare cases (e.g., residual lesions in tumor types, such as 
germ cell tumors, where known residual benign tumors can remain). 
 
The cytological confirmation of the neoplastic origin of any effusion that appears or worsens 
during treatment when the measurable tumor has met criteria for response or stable disease is 
mandatory to differentiate between response or stable disease (an effusion may be a side effect of 
the treatment) and progressive disease. 
 
FDG-PET.  While FDG-PET response assessments need additional study, it is sometimes 
reasonable to incorporate the use of FDG-PET scanning to complement CT scanning in 
assessment of progression (particularly possible 'new' disease).  New lesions on the basis of 
FDG-PET imaging can be identified according to the following algorithm:  
a. Negative FDG-PET at baseline, with a positive FDG-PET at follow-up is a sign of PD 
based on a new lesion. 
b. No FDG-PET at baseline and a positive FDG-PET at follow-up:  If the positive FDG-
PET at follow-up corresponds to a new site of disease confirmed by CT, this is PD.  If the 
positive FDG-PET at follow-up is not confirmed as a new site of disease on CT, 
additional follow-up CT scans are needed to determine if there is truly progression 
occurring at that site (if so, the date of PD will be the date of the initial abnormal FDG-
PET scan).  If the positive FDG-PET at follow-up corresponds to a pre-existing site of 
disease on CT that is not progressing on the basis of the anatomic images, this is not PD. 
c. FDG-PET may be used to upgrade a response to a CR in a manner similar to a biopsy in 
cases where a residual radiographic abnormality is thought to represent fibrosis or 
scarring.  The use of FDG-PET in this circumstance should be prospectively described in 
the protocol and supported by disease-specific medical literature for the indication.  
However, it must be acknowledged that both approaches may lead to false positive CR 
due to limitations of FDG-PET and biopsy resolution/sensitivity. 
 
Note:  A ‘positive’ FDG-PET scan lesion means one which is FDG avid with an uptake greater 
than twice that of the surrounding tissue on the attenuation corrected image. 

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12.1.4 Response Criteria 
 
12.1.4.1 
Evaluation of Target Lesions 
 
Complete Response (CR):  Disappearance of all target lesions.  Any pathological lymph nodes 
(whether target or non-target) must have reduction in short axis to <10 mm (<1 cm). 
 
Partial Response (PR):  At least a 30% decrease in the sum of the diameters of target lesions, 
taking as reference the baseline sum diameters. 
 
Progressive Disease (PD):  At least a 20% increase in the sum of the diameters of target lesions, 
taking as reference the smallest sum on study (this includes the baseline sum if that is the 
smallest on study).  In addition to the relative increase of 20%, the sum must also demonstrate an 
absolute increase of at least 5 mm (0.5 cm).  (Note:  the appearance of one or more new lesions is 
also considered progressions). 
 
Stable Disease (SD):  Neither sufficient shrinkage to qualify for PR nor sufficient increase to 
qualify for PD, taking as reference the smallest sum diameters while on study. 
 
12.1.4.2 
Evaluation of Non-Target Lesions 
 
Complete Response (CR):  Disappearance of all non-target lesions and normalization of tumor 
marker level.  All lymph nodes must be non-pathological in size (<10 mm [<1 cm] short axis). 
 
Note:  If tumor markers are initially above the upper normal limit, they must normalize for a 
patient to be considered in complete clinical response. 
 
Non-CR/Non-PD:  Persistence of one or more non-target lesion(s) and/or maintenance of tumor 
marker level above the normal limits. 
 
Progressive Disease (PD):  Appearance of one or more new lesions and/or unequivocal 
progression of existing non-target lesions.  Unequivocal progression should not normally trump 
target lesion status.  It must be representative of overall disease status change, not a single lesion 
increase. 
 
Although a clear progression of “non-target” lesions only is exceptional, the opinion of the 
treating physician should prevail in such circumstances, and the progression status should be 
confirmed at a later time by the review panel (or Principal Investigator). 
 
12.1.4.3 
Evaluation of Best Overall Response 
 
The best overall response is the best response recorded from the start of the treatment until 
disease progression/recurrence (taking as reference for progressive disease the smallest 
measurements recorded since the treatment started).  The patient's best response assignment will 
depend on the achievement of both measurement and confirmation criteria. 

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For Patients with Measurable Disease (i.e., Target Disease) 
 
Target 
Lesions 
Non-Target 
Lesions 
New 
Lesions 
Overall 
Response 
Best Overall Response when 
Confirmation is Required* 
CR 
CR 
No 
CR 
≥6 wks. Confirmation 
CR 
Non-CR/Non-
PD 
No 
PR 
≥6 wks. Confirmation 
CR 
Not evaluated 
No 
PR 
PR 
Non-CR/Non-
PD/not 
evaluated 
No 
PR 
SD 
Non-CR/Non-
PD/not 
evaluated 
No 
SD 
Documented at least once ≥6 
wks. from baseline 
PD 
Any 
Yes or No 
PD 
no prior SD, PR or CR 
Any 
PD*** 
Yes or No 
PD 
Any 
Any 
Yes 
PD 
 
See RECIST 1.1 manuscript for further details on what is evidence of a new lesion. 
***  In exceptional circumstances, unequivocal progression in non-target lesions may be 
accepted as disease progression. 
 
Note:  Patients with a global deterioration of health status requiring discontinuation of 
treatment without objective evidence of disease progression at that time should be 
reported as “symptomatic deterioration.”  Every effort should be made to document the 
objective progression even after discontinuation of treatment. 
 
For Patients with Non-Measurable Disease (i.e., Non-Target Disease) 
 
Non-Target Lesions 
New Lesions 
Overall Response 
CR 
No 
CR 
Non-CR/non-PD 
No 
Non-CR/non-PD* 
Not all evaluated 
No 
not evaluated 
Unequivocal PD 
Yes or No 
PD 
Any 
Yes 
PD 
 
‘Non-CR/non-PD’ is preferred over ‘stable disease’ for non-target disease since SD is 
increasingly used as an endpoint for assessment of efficacy in some trials so to assign this 
category when no lesions can be measured is not advised 
 
12.1.5 Duration of Response 
 
Duration of overall response:  The duration of overall response is measured from the time 
measurement criteria are met for CR or PR (whichever is first recorded) until the first date that 
recurrent or progressive disease is objectively documented (taking as reference for progressive 
disease the smallest measurements recorded since the treatment started). 
 

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The duration of overall CR is measured from the time measurement criteria are first met for CR 
until the first date that progressive disease is objectively documented. 
 
 
Duration of stable disease:  Stable disease is measured from the start of the treatment until the 
criteria for progression are met, taking as reference the smallest measurements recorded since the 
treatment started, including the baseline measurements.  
 
12.1.6 Progression-Free Survival 
 
PFS is defined as the duration of time from start of treatment to time of progression or death, 
whichever occurs first. 
 
12.1.7 Response Review 
 
It is strongly recommended that all responses be reviewed by an expert(s) independent of the 
study at the study’s completion.  Simultaneous review of the patients’ files and radiological 
images is the best approach. 
 
12.2 
Other Response Parameters 
 
N/A 
 
 
13. STUDY OVERSIGHT AND DATA REPORTING / REGULATORY 
REQUIREMENTS 
 
Adverse event lists, guidelines, and instructions for AE reporting can be found in Section 10 
(Adverse Events: List and Reporting Requirements). 
 
13.1 
Study Oversight 
 
This protocol is monitored at several levels, as described in this section.  The Protocol Principal 
Investigator is responsible for monitoring the conduct and progress of the clinical trial, including 
the ongoing review of accrual, patient-specific clinical and laboratory data, and routine and 
serious adverse events; reporting of expedited adverse events; and accumulation of reported 
adverse events from other trials testing the same drug(s).  The Protocol Principal Investigator and 
statistician have access to the data at all times through the CTMS web-based reporting portal.   
 
For the Phase 1 portion of this study, all decisions regarding dose escalation/expansion/de-
escalation require sign-off by the Protocol Principal Investigator through the CTMS/IWRS.  In 
addition, for the Phase 1 portion, the Protocol Principal Investigator will have at least monthly, 
or more frequently, conference calls with the Study Investigators and the CTEP Medical 
Officer(s) to review accrual, progress, and adverse events and unanticipated problems.  
 
For a Phase 1/2 trial, enrollment to the Phase 2 portion of the trial will not begin until a protocol 
amendment has been submitted which summarizes the Phase 1 results, the recommended Phase 2 

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dose, and the rationale for selecting it.  The amendment must be reviewed and approved by 
CTEP before enrollment to the Phase 2 portion can begin. 
 
All Study Investigators at participating sites who register/enroll patients on a given protocol are 
responsible for timely submission of data via Medidata Rave and timely reporting of adverse 
events for that particular study.  This includes timely review of data collected on the electronic 
CRFs submitted via Medidata Rave. 
 
All studies are also reviewed in accordance with the enrolling institution’s data safety monitoring 
plan. 
 
13.2 
Data Reporting 
 
Medidata Rave is the clinical data management system being used for data collection for this 
trial/study.  Access to the trial in Rave is controlled through the CTEP-IAM system and role 
assignments.   
Requirements to access Rave via iMedidata: 
 
• 
Active CTEP registration with the credentials necessary to access secure NCI/CTSU IT 
systems, and 
• 
Assigned a Rave role on the LPO or PO roster at the enrolling site of:  Rave CRA, Rave 
Read Only, Rave CRA (LabAdmin), Rave SLA, or Rave Investigator.   
 
Rave role requirements: 
 
o Rave CRA or Rave CRA (Lab Admin) role must have a minimum of an Associate 
Plus (AP) registration type, 
o Rave Investigator role must be registered as a Non-Physician Investigator 
(NPIVR) or Investigator (IVR), and 
o Rave Read Only or Rave SLA role must have at a minimum an Associate (A) 
registration type. 
• 
Refer to https://ctep.cancer.gov/investigatorResources/default.htm for registration types 
and documentation required. 
 
If the study has a DTL, individuals requiring write access to Rave must also be assigned the 
appropriate Rave tasks on the DTL. 
 
Upon initial site registration approval for the study in the Regulatory application, all persons 
with Rave roles assigned on the appropriate roster will be sent a study invitation email from 
iMedidata.  To accept the invitation, site staff must either click on the link in the email or log in 
to iMedidata via the CTSU members’ website  under Data Management > Rave Home and click 
to accept the invitation in the Tasks pane located in the upper right-corner of the iMedidata 
screen.  Site staff will not be able to access the study in Rave until all required Medidata and 
study specific trainings are completed.  Trainings will be in the form of electronic learnings 
(eLearnings) and can be accessed by clicking on the eLearning link in the Tasks pane located in 
the upper right corner of the iMedidata screen.  If an eLearning is required for a study and has 

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not yet been taken, the link to the eLearning will appear under the study name in the Studies pane 
located in the center of the iMedidata screen; once the successful completion of the eLearning 
has been recorded, access to the study in Rave will be granted, and a Rave EDC link will replace 
the eLearning link under the study name.  
 
No action will be required by site staff (to activate their account who have not previously 
activated their iMedidata/Rave account at the time of initial site registration approval for the 
study in the Regulatory.  Pending study invitations (previously sent but not accepted or declined 
by a site user) will be automatically accepted and study access in Rave will be automatically 
granted for the site user.  Account activation instructions are located on the CTSU website in the 
Data Management section under the Data Management Help Topics > Rave resource materials 
(Medidata Account Activation and Study Invitation).  Additional information on iMedidata/Rave 
is available on the CTSU members’ website in the Data Management > Rave section or by 
contacting the CTSU Help Desk at 1-888-823-5923 or by email at ctsucontact@westat.com.   
 
 
13.2.1 Method 
 
For studies assigned for CTMS Comprehensive Monitoring: 
This study will be monitored by the Clinical Trials Monitoring Service (CTMS).  Data will be 
submitted to CTMS at least once every two weeks via Medidata Rave (or other modality if 
approved by CTEP).  Information on CTMS reporting is available at 
http://www.theradex.com/clinicalTechnologies/?National-Cancer-Institute-NCI-11.  On-site 
audits will be conducted three times annually (one annual site visit and two data audits).  For 
CTMS monitored studies, after users have activated their accounts, please contact the Theradex 
Help Desk at (609) 619-7862 or by email at CTMSSupport@theradex.com for additional support 
with Rave and completion of CRFs. 
 
13.2.2 Responsibility for Data Submission 
 
For ETCTN trials, it is the responsibility of the PI(s) at the site to ensure that all investigators at 
the ETCTN Sites understand the procedures for data submission for each ETCTN protocol and 
that protocol specified data are submitted accurately and in a timely manner to the CTMS via the 
electronic data capture system, Medidata Rave.   
 
Data are to be submitted via Medidata Rave to CTMS on a real-time basis, but no less than once 
every 2 weeks.  The timeliness of data submissions and timeliness in resolving data queries will 
be tracked by CTMS.  Metrics for timeliness will be followed and assessed on a quarterly basis.  
For the purpose of Institutional Performance Monitoring, data will be considered delinquent if it 
is greater than 4 weeks past due. 
 
Data from Medidata Rave and CTEP-AERS is reviewed by the CTMS on an ongoing basis as 
data is received.  Queries will be issued by CTMS directly within Rave.  The queries will appear 
on the Task Summary Tab within Rave for the CRA at the ETCTN to resolve.  Monthly web-
based reports are posted for review by the Drug Monitors in the IDB, CTEP.  Onsite audits will 
be conducted by the CTMS to ensure compliance with regulatory requirements, GCP, and NCI 

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policies and procedures with the overarching goal of ensuring the integrity of data generated 
from NCI-sponsored clinical trials, as described in the ETCTN Program Guidelines, which may 
be found on the CTEP 
(http://ctep.cancer.gov/protocolDevelopment/electronic applications/adverse events.htm)  and 
CTSU websites. 
 
CTMS will utilize a core set of eCRFs that are Cancer Data Standards Registry and Repository 
(caDSR) compliant (http://cbiit.nci.nih.gov/ncip/biomedical-informatics-
resources/interoperability-and-semantics/metadata-and-models).  Customized eCRFs will be 
included when appropriate to meet unique study requirements.  The PI is encouraged to review 
the eCRFs, working closely with CTMS to ensure prospectively that all required items are 
appropriately captured in the eCRFs prior to study activation.  CTMS will prepare the eCRFs 
with built-in edit checks to the extent possible to promote data integrity. 
 
CDUS data submissions for ETCTN trials activated after March 1, 2014, will be carried out by 
the CTMS contractor, Theradex.  CDUS submissions are performed by Theradex on a monthly 
basis.  The trial’s lead institution is responsible for timely submission to CTMS via Rave, as 
above. 
 
Further information on data submission procedures can be found in the ETCTN Program 
Guidelines 
(http://ctep.cancer.gov/protocolDevelopment/electronic_applications/adverse_events.htm). 
13.3 Data Quality Portal 
 
 The Data Quality Portal (DQP) provides a central location for site staff to manage 
unanswered queries and form delinquencies, monitor data quality and timeliness, 
generate reports, and review metrics.  
 
The DQP is located on the CTSU members’ website under Data Management.  The Rave 
Home section displays a table providing summary counts of Total Delinquencies and 
Total Queries.  DQP Queries, DQP Delinquent Forms, DQP Form Status and the DQP 
Reports modules are available to access details and reports of unanswered queries, 
delinquent forms, forms with current status, and timeliness reports.  Site staff should 
review the DQP modules on a regular basis to manage specified queries and delinquent 
forms. 
 
The DQP is accessible by site staff who are rostered to a site and have access to the 
CTSU website.  Staff who have Rave study access can access the Rave study data via 
direct links available on the DQP modules. 
 
CTSU Delinquency Notification emails are sent to primary contacts at sites twice a 
month. These notifications serve as alerts that queries and/or delinquent forms require 
site review, providing a summary count of queries and delinquent forms for each Rave 
study that a site is participating in. Additional site staff can subscribe and unsubscribe to 

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these notifications using the CTSU Report and Information Subscription Portal on the 
CTSU members’ website. 
 
To learn more about DQP use and access, click on the Help Topics button displayed on 
the Rave Home, DQP Queries, DQP Delinquent Forms, DQP Form Status, and DQP 
Reports modules.  
 
13.4 
CTEP Multicenter Guidelines 
 
N/A 
 
13.5 
Collaborative Agreements Language 
 
The agent(s) supplied by CTEP, DCTD, NCI used in this protocol is/are provided to the NCI 
under a Collaborative Agreement (CRADA, CTA, CSA) between the Pharmaceutical 
Company(ies) (hereinafter referred to as “Collaborator(s)”) and the NCI Division of Cancer 
Treatment and Diagnosis.  Therefore, the following obligations/guidelines, in addition to the 
provisions in the “Intellectual Property Option to Collaborator”  
(http://ctep.cancer.gov/industryCollaborations2/intellectual property.htm) contained within the 
terms of award, apply to the use of the Agent(s) in this study: 
 
1. Agent(s) may not be used for any purpose outside the scope of this protocol, nor can 
Agent(s) be transferred or licensed to any party not participating in the clinical study.  
Collaborator(s) data for Agent(s) are confidential and proprietary to Collaborator(s) and shall 
be maintained as such by the investigators.  The protocol documents for studies utilizing 
Agents contain confidential information and should not be shared or distributed without the 
permission of the NCI.  If a copy of this protocol is requested by a patient or patient’s family 
member participating on the study, the individual should sign a confidentiality agreement.  A 
suitable model agreement can be downloaded from: http://ctep.cancer.gov. 
 
2. For a clinical protocol where there is an investigational Agent used in combination with 
(an)other Agent(s), each the subject of different Collaborative Agreements, the access to and 
use of data by each Collaborator shall be as follows (data pertaining to such combination use 
shall hereinafter be referred to as "Multi-Party Data”): 
 
a. NCI will provide all Collaborators with prior written notice regarding the existence and 
nature of any agreements governing their collaboration with NCI, the design of the 
proposed combination protocol, and the existence of any obligations that would tend to 
restrict NCI's participation in the proposed combination protocol. 
 
b. Each Collaborator shall agree to permit use of the Multi-Party Data from the clinical trial 
by any other Collaborator solely to the extent necessary to allow said other Collaborator 
to develop, obtain regulatory approval or commercialize its own Agent. 
 
c. Any Collaborator having the right to use the Multi-Party Data from these trials must 
agree in writing prior to the commencement of the trials that it will use the Multi-Party 

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Data solely for development, regulatory approval, and commercialization of its own 
Agent. 
 
3. Clinical Trial Data and Results and Raw Data developed under a Collaborative Agreement 
will be made available to Collaborator(s), the NCI, and the FDA, as appropriate and unless 
additional disclosure is required by law or court order as described in the IP Option to 
Collaborator (http://ctep.cancer.gov/industryCollaborations2/intellectual_property.htm).  
Additionally, all Clinical Data and Results and Raw Data will be collected, used and 
disclosed consistent with all applicable federal statutes and regulations for the protection of 
human subjects, including, if applicable, the Standards for Privacy of Individually 
Identifiable Health Information set forth in 45 C.F.R. Part 164. 
 
4. When a Collaborator wishes to initiate a data request, the request should first be sent to the 
NCI, who will then notify the appropriate investigators (Group Chair for Cooperative Group 
studies, or PI for other studies) of Collaborator's wish to contact them. 
 
5. Any data provided to Collaborator(s) for Phase 3 studies must be in accordance with the 
guidelines and policies of the responsible Data Monitoring Committee (DMC), if there is a 
DMC for this clinical trial. 
 
6. Any manuscripts reporting the results of this clinical trial must be provided to CTEP by the 
Group office for Cooperative Group studies or by the principal investigator for non-
Cooperative Group studies for immediate delivery to Collaborator(s) for advisory review and 
comment prior to submission for publication.  Collaborator(s) will have 30 days from the 
date of receipt for review.  Collaborator shall have the right to request that publication be 
delayed for up to an additional 30 days in order to ensure that Collaborator’s confidential and 
proprietary data, in addition to Collaborator(s)’s intellectual property rights, are protected.  
Copies of abstracts must be provided to CTEP for forwarding to Collaborator(s) for courtesy 
review as soon as possible and preferably at least three (3) days prior to submission, but in 
any case, prior to presentation at the meeting or publication in the proceedings.  Press 
releases and other media presentations must also be forwarded to CTEP prior to release.  
Copies of any manuscript, abstract and/or press release/ media presentation should be sent to: 
 
Email:  ncicteppubs@mail.nih.gov 
 
The Regulatory Affairs Branch will then distribute them to Collaborator(s).  No publication, 
manuscript or other form of public disclosure shall contain any of Collaborator’s confidential/ 
proprietary information. 
 
 
 
 
 

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APPENDIX A 
PERFORMANCE STATUS CRITERIA 
 
ECOG Performance Status Scale 
Karnofsky Performance Scale 
Grade 
Descriptions 
Percent 
Description 
0 
Normal activity.  Fully active, able 
to carry on all pre-disease 
performance without restriction. 
100 
Normal, no complaints, no evidence 
of disease. 
90 
Able to carry on normal activity; 
minor signs or symptoms of disease. 
1 
Symptoms, but ambulatory.  
Restricted in physically strenuous 
activity, but ambulatory and able 
to carry out work of a light or 
sedentary nature (e.g., light 
housework, office work). 
80 
Normal activity with effort; some 
signs or symptoms of disease. 
70 
Cares for self, unable to carry on 
normal activity or to do active work. 
2 
In bed <50% of the time.  
Ambulatory and capable of all 
self-care, but unable to carry out 
any work activities.  Up and about 
more than 50% of waking hours. 
60 
Requires occasional assistance, but 
is able to care for most of his/her 
needs. 
50 
Requires considerable assistance and 
frequent medical care. 
3 
In bed >50% of the time.  Capable 
of only limited self-care, confined 
to bed or chair more than 50% of 
waking hours. 
40 
Disabled, requires special care and 
assistance. 
30 
Severely disabled, hospitalization 
indicated.  Death not imminent. 
4 
100% bedridden.  Completely 
disabled.  Cannot carry on any 
self-care.  Totally confined to bed 
or chair. 
20 
Very sick, hospitalization indicated. 
Death not imminent. 
10 
Moribund, fatal processes 
progressing rapidly. 
5 
Dead. 
0 
Dead. 
 
 
 

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APPENDIX C 
LIST OF PROHIBITED MEDICATIONS WHILE ON COPANLISIB 
TREATMENT 
 
This list is not comprehensive. Because the lists of these agents are constantly changing, it is important to 
regularly consult a frequently-updated medical reference for a list of drugs to avoid or minimize use of. 
 
Category 
Drug name 
Strong CYP3A Inhibitors 
Voriconazole, Boceprevir, clarithromycin, 
cobicistat, conivaptan, danoprevir/ritonavir, 
eltegravir/ritonavir, grapefruit juice, 
indinavir/ritonavir, itraconazole, ketoconazole, 
lopinavir/ritonavir, mibefradil, nefazodone, 
nelfinavir, posaconazole, ritonavir, saquinavir, 
saquinavir/ritonavir, telaprevir, telithromycin, 
tipranavir/ritonavir, troleandomycin, 
Strong CYP3A Inducers 
Avasimibe, carbamazepine, mitotane, 
phenobarbital, phenytoin, rifabutin, rifampin 
(rifampicin), St. John's wort (hypericum 
perforatum) 
Herbal Preparations/ 
Medications 
Herbal preparations/medications are prohibited 
throughout the study. These herbal medications 
include, but are not limited to: St. John’s Wort, 
Kava, ephedra (ma huang), ginkgo biloba, 
dehydroepiandrosterone (DHEA), yohimbe, saw 
palmetto, and ginseng. Patients should stop using 
these herbal medications 7 days prior to first 
dose of study drug 
 
 
 

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APPENDIX G 
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 
<150/90 mmHgc. 
Consider BP lowering medication. 
Dosing can proceed on the 
scheduled day if after at least 
2 consecutive measurements BP 
returns to <150/90 mmHg. If BP 
does not  return to <150/90 
mmHg,  copanlisib can be held for 
a maximum of 2 days for pre-dose 
BP ≥150/90 with appropriate 
intervention with BP lowering 
medication as per investigator.  
 
Eribulin and copanlisib should be 
given on the same day, therefore if 
copanlisib is held for a maximum 
of 2 days for BP ≥150/90, eribulin 
must also be held. If pre-dose BP 
improves to <150/90 within 2 
days, copanlisib will be given at 
same dose level along with 
eribulin (within 2 days).*  
 
If pre-dose BP ≥150/90 persists 
within 2 days, copanlisib dose will 
be omitted and eribulin must be 
given (if meets criteria for eribulin 
administration so as to limit dose 
interruption of eribulin).** 
 
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 

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Post-dose: 
Drug-related 
CTCAE hypertension of 
grade 3 
or ≥160/100 mmHg a  
(non-life-threatening) 
If anti-hypertensive 
treatment is not required, 
continue copanlisib at 
previous dose.  
 
If anti-hypertensive 
treatment is required, 
consider reduction of 
copanlisib by 1 dose level.  
 
Discontinue if BP remains 
uncontrolled (BP greater 
than 150/90) despite anti-
hypertensive treatment. 
 
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 allowed copanlisib dose level is 30mg. 
c: Both systolic of less than 150 mmHg and diastolic of less than 90 mmHg are required. 
 
*Eribulin should be given before copanlisib when both drugs are given. 
**Ensure minimum of 7 days between any two consecutive infusions. 
 
 
 

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APPENDIX H 
TISSUE BIOPSY VERIFICATION 
 
A copy of the diagnostic pathology report must be shipped with all tissue specimens sent to the 
EET Biobank. 
 
If the corresponding pathology report is not available for the biopsy, then a copy of the 
radiology report or operative report from the biopsy procedure and the diagnostic 
pathology report must be sent to the EET Biobank. A completed copy of this appendix 
(i.e., Tissue Biopsy Verification) must also be submitted to the EET Biobank. 
 
Note: If this information is not provided with the biopsy specimen, then it will not be accepted 
by the EET Biobank. 
 
 
 
Please have the Clinician* responsible for signing out this patient’s case complete the following: 
 
ETCTN Universal Patient ID:  
 
 
ETCTN Patient Study ID:   
 
 
Date of Procedure (mm/dd/yyyy):   
 
 
Tissue Type (circle one): 
Primary 
Metastatic 
 
Time point (circle one):  Baseline 
C2D1-2 
 
Disease Progression 
 
Site Tissue Taken From:   
 
 
Diagnosis:   
 
 
I agree that this tissue may be released for research purposes only and that the release of this 
tissue will not have any impact on the patient’s care. 
 
 
 
Clinician Signature 
Date 
 
 
 
Clinician Printed Name 
 
*Note: For the purposes of this form, Clinician could include the Nurse Practitioner, Registered Nurse, Pathologist, 
Radiologist, Interventional Radiologist, Surgeon, Oncologist, Internist, or other medical professional responsible for 
the patient’s care.  
 
Version: 1 
Effective Date: 9/2019