Clinical trial NCT02728258
Conditions: Endometrial Endometrioid Adenocarcinoma Endometrial Mixed Cell Adenocarcinoma Endometrial Serous Adenocarcinoma Endometrial Undifferentiated Carcinoma Metastatic Endometrioid Adenocarcinoma Recurrent Uterine Corpus Cancer
Sponsor: NRG Oncology
Start date: 2016-09-16; Completion date: 2020-02-14
Enrollment: 11 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
This phase II trial studies how well copanlisib works in treating patients with endometrial cancer that has not decreased or disappeared, and the cancer may still be in the body despite treatment (persistent) or has come back (recurrent). Copanlisib may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth.

Detailed description:
PRIMARY OBJECTIVES:

I. To assess the activity of copanlisib (BAY 80-6946) in patients with persistent or recurrent endometrial carcinoma harboring phosphatidylinositol-4,5-bisphosphate 3-kinase, catalytic subunit alpha (PI3KCA) hotspot mutations with the frequency of objective response.

SECONDARY OBJECTIVES:

I. To estimate 6 month progression-free survival (PFS) and median PFS. II. To estimate the distribution of the duration of overall survival (OS). III. To assess the safety profile of copanlisib in endometrial cancer patients.

TERTIARY OBJECTIVES:

I. To systematically evaluate by sequencing the site (i.e., exome) and characteristics of PIK3CA mutations in endometrial cancer patients and correlate such mutations to overall response (OR), PFS, and OS in patients treated with copanlisib.

OUTLINE:

Patients receive copanlisib intravenously (IV) over 1 hour on days 1, 8, and 15. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed up every 3 months for 2 years and then every 6 months for 3 years.

Arms: arm 1: Patients receive copanlisib IV over 1 hour on days 1, 8, and 15. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity.
Interventions: intervention 1: Copanlisib intervention 2: Laboratory Biomarker Analysis
Intervention descriptions: intervention 1: Given IV intervention 2: Correlative studies

Protocol documents:
Prot_SAP_000.pdf: 
NRG-GY008 
NCI Version Date:  03/21/2017 
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NRG ONCOLOGY  
NRG-GY008 
(ClinicalTrials.gov NCT #02728258) 
A PHASE II EVALUATION OF COPANLISIB (BAY 80-6946) (IND #130822), A SELECTIVE 
INHIBITOR OF PI3KCA, IN PATIENTS WITH PERSISTENT OR RECURRENT 
ENDOMETRIAL CARCINOMA HARBORING PIK3CA HOTSPOT MUTATIONS 
NCI Version Date:  03/21/2017 
 
This trial is sponsored by the National Cancer Institute (NCI) and will be led by NRG Oncology. 
Lead Organization: NRG / NRG Oncology 
This study is limited to NRG Oncology participation 
Coordinating Center:  
NRG Oncology 
Four Penn Center; 1600 JFK Blvd; Suite 1020 
Philadelphia, PA 19103
Study Chair 
Study Co-Chair 
Alessandro Santin, M.D. 
Michael Birrer, M.D., M.P.H 
Yale University, Obstetrics and Gynecology 
Massachusetts General Hospital 
Division of Gyn Oncology 
Yawkey 9072 
375 Congress Avenue, LSOG Building, Room 312 
55 Fruit St 
New Haven, CT 06510 
Boston, MA 02114 
203-737-4450/Fax: 203-737-4339 
317-724-4800 
Alessandro.santin@yale.edu  
mbirrer@partners.org  
 
 
Statistician 
Research Nurse 
Virginia Filiaci, Ph.D. 
Lisa D. Baker, RN, BSN, OCN 
NRG Statistics and Data Management Center-Buffalo Yale University School of Medicine 
Roswell Park Cancer Center 
Gyn Oncology 
716-845-5702 
333 Cedar Street, FMB340 
filiaciv@nrgoncology.org  
New Haven, CT 06520 
 
203-785-6398/FAX: 203-785-7480 
Study Pathologist 
Lisa.baker@yale.edu 
Kelley Carrick, M.D. 
 
UT Southwestern Medical Center 
Translational Scientist 
5323 Harry Hines Boulevard, Room UH 04.244 
Heather A Lankes, PhD, MPH 
Dallas TX 75390 
NRG Statistics and Data Management Ctr-Buffalo  
214-633-6352/FAX: 214-633-8817 
Roswell Park Cancer Institute 
kelley.carrick@utsouthwestern.edu  
Elm and Carlton Streets 
 
Buffalo NY 14263 
 
716-845-8508/FAX: 716-845-8393 
 
lankesh@nrgoncology.org  


NRG-GY008 
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NRG-GY008 
(ClinicalTrials.gov NCT #02728258) 
A PHASE II EVALUATION OF COPANLISIB (BAY 80-6946) (IND #130822), A SELECTIVE 
INHIBITOR OF PI3KCA, IN PATIENTS WITH PERSISTENT OR RECURRENT 
ENDOMETRIAL CARCINOMA HARBORING PIK3CA HOTSPOT MUTATIONS 
NCI Version Date:  03/21/2017 
 
 
Protocol Agent 
 
 
 
Participating Sites 
 U.S. 
 Canada 
 Approved International Member Sites 
 
Document History 
 
Version/Update Date 
Broadcast Date 
Closure 
 
 
Amendment 4 
03/21/2017 
05/01/2017 
Amendment 3 
03/13/2017 
04/10/2017 
Amendment 2 
12/07/2016 
Amendments #1 and #2 
Broadcast together: 01/09/2017 
Amendment 1 
11/04/2016 
Activation 
08/18/2016 
09/16/2016 
 
 
NRG ONCOLOGY 
 
NRG-GY008 
 
TABLE OF CONTENTS 
 
 
 
Data Manager   
Protocol Coordinator 
Lisa Barry, M.Ed., CCRP 
Meg Colahan, M.A. 
201 N. Craig St., Suite 500 
NRG Oncology-Philadelphia East 
Pittsburgh, PA 15213 
Four Penn Center, 1600 JFK Blvd., Ste 1020,  
412-383-4916/FAX: 412-624-1082 
Philadelphia, PA 19103 
barryl@nrgoncology.org 
215-854-0770 /FAX: 2150854-0770 
 
colahanm@nrgoncology.org 
Agent 
Supply 
NSC # 
IND # 
IND Sponsor 
Copanlisib (BAY 80-6946) 
Bayer 
784727 
130822 
NRG Oncology 
This protocol was designed and developed by NRG Oncology. It is intended 
to be used only in conjunction with institution-specific IRB approval for 
study entry.  No other use or reproduction is authorized by NRG Oncology 
nor does NRG Oncology assume any responsibility for unauthorized use of 
this protocol. 


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TABLE OF CONTENTS 
1. 
OBJECTIVES ................................................................................................................ - 7 - 
1.1 
Primary Objective ............................................................................................... - 7 - 
1.2 
Secondary Objectives.......................................................................................... - 7 - 
1.3 
Exploratory/Correlative Objective ...................................................................... - 7 - 
2. 
BACKGROUND ............................................................................................................ - 7 - 
2.1 
Copanlisib (BAY 80-6946) ............................................................................... - 10 - 
2.2 
Clinical Experience ........................................................................................... - 10 - 
2.3 
Pharmacokinetics .............................................................................................. - 10 - 
3. 
PATIENT SELECTION, ELIGIBILITY, AND INELIGIBILTY CRITERIA............ - 15 - 
3.1 
Patient Selection Guidelines ............................................................................. - 15 - 
3.2 
Eligibility Criteria ............................................................................................. - 16 - 
3.3 
Ineligibility Criteria .......................................................................................... - 18 - 
4. 
REQUIREMENTS FOR STUDY ENTRY, TREATMENT, AND FOLLOW-UP ..... - 20 - 
4.1 
PRE-TREATMENT ASSESSMENTS ............................................................. - 20 - 
4.2 
ASSESSMENTS DURING TREATMENT ..................................................... - 22 - 
4.3 
ASSESSMENTS IN FOLLOW-UP ................................................................. - 23 - 
5. 
TREATMENT PLAN/Regimen description ................................................................ - 23 - 
5.1 
Chemotherapy/Hormonal Therapy/Other Agent-Based Therapy ..................... - 23 - 
5.2 
Radiation Therapy ............................................................................................. - 26 - 
5.3 
Surgery .............................................................................................................. - 26 - 
5.4 
Device ............................................................................................................... - 26 - 
5.5 
Imaging (for imaging-focused study) ............................................................... - 26 - 
5.6 
Integral Assay/Biomarker ................................................................................. - 26 - 
5.7 
Intervention Not Otherwise Categorized .......................................................... - 26 - 
5.8 
General Concomitant Medication and Supportive Care Guidelines ................. - 27 - 
5.9 
Duration of Therapy .......................................................................................... - 28 - 
5.10 
Duration of Study .............................................................................................. - 28 - 
6. 
TREATMENT MODIFICATIONS/MANAGEMENT ............................................... - 28 - 
6.1 
Dose modification ............................................................................................. - 28 - 
6.2 
Hematological toxicity ...................................................................................... - 29 - 
6.3 
Non-hematological toxicity .............................................................................. - 30 - 
6.4 
Dermatologic toxicity ....................................................................................... - 30 - 
6.5 
Non-infectious pneumonitis (NIP) .................................................................... - 31 - 
6.6 
Glucose increases and blood pressure increases ............................................... - 31 - 
7. 
ADVERSE EVENTS REPORTING REQUIREMENTS ............................................ - 36 - 
7.1  
Protocol Agents ................................................................................................. - 36 - 
7.2  
Adverse Events and Serious Adverse Events ................................................... - 36 - 
7.3 
Adverse Events for Investigational Study Agents Not Provided by CTEP ...... - 37 - 
7.4 
Expedited Reporting of Adverse Events ........................................................... - 37 - 


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Non-infectious pneumonitis (NIP) ................................................................................ - 39 - 
8. 
REGISTRATION, STUDY ENTRY, AND WITHDRAWAL PROCEDURES ......... - 40 - 
8.1 
Access requirements for OPEN and Medidata Rave ........................................ - 40 - 
8.2 
Pre-registration Requirements .......................................................................... - 42 - 
8.3 
Patient Enrollment ............................................................................................ - 43 - 
9. 
DRUG AND DEVICE INFORMATION .................................................................... - 43 - 
9.1 
Investigational Study Agent .............................................................................. - 43 - 
9.2 
Glucometer and Glucometer Test Strips ........................................................... - 49 - 
10. 
PATHOLOGY/BIOSPECIMEN .................................................................................. - 50 - 
10.1 
Central Pathology Review Guidelines .............................................................. - 50 - 
10.2 
Tissue Selection for Integral Marker Testing ................................................... - 50 - 
10.3 
Tissue Selection for Integrated Marker Testing ................................................ - 51 - 
10.4 
Biospecimen Submission Tables ...................................................................... - 51 - 
10.5 
Laboratory Testing ............................................................................................ - 51 - 
11. 
SPECIAL STUDIES (Non-Tissue) .............................................................................. - 52 - 
12. 
MODALITY REVIEWS .............................................................................................. - 52 - 
13. 
ASSESSMENT OF EFFECT ....................................................................................... - 52 - 
13.1 
Antitumor Effect – Solid Tumors ..................................................................... - 52 - 
13.2  Response Criteria .............................................................................................. - 54 - 
13.3 
Duration of Response ........................................................................................ - 57 - 
13.4 
Progression-Free Survival ................................................................................. - 58 - 
13.5 
Survival ............................................................................................................. - 58 - 
14. 
DATA AND RECORDS .............................................................................................. - 58 - 
14.1 
Data Management/Collection ........................................................................... - 58 - 
14.2 
Summary of Data Submission .......................................................................... - 58 - 
14.3 
Global Reporting/Monitoring ........................................................................... - 59 - 
15. 
STATISTICAL CONSIDERATIONS ......................................................................... - 59 - 
15.1 
Study Design ..................................................................................................... - 59 - 
15.2 
Study Endpoints ................................................................................................ - 59 - 
15.3 
Primary Objectives Study Design ..................................................................... - 59 - 
15.4 
Study Monitoring of Primary Objectives .......................................................... - 61 - 
15.5 
Accrual/Study Duration Considerations ........................................................... - 61 - 
15.6 
Dose Level Guidelines ...................................................................................... - 61 - 
15.7 
Secondary or Exploratory Endpoints (including correlative science aims) ...... - 61 - 
15.8 
Exploratory Hypothesis and Endpoints ............................................................ - 62 - 
15.9 
Gender/Ethnicity/Race Distribution.................................................................. - 63 - 
16. 
REFERENCES ............................................................................................................. - 63 - 
APPENDIX I - PERFORMANCE STATUS CRITERIA ....................................................... - 66 - 


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APPENDIX II - NYHA CLASSIFICATION .......................................................................... - 67 - 
APPENDIX III – GLYCEMIC INDEX FOR COMMON FOODS ......................................... - 68 - 
APPENDIX IV – P-gp, BCRP and MATE2K Substrates ........................................................ - 69 - 
APPENDIX V – CYP3A4 INHIBITORS AND INDUCERS ................................................. - 70 - 
APPENDIX VI:  PATIENT DRUG INFORMATION HANDOUT AND WALLET CARD - 71 - 
APPENDIX VII – TRANSLATIONAL SCIENCE BIOSPECIMEN PROCEDURES .......... - 72 - 
Appendix VIII – BLOOD GLUCOSE DIARY ....................................................................... - 76 - 
 
 
 
 


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Patients with recurrent or persistent endometrial cancer with 
PIK3CA mutation as determined by Roche COBAS® PIK3CA 
Mutation Test 
(See Section 3 for specific eligibility criteria.) 
 
Copanlisib (BAY 80-6946) 60 mg IV weekly, Days 1, 8 and 15 of a 28-day 
cycle (3 weeks on/1 week off) until disease progression or adverse effects 
prohibit further treatment. 
NRG-GY008 
SCHEMA (01/09/2017) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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1. 
OBJECTIVES 
 
1.1 
Primary Objective 
To assess the activity of copanlisib (BAY 80-6946) in patients with persistent or recurrent 
endometrial carcinoma harboring PIK3CA hotspot mutations with the frequency of objective 
response. 
 
1.2 
Secondary Objectives 
 
1.2.1 To estimate 6 month progression-free survival (PFS) and median PFS 
 
1.2.2 To estimate the distribution of the duration of overall survival (OS)  
 
1.2.3 To assess the safety profile of copanlisib in endometrial cancer patients 
 
1.3 
Exploratory/Correlative Objective 
To systematically evaluate by sequencing the site (i.e., exome) and characteristics of PIK3CA 
mutations in endometrial cancer patients and correlate such mutations to overall response 
(OR), PFS, and OS in patients treated with copanlisib. 
 
2. 
BACKGROUND 
Endometrial cancer is the most common gynecologic malignancy with approximately 54,870 
new cases and 10,170 estimated deaths related to the disease in the United States annually.1 
Endometrial cancers have historically been designated as Type I or Type II.2 Type I 
endometrial cancer accounts for 65-70% of cases and is associated with grade 1-2 
endometrioid histology, younger age of onset, retention of estrogen receptor (ER) and 
progesterone receptor (PR) status, a history of unopposed estrogen, and deletions in k-Ras, 
PTEN, or mismatch repair mechanisms.2,3 In contrast, Type II endometrial cancer is associated 
with serous, clear cell or grade 3 endometrioid histology, loss of ER/PR, black race, absence of 
unopposed estrogen, presentation at later stage, reduced E-cadherin expression, aneuploidy, 
mutations in p53 and HER2/Neu overexpression.2-4 Type II endometrial cancer is typically 
more aggressive than type I cancer and has a poorer prognosis. Recently, using an integrated 
genomic, epigenomic, transcriptomic and proteomic approach, The Cancer Genome Atlas 
(TCGA) Research Network provided compelling evidence that endometrial cancers result from 
heterogeneous somatic mutations and, accordingly, classified endometrial cancers into four 
categories: 1) polymerase epsilon (POLE)-ultramutated, 2) microsatellite instability 
hypermutated, 3) copy-number low and 4) copy-number high, serous-like.5 The genetic 
aberrations of endometrial carcinomas may therefore represent a novel tool to classify these 
tumors and guide adjuvant treatment in women with recurrent chemotherapy-resistant disease. 
 
The phosphatidylinositol-3-kinase (PI3KCA) gene encodes for a heterodimeric protein with an 
85-kDa regulatory subunit (PI3KR1) and a 110-kDa catalytic subunit (PI3KCA).6 PI3K 
phosphorylates a series of membrane phospholipids, catalyzing the transfer of ATP (adenosine 
triphosphate)-derived phosphate, thereby forming secondary messenger lipids 
phosphatidylinositol3,4-bisphosphate and phosphatidylinositol3,4,5-trisphosphate and 
initiating the downstream AKT/mTOR signaling cascade that regulates cell growth.6 The 


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central role of PI3K activation in tumor cell biology has prompted an effort to target PI3K 
and/or downstream kinases such as AKT and mammalian target of rapamycin (mTOR) in 
endometrial cancer.7  Consistent with this view several research groups  have recently reported 
the activity of multiple PI3KCA and mTOR inhibitors in endometrial cancer in preclinical 
studies. For example, apitolisib (GDC-0980, Genentech, South San Francisco, CA), a potent 
inhibitor of class I PI3K and mTOR kinase (TORC1/2), has shown significant activity in vitro 
and in vivo against biologically aggressive endometrial tumors harboring PI3K driver 
mutations.8  Furthermore, AZD8055, a novel dual mTORC1/2 inhibitor, demonstrated 
significant tumor growth inhibition in high HER-2/neu-expressor endometrial cancers in vitro9  
as well as in vivo regression in breast, lung, colon, prostate, and uterine xenograft models.10  
Taselisib, GDC-0032 (Genentech, South San Francisco, CA), a novel, oral, selective inhibitor 
of PI3KCA, has been shown to be highly active in uterine serous carcinoma (USC) mouse 
xenografts harboring PI3KCA mutations and overexpressing HER2/neu (p = 0.007).11 Finally, 
copanlisib (BAY80-6946), a novel PI3K-alpha and delta-inhibitor with promising early clinical 
signal of activity in heavily pretreated patients including endometrial cancer patients in Phase I 
studies, has shown remarkable activity against multiple primary endometrial cancer cell lines 
harboring PI3K driver mutations  (Figure 1 below and Santin AD, unpublished data). 
(01/09/2017) 
 
Multiple phase I, II, and III clinical trials with inhibitors targeting PI3K, AKT or mTOR 
pathways are currently ongoing or have been recently completed.12  Unfortunately, emerging 
clinical data show limited single-agent activity of these inhibitors at tolerated doses.13-15  
However, it is important to note that the response rate for patients with heavily-pretreated, 
advanced cancers and PI3KCA mutations who were given PI3K/AKT/mTOR axis inhibitors 
was significantly higher than that for patients without documented PI3KCA mutations treated 
on the same trials.13-15 This observation is consistent with data that demonstrate low response 
rates on traditional phase I and II trials, in which molecular testing is not used, and suggests 
that selecting PI3KCA-mutant patients for treatment with PI3K/AKT/mTOR axis inhibitors 
may potentially predict response. Importantly, in endometrial cancers multiple studies have 
shown that unlike other human tumors, PI3KCA mutations are distributed throughout the gene. 
Consistent with this view, Rudd et al.,16  reported that half (29 of 58) of non-synonymous 
PIK3CA mutations in Type I and Type II cancers are located in exons 1-7 while half are in 
exons 9 and 20 (i.e., known hotspot mutations). Importantly, the exons 1-7 mutations have 
been shown to localize to the ABD, ABD-RBD linker and C2 domains of p110α and similarly 
to the hot spot mutations located in exon 9 and 20, may increase the levels of phospho-
AKTSer473 compared to wild-type p110α.16  Taken together, these data suggest that in 
endometrial cancer patients PI3KCA mutations located outside exons 9 and 20 may also 
represent potential targets for selective pan-Class I PI3K inhibitors such as copanlisib (BAY 
80-6946).  


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Figure 1: Representative dose response curves with IC50 of two PI3KCA mutated endometrial 
cancer cell lines [USPC-ARK-1 (E542K) and USPC-ARK-20 (H1047R)] versus four PI3KCA 
wild-type cell lines after in vitro exposure to BAY80-6946 for 72 hrs. As shown in figure 1, 
PI3KCA mutated endometrial cancer cell lines were found to be significantly more sensitive 
than PI3KCA wild-type cell lines to BAY80-6946 (P=0.004). Similar results were obtained 
when UTE4 (i.e., a poorly differentiated endometrioid adenocarcinoma cell line harboring the 
R88Q mutation in exon 1 (ref. 17 and data not shown), was exposed in vitro to BAY80-6946. 
The results with copanlisib are in full agreement with recently published preclinical data 
obtained exposing a large number of primary endometrial cancer cell lines to others  
mTOR/PIK3CA inhibitors (i.e., AZD8055, GDC-0980, GDS-0032).8, 9, 11  
 
Copanlisib (BAY 80-6946) is an intravenous, potent and highly selective pan-Class I PI3K 
inhibitor showing superior antitumor activity (>40-fold) in PI3KCA mutant tumors in 
preclinical studies and promising clinical activity and manageable toxicity in Phase I and II 
clinical trials.18-20 Most common side effects of copanlisib in phase I/II clinical studies included 
hyperglycemia and transient Grade 3 or 4 hypertension in up to 43% of the patients.  
Copanlisib not only inhibits PI3Kα with IC50 of 0.5 nM, but also PI3Kδ with IC50 of 0.7 nM. 
In vivo, single intravenous administration of copanlisib exhibited higher exposure and 
prolonged inhibition of pAKT levels in tumors versus plasma. Copanlisib also potently 
regulates nuclear localization of the forkhead family members resulting in the induction of 
transcriptional programs that lead to rapid cell death by apoptosis. Thus, copanlisib is a 
promising agent with differential pharmacologic and pharmacokinetic properties for the 


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treatment of PI3K-dependent human tumors. Because of the promising activity and tolerability 
of copanlisib in Phase I and II clinical trials, in the proposed Phase II study we are planning to 
evaluate the biological activity of copanlisib in patients with persistent or recurrent endometrial 
carcinoma harboring PI3KCA mutations. (01/09/2017) 
 
2.1 
Copanlisib (BAY 80-6946) 
 
Class I PI3K is downstream of most cancer-associated tyrosine kinase growth factor receptors 
(such as epidermal growth factor receptor [EGFR]/ human epidermal growth factor receptor 
[HER], insulin-like growth factor 1 receptor [IGF-1R], platelet-derived growth factor receptor 
[PDGFR], vascular endothelial growth factor [VEGF], c-KIT or mesenchymal epithelial 
transition factor [Met]). 
 
Four of these PI3K isoforms (PI3Kα, PI3Kβ, PI3Kγ, and PI3Kδ) are categorized as class I 
enzymes because they can use phosphatidylinositol-4,5-bisphosphate (PI-4,5-P2) as a 
substrate to generate phosphatidylinositol-3,4,5-trisphosphate (PIP3). Elevated PIP3 in 
cellular membranes drives several hallmarks of the cancer phenotype: cell proliferation, 
survival, metabolic reprogramming, and migration. PI3Kα and β are ubiquitous; PI3Kγ and δ 
are expressed mostly in the hematopoietic tissue.  
 
Copanlisib (BAY 80-6946) is a potent pan-class I inhibitor of PI3K being developed for the 
treatment of advanced and refractory malignancies. Copanlisib is the active ingredient (free 
base) of BAY 84-1236, the dihydrochloride salt, which for clinical use is formulated as an 
intravenous (IV) drug product solution.   
 
2.2 
Clinical Experience 
 
Copanlisib is currently under investigation in various trials enrolling cancer patients. As of 
February 2015 approximately 377 patients with advanced cancer have been treated with 
copanlisib in eight different Phase I studies and one Phase II study.  
 
2.3 
Pharmacokinetics 
Pharmacokinetic (PK) results of copanlisib indicate dose proportional increases in maximum 
concentration (Cmax) and area under the curve (AUC) from time zero to 25 hours (AUC 0-25) 
in the dose range 0.1 to 1.2 mg/kg with a terminal phase half-life (t1/2) of 38.2 hours at 
0.8 mg/kg (n=28). These data indicate that copanlisib is widely distributed in tissues and 
support a once weekly dosing regimen. No accumulation was observed after once weekly 
dosing when comparing PK on Cycle 1 Days 1 and 15 and Cycle 3 Day 15. No evidence of 
time-dependency in the PK of copanlisib was observed.  
Preliminary results of the human ADME (absorption, distribution, metabolism, and excretion) 
study in healthy volunteers indicate that following a single intravenous dose of 12 mg [14C]-
BAY 80-6946, 88.3% of administered dose, with approx. 66.1% of dose excreted in feces, and 
approximately 22.2% of dose excreted in urine was recovered within 34 days. Copanlisib was 
found to be the primary circulating moiety in plasma as well as in excreta. The amount of 
copanlisib excreted unchanged amounts up to 40 to 50%. The morpholinone derivative M-1 
was found to be the only relevant metabolite. Oxidative biotransformation of copanlisib was 


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found to be predominantly mediated by cytochrome P450 isoenzyme 3A4 (CYP3A4) and its 
contribution is about 50% of the metabolic pathway. Therefore, a low DDI potential due to 
several clearance pathways is anticipated.  
A preliminary population PK analysis revealed no impact of either body weight, body surface 
area, or other body size-related factors was found on the clearance of copanlisib which was the 
basis to switch to a flat-dose regimen of copanlisib.  
The recommended (Phase II) dose of monotherapy copanlisib is 60 mg given IV weekly (q1w) 
in a 3 weeks on/1 week off schedule based on an evaluation of pharmacokinetic and clinical 
data from ongoing single-agent studies.  
2.3.1 Study 12871 
A total of 68 cancer patients were enrolled in this open-label, single agent, Phase 1 
dose-escalation study and 57 have received treatment. Copanlisib (BAY 80-6946) is infused 
intravenously over one hour on Days 1, 8, and 15, every 28 days. One cycle consists of 28 
days. All 57 patients received at least one dose of copanlisib. 
 
Seventeen patients were treated in the dose escalation part with five copanlisib dose levels: one 
in dose level 1 (0.1 mg/kg), three in dose level 2 (0.2 mg/kg), three in dose level 3 (0.4 mg/kg), 
seven in dose level 4 (0.8 mg/kg) and three in dose level 5 (1.2 mg/kg). Dose level 4 has been 
determined to be the MTD based on a dose level 5 patient with life-threatening cardiovascular 
toxicity following the first dose. Copanlisib (BAY 80-6946) has been generally safe and 
tolerable in patients treated through the MTD of 0.8 mg/kg. Forty patients have been enrolled 
in the MTD expansion cohorts, including 9 patients with NHL and 25 non-diabetics with solid 
tumors treated at the MTD, and 6 patients with solid tumors and type 2 diabetes mellitus 
treated at 0.4 mg/kg. Preliminary data on the diabetic patients has shown the tolerability of the 
0.4 mg/kg dose, albeit with the requirement of additional diabetic specific therapy. 
 
The overall median number of copanlisib infusions administered was 6 (range: 
1 to 103 infusions). Although the protocol design permits intra-subject dose escalation for 
diabetic patients, none have received a dose greater than the starting dose of 0.4 mg/kg, due to 
progressive disease or AEs before Cycle 3 Day 1. 
 
As of 10 FEB 2014, the most common drug-related TEAEs all grades, that occurred in ≥20% 
of the 57 patients (all cohorts) were: hyperglycaemia (36 patients, 63.2%); nausea 
(21 patients, 36.8%); and hypertension (12 patients, 21.1%). 0.8 mg/kg of copanlisib is the 
MTD in non-diabetic patients as single agent given intravenously in a 3 weeks on/1 week off 
schedule (total dose not to exceed 65 mg, in order to control copanlisib exposure in obese 
patients). 
 
2.3.2 Study 12874 
This is an open label Phase 1 study to determine the MTD and RP2D of copanlisib in 
combination with paclitaxel in patients with advanced cancer. 
 
As of the cut-off date of 01 FEB 2015, a total of 83 patients were enrolled into this study and 
55 were treated. Those 55 patients were treated in the following cohorts: 
 Nineteen patients in the dose-escalation cohort received treatment with paclitaxel 


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given at the dose of 80 mg/m2 (as 60 min i.v. infusion) once weekly on Days 1, 8, 15, 
and 22 and copanlisib at the starting dose of 0.6 mg/kg as 60 min i.v. infusion 
(Cohort 1, 8 patients, of whom one did not receive copanlisib but paclitaxel only) or 
at the dose of 0.8 mg/kg (Cohort 2, 11 patients) once on Days 2, 9, 16, and 23. The 
MTD of copanlisib in combination with paclitaxel has been first determined as being 
0.8 mg/kg given intravenously in a weekly schedule. 
 Sixteen patients with breast cancer, were treated in the MTD expansion cohort 
(Cohort 3) received treatment with copanlisib in combination with gemcitabine and 
cisplatin (Treatment schedule B, copanlisib at 0.8 mg/kg). Due to the increased rate 
of the non-infectious pneumonitis observed in Cohort 3, a modified schedule of both 
copanlisib and paclitaxel was evaluated in order to establish the RP2D in combination 
with paclitaxel. 
 Twenty patients with breast cancer treated in an expansion cohort with a modified 
dosing (Cohort 4) allowing a rest week between the cycles (3 weeks-on/1 week-off). 
Copanlisib is administered at 0.8 mg/kg on Days 2, 9 and 16 in the 28-day cycle. 
Paclitaxel is administered in the recommended 90 mg/m2 dose on Days 1, 8 and 15 in 
the 28-day cycle. 
 
As the cut-off date of 01 FEB 2015, preliminary safety data indicate that the tolerable dose 
with the combination has been defined as being copanlisib 0.8 mg/kg on Days 2, 9 and 16 and 
paclitaxel administered at the dose of 90 mg/m2 on Days 1, 8 and 15, both in the 28-day cycle. 
The regimen with the continuous schedule of both drugs has been shown to bear a higher, not 
acceptable risk of non-infectious pneumonitis. The study is now closed for enrollment. 
 
2.3.3 Study 12875 
This open-label, Phase 1 study involves treating advanced solid tumor patients with 
copanlisib in combination with gemcitabine 1000 mg/m2 once on Days 1, 8, and 15, every 28 
days (Treatment schedule A) or with gemcitabine 1000 mg/m2 and cisplatin 25 mg/m2 once on 
Days 1 and 8, every 21 days (Treatment schedule B). For Treatment schedule A, copanlisib 
dosing was started at a dose of 0.6 mg/kg and then 0.8 mg/kg was given once 0.6 mg/kg dose 
was tolerated (maximum dose). Once the MTD for Treatment schedule A was determined then 
Treatment schedule B using the MTD of copanlisib from Treatment schedule A was initiated 
along with the addition of cisplatin. 
 
As of the cut-off date (01 FEB 2015), final data are not yet available from this study. A total of 
65 patients were enrolled into this study and 50 were treated. Those 50 patients were treated in 
the following cohorts: 
 Sixteen patients in the dose-escalation cohort received treatment with copanlisib in 
combination with gemcitabine (Treatment schedule A, n=8 at 0.6 mg/kg of copanlisib 
and n=8 at 0.8 mg/kg of copanlisib). 
 Fourteen patients in the dose-escalation cohort received treatment with copanlisib in 
combination with gemcitabine and cisplatin (Treatment schedule B, copanlisib at 
0.8 mg/kg). One patient in this cohort did not receive copanlisib but started 
gemcitabine. 
 Twenty patients with BTC treated in the MTD expansion cohort. 
The MTD of copanlisib is 0.8 mg/kg in combination with gemcitabine 1000 mg/m2 given 


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intravenously in a 3 weeks on/1 week off schedule as well as in combination with 
gemcitabine 1000 mg/m2 and cisplatin 25 mg/m2, given intravenously in a 2 weeks on/1 week 
off schedule. There was one DLT of reversible posterior leukoencephalopathy syndrome 
(RPLS) in 1 patient treated at 0.6 mg/kg copanlisib in Treatment A.  This study is now closed 
for enrollment. 
 
2.3.4 Study 12876 
This open-label, Phase 1 study involves treating advanced solid tumor patients with 
copanlisib in combination with refametinib. The study has been completed and closed. 
As the cut-off date of 01 FEB 2015, 64 patients received treatment with refametinib and the 
PI3K inhibitor (BAY 80-6946), including a dose escalation part (49 patients) and an MTD 
expansion cohort (15 patients). Nine dose cohorts combining increasing doses and varying 
schedules of copanlisib (0.2-0.8 mg/kg; given intravenously in a 3 weeks on/1 week off 
schedule or once weekly) and refametinib (30 mg and 50 mg bid p.o.; continuous or 4 days 
on/3 days off) on 28-day cycles were studied. 
 
In the dose escalation part, 49 patients received at least one dose of study treatment, 
48 patients were treated with at least one dose of copanlisib and refametinib (one patient 
received one dose of copanlisib but no refametinib). Fifteen patients were treated in a 
mutation selected expansion cohort in mixed solid tumors. 
 
The most common copanlisib-related TEAEs that occurred in >20% of all patients were: 
diarrhea (30 patients, 46.9%); nausea (25 patients, 39.1%); hypertension (23 patients, 35.9%); 
hyperglycaemia and mucositis oral (20 patients, 31.3% each); fatigue (19 patients, 29.7%); 
vomiting (18 patients, 28.1%); rash maculo-papular and anorexia (14 patients; 22% each); and 
rash acneiform (20.3%). The most common refametinib-related TEAEs that occurred in >20% 
of the patients were: rash acneiform (33 patients, 51.6%); diarrhea (31 patients, 48.4%); nausea 
(26 patients, 40.6%); rash maculo-papular and mucositis oral (23 patients, 35.9% each); 
vomiting (20 patients, 31.3%); fatigue (18 patients, 28.1%); pruritus (16 patients, 25.0%); and 
anorexia (15 patients, 23.4%). 
 
Dose-limiting toxicities (DLTs) included mucositis oral (3 patients); fatigue and aspartate 
aminotransferase (AST) increased (2 patients each); pancreatitis, diarrhea, rash acneiform, 
hypertension, and alanine aminotransferase increased (1 patient each). One patient with the 
DLT mucositis oral also experienced further DLTs nearly concomitantly: dehydration, dry 
skin, hypernatremia. 
 
The MTD for the copanlisib-refametinib combination was 0.4 mg/kg copanlisib given 
intravenously in a weekly schedule and refametinib 30 mg bid given orally. These doses are 
below the MTDs of either compound alone: Copanlisib 0.8 mg/kg given intravenously in a 3 
weeks on/1 week off schedule and refametinib 50 mg bid or 100 mg qd p.o. 
 
2.3.5 Study 15205 
Overall, 10 patients were treated in this open-label, single-agent, Phase 1 study of copanlisib in 
patients with advanced or refractory solid tumors, which was completed and closed in 2012. 
This study consisted of two cohorts (0.4 mg/kg, i.v., Day 1, 8, and 15, every 28 days for Cohort 


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1 and 0.8 mg/kg, i.v., Day 1, 8, and 15, every 28 days for Cohort 2). Three patients were 
treated in Cohorts 1 and 7 patients in Cohort 2, respectively. 
 
The most common study drug-related TEAEs that occurred in >20% of all patients were 
hyperglycemia (80%), hypertension (70%), and constipation (50%). Based on pre-specified 
criteria in the protocol, the MTD was determined to be 0.8 mg/kg of 
copanlisib given as a single agent intravenously in a 3 weeks on/1 week off schedule in 
non-diabetic patients. 
 
2.3.6 Study 16353 
In this single center, non-randomized, open-label, non-controlled study, a total of 18 healthy 
male patients were enrolled and 6 received a 1-hour i.v. infusion of a single dose of 12 mg 
copanlisib containing 2.76 MBq [14C]copanlisib in a total volume of 40 mL. The aim of the 
study was to investigate the metabolism, excretion pattern, mass balance, safety, tolerability 
and pharmacokinetics of copanlisib. This study was completed in 2014 and is now closed. A 
single i.v. infusion of 12 mg copanlisib over 1 hour was well tolerated by healthy male 
subjects. 
 
2.3.7 Study 16790 
This Phase I multicentric pharmacodynamic study of copanlisib aims to evaluate the 
relationship between exposure and pharmacodynamics in patients with NHL or selected solid 
tumors (with high likelihood of PI3K pathway activation such as breast cancer, ovarian cancer) 
after treatment with copanlisib monotherapy at the dose of 0.8 mg/kg body weight and 0.4 
mg/kg (not to exceed 65 mg) for the non-diabetic patients as well as at the dose of 45 mg and 
60 mg for the diabetic patients. A secondary objective is to assess the safety and tolerability of 
copanlisib in patients, including patients with diabetes mellitus. This study has started 
enrollment in 2014 and is still ongoing. So far, no safety concerns appeared. 
 
2.3.8 Study 16349 
Part A of the Study 16349 is an ongoing open-label uncontrolled, parallel group, 
signal-generating, Phase 2 study to evaluate efficacy and safety of copanlisib as single agent 
(0.8 mg/kg, maximum 65 mg, i.v. dosing over 1 hour on Days 1, 8, and 15 of each 28-day 
treatment cycle) in patients with relapsed or refractory, indolent or aggressive NHL. The study 
population was planned to consist of 2 cohorts of 30 patients each with either indolent 
lymphoma, or aggressive lymphoma. The patients are relapsed or refractory after ≥2 prior lines 
of therapy (refractory defined as not responding to a standard regimen or progressing within 6 
months of the last course of a standard regimen), and must have received rituximab and 
alkylating agents. The primary efficacy variable is the objective tumor response (OR). 
 
Part B of this study evaluates the efficacy and safety of copanlisib in patients with relapsed or 
refractory indolent NHL. As of the cut-off date of the IB (01 FEB 2015), a total of 244 patients 
were enrolled into this study, 166 in Part A and 78 in Part B. The cut-off date for the below 
reported data is 16 SEP 2014. As of the cut-off date (16 SEP 2014), 76 patients (33 with 
indolent and 43 with aggressive NHL) have started treatment in Part A and 42 patients in Part 
B. In the following preliminary sections, data from the ongoing Part A is presented. No data on 
Part B patients is available at this time. 


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As of 16 SEP 2014, a total of 76 lymphoma patients started study treatment in Study 16349 
Part A. Patients were similarly distributed among indolent and aggressive cohorts with respect 
to gender (50% female), median age (68 years, range 22-90) and were heavily pretreated 
(median number of prior anti-lymphoma therapies: 3, range 1-10). Other characteristics 
included B symptoms in 20% (12.1% in indolent and 25.6% in aggressive NHL). The 
following entities were represented: follicular (FL; n=16); CLL (n=13); small cell (SLL; n=1); 
marginal zone (MZL; n=3); DLBCL (n=15); mantle cell (MCL; n=11); transformed FL (n=6); 
peripheral T-cell, no other symptoms (PTCL, NOS; n=5); mediastinal large B-cell (MLBCL; 
n=1); anaplastic large cell lymphoma (ALCL; n=2); angioimmunoblastic T-cell lymphoma 
(AITL; n=2); and follicular Grade 3b (n=1). 48.7% of patients were refractory to rituximab, 
and 15.8% were refractory to bendamustine. 
 
Limited number of patients (ie, nine) have so far been treated with Copanlisib at 30 mg (0.4 
mg/kg). Of the 9 pts at 0.4 mg/kg dose level, n=3 were non-diabetics and n=6 diabetics.  30% 
of these patients had recorded Gr.1/2 hyperglycemia after copanlisib administration.  This 
limited data suggest some target inhibition at 0.4 mg/kg (30 mg flat dosing).   
Further details can be found in the IB for copanlisib, which contains comprehensive 
information on the test drug. 
 
3. 
PATIENT SELECTION, ELIGIBILITY, AND INELIGIBILTY CRITERIA 
 
 
Note: Per NCI guidelines, exceptions to inclusion and exclusion criteria are not 
permitted.  For questions concerning eligibility, please contact the NRG Statistics and Data 
Management Center-Pittsburgh Office: 412-624-2666. 
 
3.1 
Patient Selection Guidelines 
Although the guidelines provided below are not inclusion/exclusion criteria, investigators 
should consider these factors when selecting patients for this trial. Investigators also should 
consider all other relevant factors (medical and non-medical), as well as the risks and benefits 


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of the study therapy, when deciding if a patient is an appropriate candidate for this trial. 
 
3.1.1 Patients must have the psychological ability and general health that permits completion of the 
study requirements and required follow-up. 
 
3.1.2 Women of child-bearing potential (WOCBP)  must agree to use adequate contraception when 
sexually active.  Patients should continue contraception for 6 months after finishing study drug.  
See Section 3.2.19. 
 
3.1.3 Submission of tumor tissue is required for all patients. Investigators should check with their 
site Pathology department regarding release of biospecimens before approaching patients about 
participation in the trial. (See sections 3.2.2, 4.11, 8.2.1, and 10.2 for details.) (01/09/2017) 
 
3.2 
Eligibility Criteria 
A patient cannot be considered eligible for this study unless ALL of the following conditions 
are met. 
 
3.2.1 Patients must have recurrent or persistent endometrial cancer (endometrioid adenocarcinoma, 
serous adenocarcinoma, undifferentiated carcinoma, mixed epithelial carcinoma or 
adenocarcinoma not otherwise specified [NOS]). Histologic confirmation of the primary tumor 
is required. Pathology slides will be reviewed retrospectively, semiannually by the NRG 
Pathology Committee per the standard NRG Central Pathology Review schedule. 
 
3.2.2 All patients must have a somatic PIK3CA gene mutation (i.e., R88Q in exon 1, N345K in exon 
4, C420R in exon 7, E542K, E545X [E545A, E545D, E545G, and E545K], Q546X [Q546E, 
Q546K, Q546L, and Q546R] in exon 9, and M1043I, H1047X [H1047L, H1047R, and 
H1047Y], or G1049R in exon 20) in a representative primary or metastatic tumor sample 
confirmed by the Roche COBAS® PIK3CA Mutation Test at Q2 Solutions. (See sections 4.1.1, 
5.6, 8.2.1, and 10.2 for additional details.)  (See section 8.1.2, “Screening Lab Kits” for 
information on ordering kits for mutation screening.) (01/09/2017) 
 
3.2.3 All patients must have measurable disease as defined by RECIST 1.1.  Measurable disease is 
defined as at least one lesion that can be accurately measured in at least one dimension (longest 
diameter to be recorded).  Each lesion must be ≥ 10 mm when measured by CT, MRI or caliper 
measurement by clinical exam; or ≥ 20 mm when measured by chest x-ray.  Lymph nodes must 
be ≥ 15 mm in short axis when measured by CT or MRI. 
 
3.2.4 Patients must have at least one “target lesion” to be used to assess response on this protocol as 
defined by RECIST 1.1.  Tumors within a previously irradiated field will be designated as 
‘non-target” lesions unless progression is documented or a biopsy is obtained to confirm 
persistence at least 90 days following completion of radiation therapy. 
 
3.2.5 Prior Therapy: 
 Patients must have recovered from effects of recent surgery, radiotherapy, or 
chemotherapy.  At least 4 weeks must have elapsed since the patient underwent any major 
surgery (e.g., major: laparotomy, laparoscopy).  There is no delay required for minor 


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procedures (e.g., tumor FNA or core biopsy, venous access device placement). 
 Patients may have received prior radiation therapy for treatment of endometrial cancer.  
Prior radiation therapy may have included pelvic radiation therapy, extended field 
pelvic/para-aortic radiation therapy, intravaginal brachytherapy and/or palliative radiation 
therapy.  All radiation therapy must be completed at least 4 weeks prior to registration. 
 Patients may have received prior hormonal therapy for treatment of endometrial carcinoma.  
All hormonal therapy must be discontinued at least 4 weeks prior to registration. 
 Patients may have received prior therapy (including chemotherapy, biologic/targeted 
therapy and immunotherapy) for treatment of endometrial cancer.  All therapy must be 
discontinued at least 4 weeks prior to registration.  Any investigational agent must be 
discontinued at least 30 days prior to registration. 
 Patients must have had at least one prior chemotherapeutic regimen for management of 
endometrial carcinoma.  Initial treatment may include chemotherapy, chemotherapy and 
radiation therapy, or consolidation/maintenance therapy.  Chemotherapy administered in 
conjunction with primary radiation as a radio-sensitizer WILL be counted as a systemic 
chemotherapy regimen. 
o Patients are allowed to receive, but not required to receive, up to a total of 3 lines of 
chemotherapy. 
 
3.2.6 Appropriate stage for study entry based on the following diagnostic workup: 
 History/physical examination within 28 days prior to registration; 
 Imaging of target lesion(s) within 28 days prior to registration; 
 Completion of pre-study protocol specific assessments as required in 4.1.2. 
 
3.2.7 Age ≥ 18 
 
3.2.8 The trial is open to females only 
 
3.2.9 Performance Status [ECOG/Karnofsky] of 0, 1 or 2 within 28 days prior to registration (see 
Appendix I). 
 
3.2.10 Adequate hematologic function within 14 days prior to registration defined as follows: 
 ANC ≥ 1,500/mcl 
 Platelets ≥ 75,000/mcl 
 Hgb ≥ 8 g/dL 
 
3.2.11 Adequate renal function defined as follows: 
 Creatinine ≤ 1.5 x ULN 
 
3.2.12 Adequate hepatic function defined as follows: 
 Bilirubin ≤ 1.5 x ULN (≤ 3 x ULN for patients with Gilbert syndrome)  
Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) ≤ 3 x ULN  
 
3.2.13 Cardiac Function: 
 Left Ventricular Ejection Fraction (LVEF) ≥ 50% 
 


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3.2.14 Fasting cholesterol less than or equal to 300 mg/dl; fasting triglycerides less than or equal to 
300 mg/dl. 
 
3.2.15 PT such that international normalized ratio (INR) is less than or equal to 1.5 x ULN (or an in 
range INR, usually between 2 and 3, if a patient is on a stable dose of therapeutic warfarin) and 
a PTT less than or equal to 1.5 times the upper limit of normal. 
 
3.2.16 The patient must provide study-specific informed consent prior to study entry and, for patients 
treated in the U.S., authorization permitting release of personal health information. 
 
3.2.17 Diabetic patients (Type I or II diabetes mellitus) must have baseline HbA1c levels NOT higher 
than 8.5% at study entry. 
 
3.2.18 Patients with hypertension on medical management must have systolic blood pressure < 150 
mmHG or diastolic pressure < 90 mmHG at study entry. 
 
NOTE: 
-ULN is institutional or laboratory upper limit of normal 
 
-Please see the required timing of pre-treatment assessments in Section 
4.1.2. 
 
3.2.19  Women of child-bearing potential (WOCBP) must have a negative serum pregnancy test 
within 28 days of registration. 
 
The patient and her sexual partner(s) must agree to use adequate contraception when sexually 
active for the duration of the study and for 6 months after finishing study drug.  
 
 
A woman is considered of childbearing potential following menarche and until becoming post-
menopausal unless permanently sterile.  Permanent sterilization methods include hysterectomy, 
bilateral salpingectomy and bilateral oophorectomy.  A postmenopausal state is defined as no 
menses for 12 months without an alternative medical cause.  A high follicle stimulating 
hormone (FSH) level in the postmenopausal range maybe used to confirm a post-menopausal 
state in women not using hormonal contraception or hormonal replacement therapy.  
 
3.3 
Ineligibility Criteria 
Patients with any of the following conditions are NOT eligible for this study. 
 
3.3.1 Patients who have had prior therapy with any PI3K/AKT/mTor pathway inhibitor. 
 
3.3.2 Patients who have the following histologies:  mucinous, squamous, sarcomas, 
carcinosarcomas, clear cell. 
 
3.3.3 Severe, active co-morbidity defined as follows: 
 
 Congestive heart failure > New York Heart Association (NYHA) class II (see Appendix II) 
 Myocardial infarction or unstable angina less than 6 months before registration. 


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 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 registration. (01/09/2017) 
 Non-healing wound, ulcer or bone fracture. 
 Active, clinically serious infections > CTCAE Grade 2 
 History of, or current autoimmune disease 
 HIV infection (treatment involved  in this protocol may be significantly 
immunosuppressive and protease inhibitors used in HIV+ patients are substrates and potent 
inhibitors or inducers of the cytochrome P450). Accordingly, co-administration with 
copanlisib may result in either drug accumulation and possible toxicity, or decreased 
efficacy. 
 Hepatitis B (HBV) or hepatitis C (HCV). All patients must be screened for HBV and HCV 
within 28 days prior to registration using the routine hepatitis virus laboratorial panel. 
PI3K-AKT-mTOR pathway inhibitors are known to be immune-suppressants and increase 
the risk of infection in patients with advanced solid tumors. Protease inhibitors are a class 
of antiviral drugs that are widely used to treat HIV/AIDS and hepatitis caused by hepatitis 
C virus. These agents are substrates and potent inhibitors or inducers of the cytochrome 
P450 (CYP) and co-administration with copanlisib may result in either drug accumulation 
and possible toxicity, or decreased efficacy. For the above reasons patients with active 
HBV or hepatitis C infection are not eligible for enrollment.  Patients with serologic 
markers of HBV immunization due to known vaccination (HBsAg negative, anti-HBc 
negative and anti-HBs positive) will be eligible. 
 Previous or concurrent history of malignancies within 5 years prior to study treatment 
except for curatively treated: 
• 
Cervical carcinoma in situ 
• 
Non-melanoma skin cancer 
• 
Superficial bladder cancer (Ta [non-invasive tumor], Tis [carcinoma in situ] and 
T1 [tumor invades lamina propria]) 
 Patients with seizure disorder requiring medication. Seizure disorder medications are 
substrates and potent inducers or inhibitors of the cytochrome P450 (CYP) and co-
administration with copanlisib may result in either drug accumulation and possible toxicity, 
or decreased efficacy.  
 Patients with evidence or history of bleeding diathesis. Any hemorrhage or bleeding event 
≥ CTCAE Grade 3 within 4 weeks prior to registration. 
 Proteinuria of CTCAE Grade 3 or higher (estimated by urine protein: creatinine ratio ≥ 3.5 
on a random urine sample). Patients who recently (i.e., at least 30 days prior to registration) 
discontinued  an anti-angiogenic therapy which caused proteinuria (ie, Grade 2 (> 2 to > 3 
g of protein or 1-3.5 g/24 h) or grade 3 proteinuria (> 4 of protein or > 3.5 g/24 h) are not 
eligible for enrollment until proteinuria improves to < 2 g of protein per 24 h. 
 History or concurrent condition of interstitial lung disease of any severity and/or severely 
impaired lung function (as judged by the investigator) 
 Concurrent diagnosis of pheochromocytoma. 
 Unresolved toxicity higher than CTCAE Grade 1 attributed to any prior therapy/procedure, 
excluding alopecia.  
 Known hypersensitivity to any of the test drugs, test drug classes, or excipients in the 
formulation (See Section 9.1.3). 


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3.3.4 Prohibited Therapies 
 Strong CYP3A4 inhibitors and inducers (see Appendix V). Copanlisib is primarily 
metabolized by CYP3A4. Therefore, concomitant use of strong inhibitors of CYP3A4 (e.g., 
ketoconazole, itraconazole, clarithromycin, ritonavir, indinavir, nelfinavir and saquinavir), 
and inducers of CYP3A4 (e.g., rifampin, phenytoin, carbamazepine, phenobarbital, St. 
John's Wort) are not permitted within two weeks prior to start of study treatment and for 
the duration of treatment with copanlisib. 
 Grapefruit and grapefruit juice (CYP3A4 inhibitor), Seville oranges and star fruit 
consumption is not permitted during the study. 
 Anti-arrhythmic therapy other than beta blockers or digoxin. 
 Systemic continuous corticosteroid therapy at a daily dose higher than 15 mg prednisone or 
equivalent is not allowed. Patients may be using topical or inhaled corticosteroids. 
 Concomitant therapy with any anticancer agents, immunosuppressive agents, other 
investigational anticancer therapies. 
 Concomitant radiotherapy. 
 
3.3.5 Women who are breast feeding.  
 
4. 
REQUIREMENTS FOR STUDY ENTRY, TREATMENT, AND FOLLOW-UP 
 
 
 
4.1 
PRE-TREATMENT ASSESSMENTS 
 
4.1.1 SCREENING (01/09/2017) 
 
Assessments 
 
Confirmation of a somatic PIK3CA gene 
mutation1 in a representative primary or 
metastatic tumor sample by Roche 
COBAS® PIK3CA Mutation Test at Q2 
Solutions2 
Screening Consent and Screening Registration 
Required Prior to Testing 
1. R88Q in exon 1, N345K in exon 4, C420R in exon 7, E542K, E545X (E545A, E545D, E545G, 
and E545K), Q546X (Q546E, Q546K, Q546L, and Q546R) in exon 9, and M1043I, H1047X 
(H1047L, H1047R, and H1047Y), or G1049R in exon 20  
2. Six unstained formalin-fixed, paraffin-embedded (FFPE) sections (charged, 5μm) of primary or 
metastatic tumor are required for testing. Sections must contain at least 30% tumor. Tumor must be 
obtained by surgery or biopsy only (i.e., bone metastases, FNA, and cell blocks are not 
acceptable). Testing kits will be provided by Q2 Solutions. Note: Testing kits are typically received 
7-10 business days after request. Typical testing turnaround time is five business days upon receipt 
of the sample. (See sections 3.2.2, 5.6, 8.1.2, 8.2.1, and 10.2 for details.) 
3. The NRG-GY008 Documentation page of the NRG Oncology 
website:  https://www.nrgoncology.org/Protocol-Documents/NRG-GY008 contains the most 
recent information on pre-treatment assessments including the  Q2 Solutions shipping address, pre-
screening instructions and lab report upload form.  If you have any additional questions, please 
contact NRG Support (support@nrgoncology.org). (05/01/2017) 


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4.1.2 PRE-TREATMENT 
Assessments 
Prior to Registration 
 (calendar days) 
Prior to Treatment 
(Cycle 1, Day 1) 
(calendar days) 
History and Physical 
≤ 28 days 
≤ 28 days 
Vital Signs (Temperature, Pulse Rate, 
Respiration Rate, Blood Pressure) 
≤ 28 days 
Day of treatment 
Performance Status 
≤ 28 days 
≤ 28 days 
Toxicity Assessment 
≤ 14 days 
≤ 14 days 
Concurrent Medications 
≤ 14 days 
≤ 14 days 
CBC/Differential/Platelets 
≤ 14 days 
≤ 14 days 
Electrolytes, BUN, creatinine, Ca, 
magnesium, albumin and glucose 
≤ 14 days 
≤ 14 days 
Bilirubin, ALT, AST, Alkaline 
Phosphatase, Albumin 
≤ 14 days 
≤ 14 days 
Urine Protein  (05/01/2017) 
≤ 14 days 
≤ 14 days 
HbA1c (for Diabetic patients) 
≤ 14 days 
≤ 14 days 
Cholesterol/Triglycerides (fasting) 
≤ 28 days 
≤ 28 days 
PT-INR/PTT 
≤ 14 days 
≤ 14 days 
Hepatitis panel, including hepatitis B 
surface antigen and hepatitis C Antibody 
≤ 28 days 
≤ 28 days 
Pregnancy Test (if childbearing potential 
exists)  
≤ 28 days 
≤ 7 days 
ECG 
≤ 28 days 
≤ 28 days 
LVEF2 
≤ 28 days 
≤ 28 days 
Radiographic Tumor Measurement1 
≤ 28 days 
≤ 28 days 
 
1. Radiographic tumor measurements should be obtained via imaging of the chest, abdomen 
and pelvis. See RECIST 1.1 for allowable imaging modalities used to assess disease at 
baseline and subsequent assessments. Contrast CT is the preferred modality. 
2.  Bayer will cover the cost of the LVEF test. 
 


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4.2 
ASSESSMENTS DURING TREATMENT 
Assessments 
Cycle 
1, Day 
1 
Cycle 2 and subsequent 
Cycles, 
 Day 1 
All Cycles,  
Days 8 and 15 
History and Physical 
X 
≤ 3 days of treatment 
 
Vital Signs (Temperature, 
Pulse Rate, Respiration 
Rate, Blood Pressure) 
X 
X 
X 
Performance Status 
X 
≤ 3 days of treatment 
 
Toxicity Assessment6 
X 
≤ 3 days of treatment 
X 
Concurrent Medications 
X 
≤ 3 days of treatment 
 
CBC/Differential/Platelets 
Weekly 
during 
Cycle 1 
≤ 3 days of treatment 
≤ 1 day of treatment for the 
first cycle and as clinically 
indicated thereafter 
Electrolytes, BUN, 
creatinine, Ca, magnesium, 
albumin  
X 
≤ 3 days of treatment 
 
Bilirubin, ALT, AST, 
Alkaline Phosphatase  
X 
≤ 3 days of treatment 
 
Cholesterol/Triglycerides 
(fasting) 
X 
≤ 3 days of treatment 
(every 3 cycles, e.g., 
Cycle 3, 6, 9, ect) 
 
Glucose 
1 
2 
1, 2 
Blood Pressure 
3 
4 
4 
Radiographic tumor 
measurement 
5 
1. Pre-dose glucose should be taken after 8 hours of fasting.  For Cycle 1, glucose should be 
measured at pre-dose, 1 hour and 2 hours, after the start of copanlisib infusion.  Please see Section 
5.1.2 for additional information regarding pre-dose glucose for cycle 2 and beyond. 
2. For Cycle 2 and subsequent infusions, glucose should be measured prior to and 1 hour after the 
start of copanlisib infusion. See Section 5.1.2 for fasting requirements. 
3. For Cycle 1, Day 1: measure blood pressure pre-dose, 30 minutes after starting dose, at end of 
infusion, and 2 and 3 hours after completing infusion.  For Cycle 1, Days 8 and 15:  measure blood 
pressure pre-dose, 30 minutes after starting dose and at end of infusion. 
4. For Cycle 2 and subsequent infusions, measure blood pressure pre-dose, 30 minutes after starting 
dose and at end of infusion.   
NOTE:  For all timepoints (glucose and blood pressure) a window of +/- 10 minutes is permitted 
5. Radiographic tumor measurements to follow lesion for measurable disease every 8 weeks (+/- 7 
days) from cycle 1, day 1 (regardless of delays and/or changes in treatment schedule) for the first 
12 months; then every 12 weeks (+/- 7 days) thereafter until disease progression is confirmed; also 
repeat at any other time if clinically indicated based on symptoms or physical signs suggestive of 
progressive disease.  An excel tool is provided to calculate dates of re-imaging. 
6.  Report all adverse events that occur within 30 days of last protocol treatment on the Toxicity form 
for the last cycle of therapy administered. For reporting of delayed toxicity, see Section 7. 
 


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4.3 
ASSESSMENTS IN FOLLOW-UP 
Assessments 
From end of protocol treatment: q3 mos. x 
2 yrs.; q6 mos. x 3 years1 
Vital Status 
X 
Toxicity Assessment2 
X 
LVEF 
3 
Radiographic tumor measurement4 
X 
1. Follow-up forms are collected for the 5-year follow-up period or until study termination.  See 
Section 5.10 for further information. 
2. Patients who discontinue treatment for unacceptable adverse events(s) will be followed until 
resolution of stabilization of the adverse event.  For reporting of delayed toxicity, see Section 7. 
3. LVEF to be completed at end of treatment. Bayer will cover the cost of the LVEF test. 
4. Radiographic tumor measurements should be obtained via imaging of the chest, abdomen and 
pelvis to re-assess disease using the same modality as for pre-treatment baseline imagine (see 
Section 4.1), until disease progression is confirmed according to guidelines in section 4.2. 
 
5. 
TREATMENT PLAN/REGIMEN DESCRIPTION 
 
The treatment plan consists of weekly copanlisib for the first 3 weeks of a 28-day cycle (on 
Days 1, 8 and 15), followed by a 1-week break (i.e., no infusion on Day 22) (01/09/2017) 
 
5.1 
Chemotherapy/Hormonal Therapy/Other Agent-Based Therapy  
 
5.1.1 Protocol-Directed Therapy   
 
 
Copanlisib 60 mg IV over 1 hour weekly, 3 weeks on/1 week off (i.e., Days 1, 8 and 15 of a 
28-day cycle) until disease progression or adverse effects prohibit further treatment.   
 
Study drug is administered in a normal saline solution, intravenously, over 1 hour. No 
intravenous glucose preparations should be administered on the days of infusion. 
 
No dose should be given if blood pressure is greater than or equal to 150/90 mmHg (See 
Section 6.6.2). 
 
 


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5.1.2 Requirements for fasting state and pre-dose glucose levels  
 
Fasting Requirements and Pre-dose Glucose levels 
Period 
Fasting ≥ 8 h required 
before first glucose 
measurement 
Pre-dose glucose levels 
Fasting 
required 
before study 
drug infusion 
Day 1 of Cycle 1 
Yes 
≤ 125 mg/dL (non-diabetic 
patients) 
Yes 
< 160 mg/dL (diabetic patients) 
Day 1 of 
Subsequent 
Cycles 
Yes 
< 160 mg/dL (fasting) 
 
Conditionalb 
< 200 mg/dL (non-fasting)a 
Days 8 and 15 of 
each Cycle 
No 
< 160 mg/dL (fasting) 
 
Conditionalb 
< 200 mg/dL (non-fasting) 
 
a In case of non-compliance with the fasting requirement. 
 
b The conditional decision regarding meal timing and fasting will be made on Cycle 1 Day 8, based on 
the glucose response patterns of meal timing during Cycle 1 Day 1.  This decision will be applied to 
subsequent infusion days (see text below “Recommendations of meal timing on infusion days” for 
further details). 
 
The investigator will accurately document fasting/non-fasting for each glucose measurement 
done at the site and will also document the timing of any caloric intake (meal, snack, Juice, etc). 
Fasting for this purpose refers to a ≥ 8 hour fast. Non-fasting status includes any caloric intake such as 
meals and also juice, snacks, and other caloric intake not consistently called a meal. 
 
From Cycle 1 Day 1 onwards, glucose measurements at the site may be done either by 
laboratory analysis or in capillary blood, using a hand-held glucose meter. Any capillary blood (using 
hand-held glucose meter) glucose of > 250 mg/dL should be repeated via laboratory analysis. 
 
5.1.2.1 Recommendations on meal timing on infusion days 
The investigator will review the glucose profile during and post the copanlisib infusion of 
C1D1).  
C1D1: 
On C1D1 a low glycemic index meal (see Appendix III) may be taken 3 hours after the start of 
the study drug infusion. 
C1D8: 
The following recommendations apply to subsequent infusion days starting from C1D8:  
If the maximum glucose during C1D1 was: 
 < 200 mg/dL, the patient may have a low glycemic index meal or snack before, during or 
after the study drug infusion.  
If the maximum glucose during C1D1 was 
 ≥ 200 mg/dL, a low glycemic index meal can be taken 3 hours after the start of the study 
drug infusion (approximately 2 hours after the study drug infusion is completed).  


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The investigator should consider the administration of oral glucose lowering medication on 
C1D8 and subsequent infusion days of copanlisib. See Section 6.6.3 for additional 
guidance on glucose management. 
 
5.1.3 Dosing criteria 
On Day 1 of each subsequent cycle, the dose of study treatment will be given only if the 
criteria described in the table below are met. Glucose lowering medication can be used to 
optimize pre-infusion glucoses (see Section 6.6.3). 
 
Laboratory test criteria for Day 1 dose of SUBSEQUENT cycles 
Laboratory Test 
Criteria for Day 1 dose 
Glucose 
< 160 mg/dL (fasting) or < 200 mg/dL (non-fasting) 
Hemoglobin 
≥ 8 g/dLa 
ANC 
≥ 1,500/mm3 
Platelets 
≥ 75,000/mm3 
ALT 
≤ 3 x ULN  
AST 
≤ 3 x ULN  
Total bilirubin 
≤ 1.5 x ULN b 
Creatinine 
≤ 1.5 x ULN  
 
a:  If hemoglobin is < 8g/dL on the day of planned study drug administration patient must be 
transfused to reach an Hb ≥ 8g/dL to continue on study treatment. Rationale and treatment 
should be recorded in source document and eCRF. 
b:   ≤ 3 x ULN in patients with Gilbert syndrome 
 
A blood count and glucose will be performed and assessed prior to study drug infusion on Day 
8 and 15 of the first cycle and as clinically indicated thereafter. On Days 8 and 15, the dose of 
copanlisib will be administered if, on the day of scheduled dosing, the laboratory test criteria 
for hemoglobin, ANC, platelets and glucose described in the table above are met. A delay >21 
days in study drug administration due to toxicities will cause permanent discontinuation of 
study treatment. A patient will be permitted to have a new cycle of therapy delayed up to 7 
days (without this being considered to be a protocol violation) for major life events (e.g., 
serious illness in a family member, major holiday, vacation which is unable to be re-
scheduled). Documentation to justify this decision should be provided.  
 
It will be acceptable for individual chemotherapy doses to be delivered within a “24-hour 
window before and after the protocol-defined date” for “Day 1” treatment of 28 day cycles. If 
the treatment due date is a Friday, and the patient cannot be treated on that Friday, then the 
window for treatment would include the Thursday (1 day earlier than due) through the Monday 
(day 3 past due). 
 
It will be acceptable for “Day 8 chemotherapy” to be delivered on Day 7, Day 8, or Day 9 and 
“Day 15 chemotherapy” to be given on Day 14, Day 15, or Day 16.  A delay of more than this 


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one day window will be considered a missed dose. Missed doses will not be replaced. The 
minimum interval needed between two infusions of study drug is 5 days. 
 
5.2 
Radiation Therapy 
 
Not Applicable. 
 
5.3 
Surgery  
 
Not Applicable. 
 
5.4 
Device  
Not Applicable. 
 
5.5 
Imaging (for imaging-focused study) 
Not Applicable. 
 
5.6 
Integral Assay/Biomarker (01/09/2017) 
The COBAS® PIK3CA mutation test is a real-time PCR test for the qualitative 
detection and identification of mutations in exons 1, 4, 7, 9, and 20 in the PIK3CA 
gene. This assay has been validated for the analysis of clinical samples in various solid tumor 
tissues and is performed per Q2 Solutions Standard Operating Procedures (SOPs). Additional 
qualification on endometrial carcinoma tissue may be required.  
 
All molecular analyses at Q2 Solutions are done in compliance with College of American 
Pathologists (CAP) requirements for molecular testing and in accordance with Clinical 
Laboratory Improvement Amendments (CLIA) and Good Clinical Laboratory Practice (GCLP) 
guidelines. Validation report and SOPs are available upon request.  
 
As part of Q2 Solutions standard quality control measures for somatic mutation analysis from 
FFPE tissue, all samples will undergo H&E assessment by a board-certified pathologist prior to 
testing. This will ensure the specimen contains sufficient tissue area and the minimum tumor 
percentage (≥10%) required for testing. If less than 10% tumor nuclei are present, the sample 
will undergo macrodissection to enrich for tumor content. If sufficient material cannot be 
obtained from a single section, additional sections may be used. 
 
Note: Testing kits are typically received 7-10 business days after request. Typical testing 
turnaround time is five business days upon receipt of the sample. 
 
Any remaining slides or extracted DNA will be stored at Q2 Solutions until returned to the 
NRG BB-Columbus for future (approved) research projects. 
 
5.7 
Intervention Not Otherwise Categorized 
 
Not Applicable. 
 
 
 


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5.8 
General Concomitant Medication and Supportive Care Guidelines 
 
5.8.1 Permitted Supportive/Ancillary Care and Concomitant Medications 
 
All supportive therapy for optimal medical care will be given during the study period at the 
discretion of the attending physician(s) within the parameters of the protocol and documented 
on each site’s source documents as concomitant medication.  
 Standard therapies for concurrent medical conditions 
 Treatment with non-conventional therapies including herbs, vitamins, and other over-the-
counter medications can interfere with copanlisib metabolism. Consult the study investigator 
prior to use. 
 Bisphosphonates 
 Patients who are therapeutically treated with an agent such as warfarin or low molecular 
weight heparin will be allowed to participate provided that their medication dose and INR/PTT 
is stable. Close monitoring is recommended according to standard of care. If either of these 
values is above the therapeutic range, the doses should be modified and the assessments should 
be repeated weekly until it is stable. 
 Antiemetics: Anti-emetics may be administered according to standard practice upon 
identification of symptoms requiring intervention. The use of standard antiemetics, including 
5-HT3 blockers, such as granisetron, ondansetron, or an equivalent agent, is allowed as needed 
to manage symptoms.  
 The use of corticosteroids as antiemetics prior to copanlisib administration is not allowed. 
 Palliative and supportive care for the other disease-related symptoms and for toxicity 
associated with treatment will be offered to all patients in this trial. 
 Low-dose aspirin (maximum 100 mg/day) and low-dose heparin or low molecular weight 
heparin are permitted. 
 Patients taking narrow therapeutic index medications should be monitored proactively, if these 
medications cannot be avoided. These medications may include quinidine, cyclosporine, and 
digoxin. 
 Therapeutic drugs known to be 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 (see Appendix IV). Calcium channel blockers may be used to control pre-existing 
hypertension. Non-dihydropyridine calcium channel blockers (Verapamil and diltiazem) 
should be avoided due to a potential CYP3A4 interaction (See Appendix V). 
 Short term (up to 7 days) systemic corticosteroids above 15 mg prednisone or equivalent will 
be allowed only for the management of acute conditions.  
 
5.8.2 Prohibited Therapies 
 CYP3A4 inhibitors and inducers (see Appendix V). Copanlisib is primarily metabolized by 
CYP3A4. Therefore, concomitant use of strong inhibitors of CYP3A4 (e.g., ketoconazole, 
itraconazole, clarithromycin, ritonavir, indinavir, nelfinavir and saquinavir), and inducers 
of CYP3A4 (e.g., rifampin, phenytoin, carbamazepine, phenobarbital, St. John's Wort) are 
not permitted within two weeks prior to start of study treatment and for the duration of 
treatment with copanlisib. 


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 Grapefruit and grapefruit juice (CYP3A4 inhibitor), Seville oranges and star fruit 
consumption is not permitted during the study. 
 Anti-arrhythmic therapy other than beta blockers or digoxin. 
 Concomitant therapy with any anticancer agents, immunosuppressive agents, other 
investigational anticancer therapies.  
 Concomitant radiotherapy. 
 Systemic continuous corticosteroid therapy at a daily dose higher than 15 mg prednisone or 
equivalent is not allowed. Patients may be using topical or inhaled corticosteroids. 
 
5.8.3 Participation in Other Trials 
 
Not applicable. 
 
5.9 
Duration of Therapy 
In the absence of treatment delays due to adverse event(s), treatment may continue as specified 
in the above treatment modality sections or until one of the following criteria applies: 
 
Disease progression, 
 
Intercurrent illness that prevents further administration of treatment, 
 
Unacceptable adverse event(s), as described in Section 6 
 
Patient decides to withdraw consent for participation in the study, or 
 
General or specific changes in the patient's condition render the patient unacceptable for 
further treatment in the judgment of the investigator. 
 
Non-compliance to protocol 
 
5.10 
Duration of Study 
All patients will be treated (with completion of all required case report forms) until disease 
progression or study treatment withdrawal. Thereafter, patients will be monitored for delayed 
toxicity and survival with follow-up forms for no more than 5 years or until study termination, 
unless consent is withdrawn.  
 
A patient is considered off study therapy when the patient has progressed or died, a non-
protocol drug or therapy (directed at the disease) is initiated or all study therapy is totally 
discontinued. Report all treatment received on treatment reporting forms and adverse events on 
adverse event forms up until the patient qualifies as being off study therapy. 
 
6. 
TREATMENT MODIFICATIONS/MANAGEMENT 
 
6.1 
Dose modification 
It is recognized that attribution of causality of any AE to the test drug specifically may be 
difficult. However, in Phase I and II trials, certain toxicities were seen only in relation to 
copanlisib (e.g., transient increases in glucose and blood pressure). Based on this knowledge 
the investigator may decide on the necessary dose modifications.  
 
Dose modifications and treatment interruptions for copanlisib must be done according to the 
guidelines in Hematological toxicity and nonhematological toxicity sections. 
 


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The dose modification levels of copanlisib are: 
 
Dose levels of Copanlisib 
Dose Level 1 (starting dose) 
60 mg  
Dose Level -1 
45 mg 
Dose Level -2 
30 mg 
 
Patients who do not tolerate the copanlisib dose of 30 mg must discontinue study 
treatment permanently. 
 
6.2 
Hematological toxicity 
Neutropenia and febrile neutropenia are listed in the current version of IB as expected adverse 
events.  
 
Dose Modification of Copanlisib for hematological toxicity 
Review laboratory test criteria for Day 1 dose 
of Subsequent Cycles (Section 5.1.3) 
 
For platelets and ANC delay infusion until 
criteria displayed in the table in Section 
5.1.3, “Laboratory test criteria for Day 1 
dose of Subsequent cycles” are met.  
Febrile neutropenia a 
INR or PTT CTCAE Grade 3 or greater with 
bleeding b 
Grade 3 
1st appearance 
Delay  until Grade ≤ 2 
No change 
2nd appearance 
Delay  until Grade ≤ 2 
Decrease by one dose 
levelc 
3rd appearance 
Delay  until Grade ≤ 2 
Decrease by one dose 
levelc 
4th appearance 
Permanently discontinue 
copanlisib 
 
Grade 4 
 
Permanently discontinue 
copanlisib 
 
 
a: These patients should recover from neutropenia, without fever 
 
b: INR and PTT should have returned to ≤1.5 x ULN with no signs of bleeding 
 
c:  Not applicable for 30 mg dose level 
 
A delay >21 days in study drug administration due to toxicities will cause permanent 
discontinuation of study treatment. Copanlisib must be discontinued if the lowest dose level of 30 
mg is not tolerated.  
 
 


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6.3 
Non-hematological toxicity 
Dose modifications for non-hematologic toxicities attributable to copanlisib except glucose 
increases, dermatologic toxicity, non-infectious pneumonitis and blood pressure increases are 
outlined in the table below: 
 
Dose modification of copanlisib for non-hematological toxicity (except hyperglycemia, 
dermatologic toxicity, non-infectious pneumonitis and hypertension) 
Toxicitya 
Occurrence 
For Current cycle of 
therapy 
For next cycle of therapy 
Grade 1-2 
Any appearance 
No change 
No change 
Grade 3b 
1st appearance 
Delay  until Grade ≤ 2 
No change 
2nd appearance 
Delay  until Grade ≤ 2 
Decrease by one dose 
levelc 
3rd appearance 
Delay  until Grade ≤ 2 
Decrease by one dose 
levelc 
4th appearance 
Permanently discontinue 
copanlisib 
 
Grade 4 
 
Permanently discontinue 
copanlisib 
 
 
a:  Toxicities according to CTCAE version 4.0 
b:  Despite maximum supportive therapy 
c:  Not applicable for 30 mg dose level 
 
A delay >21 days in study drug administration due to toxicities will cause permanent 
discontinuation of study treatment. Copanlisib must be discontinued if the lowest dose level of 
30 mg is not tolerated.  
 
6.4 
Dermatologic toxicity 
The guidelines for dose modifications in cases of dermatologic toxicity are outlined in the table 
below. 
 
Dose Modification of copanlisib for dermatologic toxicity 
Toxicitya 
Occurrence 
For current cycle of 
therapy 
For next cycle of 
therapy 
Grade 1 
Any appearance 
No change 
No change 
Grade 2b 
1st appearance 
Interruption until 
Grade ≤ 1 
No change 
2nd appearance 
Interruption until 
Grade ≤ 1 
Decrease by one 
dose level c 
3rd appearance 
Interruption until 
Grade ≤ 1 
Decrease by one 
dose level c 
4th appearance 
Permanent 
discontinuation 
 
Grade 3b 
1st appearance 
Interruption until 
Grade ≤ 1 
Decrease by one 
dose level c 


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2nd appearance 
Interruption until 
Grade ≤ 1 
Decrease by one 
dose level c 
3rd appearance 
Permanent 
discontinuation 
 
Grade 4 
1st appearance 
Permanent 
discontinuation 
 
 
a Toxicities according to CTCAE version 4.0 
b Despite maximum supportive therapy 
c Not applicable for 30 mg dose level 
 
The lowest dose level is 30 mg; if a patient is already on the 30 mg dose level study drug and 
meets criteria for further decrease of dose, study drug will be discontinued permanently. 
 
6.5 
Non-infectious pneumonitis (NIP) 
In the event of suspected NIP of any grade, copanlisib must be interrupted. If NIP is the final 
diagnosis, copanlisib must be permanently discontinued.  Pneumonitis is to be reported as such 
only in the event of NIP. Study Chair notification in the event of any grade NIP is required.  
 
The investigator is requested to differentiate between non-infectious pneumonitis (NIP), and 
infectious pneumonitis (viral, bacterial, fungal), aspiration pneumonitis, or other pneumonitis 
clearly not due to a potential hypersensitivity reaction to the copanlisib infusion, and provide 
the basis for his/her assessment that it is infectious or other, as appropriate. The investigator is 
requested to report with the most specific clinical terms to describe the condition, not simple 
“pneumonitis”. 
 
6.6 
Glucose increases and blood pressure increases 
 
6.6.1  Glucose increases 
Patients who develop transient post-infusion glucose > 250 mg/dL after copanlisib 
administration may continue treatment. However, the next infusion must be delayed until the 
patient’s pre-infusion glucose levels return to < 160 mg/dL (fasting) or < 200 mg/dL (non-
fasting). Glucose levels >250 mg/dL should be confirmed by repeated laboratory analysis. 
Guidelines for the treatment of glucose increases are given in Section 6.6.3. 
 
A dose reduction of copanlisib by one dose level is mandatory in the event of hyperglycemia > 
500 mg/dL (repeated immediately and confirmed by laboratory glucose test) or in the event of 
persistent CTCAE Grade ≥ 3 glucose (persistent > 250 mg/dL value confirmed by repeated 
laboratory analysis) despite optimal glucose lowering therapy. Treatment will be permanently 
discontinued if persistent CTCAE Grade ≥ 3 glucose occurs at 30 mg dose level despite 
optimal glucose lowering therapy. 
 
6.6.2 Blood pressure increases 
No dose should be given if blood pressure is ≥ 150/90 mmHg. Instructions for blood 
pressure measurement are given in the table below. Antihypertensive medication may be given 
to control the hypertension. Dosing can proceed on the scheduled day if there are at least 2 


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consecutive measurements <150/90 mmHg. Otherwise dosing must be delayed.  
 
The guidelines for dose modifications of study treatment in case of increased blood pressure 
are given in the table below. 
 
Dose modification of study treatment for increases of blood pressure 
Toxicity 
Study Drug action 
Recommendation 
 
Pre-dose measurements 
BP ≥ 150/90 mmHG 
 
No dose should be given until 
recovery to < 150/90 mmHg 
Consider administering BP lowering 
medication. Dosing can proceed on the 
scheduled day if after at least 2 
consecutive measurements BP returns to 
< 150/90 mmHG.  If BP does not return 
to < 150/90 mmHG then delay dosing 
until next visit. 
 
During infusion: 
BP ≥ 160/100 mmHG 
(or CTCAE Grade ≥ 3) 
Infusion can be interrupted or 
slowed down and 
administration of anti-
hypertensive therapy should 
be initiated. 
Infusion may be resumed immediately 
when BP has returned to < 150/90 mmHg 
or skipped. 
Subsequent study drug administrations 
may be reduced by 1 dose level at the 
investigator’s discretionb 
Post-dose: 
BP ≥ 160/100 mmHGa 
 
____________ 
Subsequent study drug administrations 
may be reduced by 1 dose level at the 
investigator’s discretion 
Life-threatening 
consequences (e.g., 
malignant hypertension, 
transient or permanent 
neurologic deficit, 
hypertensive crisis); 
urgent 
intervention 
indicated(CTCAE 
Grade 4) 
Permanent Discontinuation 
 
 
____________ 
 
a:  Not manageable despite optimal hypertensive treatment 
 
b:  The lowest dose level is 30 mg;  if a patient is already on the 30 mg dose level and experiences 
post-dose increase BP of ≥ 160/100 mmHg, consider more intensive therapy than previously used. 
 
Treatment of blood pressure increases associated with copanlisib 
It is important that patients with pre-existing arterial hypertension adhere to their regular medication 
schedule, and take their usual doses on the days of study drug infusion. The management of acute 
blood pressure increases following copanlisib will need to be individualized for each patient, but the 
experience in Phase I has suggested the benefit of dihydropyridine calcium channel blockers (i.e., 
amlodipine, felodipine). Topical nitrates should also be considered. Verapamil and diltiazem (non-
dihydropyridine calcium channel blockers) should be avoided due to a potential CYP 3A4 interaction. 


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In general, it is advisable for sites to be prepared, so that antihypertensive medication is readily 
available in case of need.  
 
6.6.3  Management of glucose increases that can occur with copanlisib 
 
6.6.3.1 Management of transient post-infusion glucose increases in non-diabetic patients 
Mild to moderate asymptomatic increases of blood glucose may occur with copanlisib infusion, 
and with larger increases potentially occurring post-prandially. 
 
6.6.3.2 Asymptomatic transient glucose increases 
 Blood glucose ≤ 250 mg/dL. Does not generally require treatment with glucose 
lowering medication. 
 Blood glucose > 250 mg/dL. Should have repeated laboratory glucose determination. If 
the repeated glucose value is decreasing, the glucose may be followed without glucose 
lowering medication if hydration status is normal as clinically assessed. 
 
6.6.3.3 Symptomatic or persisting glucose increases 
 Symptomatic glucose increase of any grade. Hydration status should be clinically 
assessed. If clinical assessment is consistent with dehydration, fluids should be given as 
clinically appropriate (orally or IV). 
 Blood glucose > 250 mg/dL. Should have repeated laboratory glucose determination. If 
the repeated glucose value is persistent and/or patient is symptomatic and/or the 
hydration status indicate the need for hydration, glucose lowering medication should be 
administered. 
 
6.6.3.4 Glucose lowering medication 
During the same infusion day as increased glucose is identified: 
 Rapid or short acting (or Regular) insulin may be given for glucose levels that are 
persisting at > 250 mg/dL, or if the patient is symptomatic during the infusion day. 
 “Sliding scale” or short acting (or Regular) insulin coverage of glucose levels that are 
persisting at > 250 mg/dL is recommended, with oral or IV hydration as clinically 
appropriate. 
During the subsequent infusions:  
Administration of oral glucose lowering medication that will cover meals on the subsequent 
infusion day(s) is recommended. Recommended oral glucose lowering medications include use 
of either a morning dose of sodium/glucose co-transporter 2 (SGLT2) inhibitor or dipeptidyl 
peptidase-4 (DPP4) inhibitor. Please refer to local prescribing information on oral glucose 
lowering medications (consider endocrinology consult for guidance). The use of 
sulphonylurea/metaglinide medications to manage increased glucose levels post copanlisib 
infusions is not recommended. 
 
6.6.3.5 Persisting glucose > 250 mg/dL that does not promptly improve with insulin/oral 
medication/clinically appropriate hydration: 
 Prompt input from a diabetes specialist (endocrinologist) should be obtained.  
 Consider hospitalization to stabilize the patient metabolically if intravenous 


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hydration is needed. 
 
6.6.3.6 Management of post-infusion glucose increases in diabetic patients 
 
Patients with diabetes mellitus (types 1 and 2) will require the input of a diabetes specialist 
(endocrinologist) to anticipate glucose lowering needs on study drug infusion days. Adjustment 
of the patient’s glucose lowering regimen (whether adjustments to prior use of oral 
hypoglycemic medication, insulin, or a combination of both) with special attention to post-
infusion meal coverage should be considered for post-prandial glucose increases. 
 
Patients who have experienced glucose increases requiring supplemental glucose lowering 
medication on the infusion day, may benefit from glycemic observation and potential glucose 
lowering medication on days subsequent to the infusion day. These patients may be referred to 
a local diabetes specialist/endocrinologist for glucose management if appropriate. 
Alternatively, the investigator will be free to adequately manage these patients in the same way 
as indicated above.  
 
6.6.3.7 Monitoring period continuation: infusion clinic visit days and during continued monitoring 
periods 
 
All patients (diabetic and non-diabetic) should be kept under close observation if the glucose 
level is > 250 mg/dL until the non-fasting glucose level decreases to < 200 mg/dL at any cycle.  
 
All diabetic patients, as well as non-diabetic patients who experience persisting glucose 
> 250 mg/dL or who require insulin administration post-infusion will be instructed to check 
blood glucose at home at least 3 times per full day for at least 72 hours after the start of 
infusion. This includes fasting glucose (morning before breakfast) and 2 further measurements 
approximately 2 hours after intake of food. If after the required 72 hours the glucose values are 
not at goal (non-fasting glucose < 200 mg/dL), this monitoring will continue until blood 
glucose values are at goal. 
 
Patients will be trained how to measure their capillary blood glucose levels at home. If 
applicable, patients will be provided with glucose meter and supplies (lancets, test strips and 
diary) to register measured values and record oral glucose lowering medication and/or insulin 
administration.  (See Section 9.2.)  
 
In the event of rapid or short acting (Regular) insulin administration was administered on an 
infusion day at any cycle, a minimum 3-hour close observation time is required post insulin 
administration. 
 
Low glycemic index meals should be advised for patients who are kept in the clinic in for 
continued observation (see Appendix III). A low glycemic index diet is recommended for the 
first 48 hours after study drug infusion. However, caloric restriction is not intended for the 
population under study. 
 


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All glucose measurements, oral glucose lowering medication and/or insulin administration, if 
applicable, and meal timing will be collected as part of the clinic source documentation. See 
Appendix VIII. 
 
6.6.3.8 Monitoring of diabetic patients 
If the patient has known diabetes and already monitors her blood glucose as part of routine 
diabetes care, the routine measurements should not be replaced by the study-specific 
measurements. In this situation, patients should add the study-specific measurements to their 
routine, if applicable. After the required 72 hour post-infusion, if blood glucose values are at 
goal (non-fasting glucose < 200 mg/dL), patients can then stop only the study-specific 
measurements until the next day of infusion, but should keep their routine measurements 
unchanged and ongoing as usual. 
 
6.6.4 Management of hyperlipidemia 
As lipids are monitored for the duration of this study it is recommended to treat significant 
deviations from normal range with standard interventions and therapy in standard doses 
according to local medical practice. Significant deviations from normal range are defined as 
fasting cholesterol less than or equal to 300 mg/dl; fasting triglycerides less than or equal to 
300 mg/dl (ie, eligibility criteria). In case of significant deviations the use of therapeutic life-
style changes (TLC), fibrates (fenofibrate or gemfibrozil) or statin, will be recommended to 
sites per published algorithm (ie, Management of metabolic effects associated with anticancer 
agents targeting the PI3K-Akt-mTOR pathway” (J Clin Oncol 30:2919-2928, 2012).  
 
Although there is a paucity of data on the effects of hyperlipidemia and cancer outcomes, these 
goals have been chosen to decrease risk of established complications of hypertriglyceridemia 
(pancreatitis) and hypercholesterolemia (cardiovascular events). 
 
6.6.5 Treatment of vomiting and diarrhea 
The hydration status of the patient should be clinically assessed, with fluid replacement (oral or 
IV) as appropriate.  Adequate hydration through appropriate fluid maintenance is essential in 
the treatment of diarrhea or vomiting. Anti-diarrhea medications may be introduced if 
symptoms occur.  
 
The recommended dose of loperamide is 4 mg at first onset, followed by 2 mg every 2 to 4 
hours until diarrhea-free for 12 hours; a maximum daily dose of 16 mg is not to be exceeded. If 
clinically indicated, diphenoxylate hydrochloride with or without atropine sulfate can be used. 
The routine use of standard antiemetics, including 5-HT3 blockers is allowed, see permitted 
concomitant therapy section below. In the event of CTCAE Grade 3 diarrhea with maximal 
pharmacological support, the administration of the test drug should be delayed. 
 
6.6.6 Treatment of dermatologic toxicity 
 
If dermatologic changes occur, the patient should be treated quickly and aggressively. 
 
Guidance on treatment of skin toxicities 
MILD (CTCAE Grade 1) 
Dry Skin/Fissures 
Emollients, Eucerin or Aquaphor plus gentle soaps (Dove, 


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Cetaphil, Basis), use fragrance-free detergents 
Rash 
Topical hydrocortisone 2.5% and/or clindamycin 1% gel plus 
doxycycline 100 mg BID or Minocyclin 100 mg BID 
Nail Changes 
Moisturizers 
Pruritus 
Pramoxine 1% cream of Sama Ultra Cream 
MODERATE (CTCAE Grade 2) 
Dry Skin/Fissures 
Emollients and topical as above plus Ammonium lactate or Ureas 
20% 
Rash 
Topical hydrocortisone 2.5% and/or clindamycin 1% gel plus 
doxycycline 100 mg BID or Minocycline 100 mg BID 
Nail Changes 
Vinegar soaks (dilute 1:1 white vinegar in water and soak fingers 
for 10 minutes a day) 
Pruritus 
H1-anti-histamines 
SEVERE (CTCAE Grade 3 or 4) 
Dry Skin/Fissures 
As above for Moderate 
Rash 
As above for Moderate plus Medrol dose packa 
Nail Changes 
Topical antibacterials/antifungals (ciclopirox) cream or Topical 
high potency steroids (closbetasol ointment) 
Consider dermatology consult for nail avulsion 
Pruritus 
Pregabalin 50-100 mg BID 
 
a Cross check with short-term corticosteroid administration (see Exclusion Criteria and 
Permitted concomitant therapy)  
If concomitant corticosteroids are used for dermatologic conditions, the investigator should be 
alert to potential impact of corticosteroids on increases in blood glucose and in blood pressure. 
Please refer to excluded previous therapies in Exclusion Criteria section. If glucose increases 
or blood pressure increases during the period of corticosteroid use, please see Section 6.6.3 for 
glucose management, and see Section 6.6.5 for blood pressure management. 
 
7. 
ADVERSE EVENTS REPORTING REQUIREMENTS 
 
7.1  
Protocol Agents 
 
Investigational Agents 
The investigational agent administered in NRG-GY008, copanlisib, is being made available 
under an IND sponsored by NRG Oncology.  For patients receiving copanlisib, determination 
of whether an adverse event meets expedited reporting criteria, see the reporting table in 
section 7.42 of the protocol. (01/09/2017) 
7.2  
Adverse Events and Serious Adverse Events 
 
7.2.1 This study will utilize the NCI Common Terminology Criteria for Adverse Events (CTCAE) 
version 4.0 for CTEP-AERS (CTEP Adverse Event Reporting System) CAERs reporting of 
adverse events (AEs), located on the CTEP web site, 
http://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm. All appropriate 
treatment areas should have access to a copy of the CTCAE version 4.0. 
 


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7.2.2 Definition of an Adverse Event (AE) 
Any untoward medical occurrence associated with the use of a drug in humans, whether or not 
considered drug related.  Therefore, an AE can be any unfavorable and unintended sign 
(including an abnormal laboratory finding), symptom, or disease temporally associated with 
the use of a medicinal (investigational) product, whether or not considered related to the 
medicinal (investigational) product (attribution of unrelated, unlikely, possible, probable, or 
definite). (International Conference on Harmonisation [ICH], E2A, E6).  
 
For multi-modality trials, adverse event reporting encompasses all aspects of protocol 
treatment including radiation therapy, surgery, device, and drug. 
 
Due to the risk of intrauterine exposure of a fetus to potentially teratogenic agents, the 
pregnancy of a study participant must be reported via CTEP-AERS in an expedited manner. 
 
7.3 
Adverse Events for Investigational Study Agents Not Provided by CTEP 
 
Refer to the copanlisib Investigator Brochure (IB). (01/09/2017) 
  
7.4 
Expedited Reporting of Adverse Events 
All serious adverse events that meet expedited reporting criteria defined in the reporting table 
below will be reported via the CTEP Adverse Event Reporting System, CTEP-AERS, accessed 
via the CTEP web site,  
https://eapps-ctep.nci.nih.gov/ctepaers/pages/task?rand=1390853489613 
 
Submitting a report via CTEP-AERS serves as notification to and satisfies NRG requirements 
for expedited adverse event reporting. 
 
CTEP-AERS provides a radiation therapy-only pathway for events experienced that involve 
radiation therapy only. These events must be reported via the CTEP-AERS radiation therapy-
only pathway. 
 
In the rare event when Internet connectivity is disrupted, a 24-hour notification must be made 
to the NRG Regulatory Affairs by phone at 215-854-0770. An electronic report must be 
submitted immediately upon re-establishment of the Internet connection. 
 
7.4.1 Expedited Reporting Methods 
 CTEP-AERS-24 Hour Notification requires that a CTEP-AERS 24-hour notification is 
electronically submitted within 24 hours of learning of the adverse event. Each CTEP-
AERS24-hour notification must be followed by a complete report within 3 days.  
 Supporting source documentation is requested by NRG as needed to complete adverse 
event review. When submitting supporting source documentation, include the protocol 
number, patient ID number, and CTEP-AERS ticket number on each page, and fax 
supporting documentation to the NRG Regulatory Affairs at 215-854-0716. 
 A serious adverse event that meets expedited reporting criteria outlined in the AE 
Reporting Tables but is assessed by the CTEP-AERS as “an action not recommended” 
must still be reported to fulfill NRG safety reporting obligations. Sites must bypass the 
“NOT recommended” assessment; the CTEP-AERS allows submission of all reports 


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regardless of the results of the assessment.  
 
7.4.2 Expedited Reporting Requirements for Adverse Events  
 
Phase 1, 2 and 3 Studies:  Expedited Reporting Requirements for Adverse Events that Occur on 
Studies under a non-CTEP IND/IDE within 30 Days of the Last Administration of the Investigational 
Agent/Intervention 1, 2  
FDA REPORTING REQUIREMENTS FOR SERIOUS ADVERSE EVENTS (21 CFR Part 312) 
NOTE:  Investigators MUST immediately report to the sponsor (NCI) ANY Serious Adverse Events, whether or not 
they are considered related to the investigational agent(s)/intervention (21 CFR 312.64) 
An adverse event is considered serious if it results in ANY of the following outcomes:   
1) Death 
2) A life-threatening adverse event  
3) An adverse event that results in inpatient hospitalization or prolongation of existing hospitalization for ≥ 24 
hours  
4) A persistent or significant incapacity or substantial disruption of the ability to conduct normal life functions  
5) A congenital anomaly/birth defect.  
6) Important Medical Events (IME) that may not result in death, be life threatening, or require hospitalization 
may be considered serious when, based upon medical judgment, they may jeopardize the patient or subject and 
may require medical or surgical intervention to prevent one of the outcomes listed in this definition. (FDA, 
21 CFR 312.32; ICH E2A and ICH E6). 
 
ALL SERIOUS adverse events that meet the above criteria MUST be immediately reported to NRG via CTEP-
AERS within 24 hours of learning of the AE, followed  by a complete report within 3 calendar days of the initial 
24-hour report. 
Hospitalization 
Grade 1 and Grade 2 Timeframes 
Grade 3-5 Timeframes 
Resulting in 
Hospitalization  
≥ 24 hrs 
24-Hour 3 Calendar Days 
24-Hour 3 Calendar Days 
Not resulting in 
Hospitalization  
≥ 24 hrs 
Not required 
 
Expedited AE reporting timelines are defined as: 
o “24-Hour; 3 Calendar Days” - The AE must initially be reported via CTEP-AERS within 24 hours of 
learning of the AE, followed by a complete expedited report within 3 calendar days of the initial 24-
hour report. 
 
1Serious adverse events that occur more than 30 days after the last administration of investigational 
agent/intervention and have an attribution of possible, probable, or definite require reporting as follows:  
Expedited 24-hour notification followed by complete report within 3 calendar days for: 
 
All Grade 3, 4, and Grade 5 AEs 
 
Grade 1 and 2 AEs resulting in hospitalization or prolongation of hospitalization 
 
 
 
 


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Additional Protocol-Specific Instructions or Exceptions to Expedited Reporting 
Requirements: 
 
Non-infectious pneumonitis (NIP) 
Non-infectious pneumonitis (NIP) of any grade requires expedited reporting via CTEP-AERS.  
Pneumonitis is to be reported as such only in the event of NIP.  
 
The investigator is requested to differentiate between non-infectious pneumonitis (NIP), and 
infectious pneumonitis (viral, bacterial, fungal), aspiration pneumonitis, or other pneumonitis 
clearly not due to a potential hypersensitivity reaction to the copanlisib infusion, and provide 
the basis for his/her assessment that it is infectious or other, as appropriate. The investigator is 
requested to report with the most specific clinical terms to describe the condition, not simple 
“pneumonitis”. 
 
7.4.3 Reporting to the Site IRB/REB 
Investigators will report serious adverse events to the local Institutional Review Board (IRB) or 
Research Ethics Board (REB) responsible for oversight of the patient according to institutional 
policy. 
 
7.4.4 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 during or subsequent to treatment with an 
agent under an NCI IND/IDE be reported via CTEP-AERS. In addition, secondary 
malignancies following radiation therapy must be reported 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.  
 
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 reporting 
via CDUS unless otherwise specified. 
 
7.4.5   Reporting to the Pharmaceutical Company:  The CTEP-AERS report will be sent directly to 
Bayer via the CTEP-AERS system upon submission to NCI.  
 
7.4.6 Reporting to the FDA:  The NRG Oncology Regulatory Department will submit an IND safety 
report to the FDA and all participating investigators no later than 15 calendar days after 
determining that the suspected adverse reaction or other information qualifies for reporting (21 


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CFR 312.32(c)(1)).  Any unexpected fatal or life-threatening suspected adverse reaction will be 
reported to the FDA no later than 7 calendar days after initial receipt of the information by 
GOG (21 CFR 312.32(c)(2).  Each report will be submitted on FDA Form 3500A (21 CFR 
320.31(d)(3)). 
 
8. 
REGISTRATION, STUDY ENTRY, AND WITHDRAWAL PROCEDURES 
 
8.1 
Access requirements for OPEN and Medidata Rave 
 
Site staff will need to be registered with CTEP and have a valid and active CTEP Identity 
and Access Management (IAM) account.  
 
The Cancer Therapy Evaluation Program (CTEP) Identity and Access Management (IAM) 
application is a web-based application intended for use by both Investigators (i.e., all 
physicians involved in the conduct of NCI-sponsored clinical trials) and Associates (i.e., all 
staff involved in the conduct of NCI-sponsored clinical trials). Associates will use the CTEP-
IAM application to register (both initial registration and annual re-registration) with CTEP and 
to obtain a user account.  
 
Investigators will use the CTEP-IAM application to obtain a user account only. (See CTEP 
Investigator Registration Procedures below for information on registering with CTEP as an 
Investigator, which must be completed before a CTEP-IAM account can be requested.)  
 
An active CTEP-IAM user account will be needed to access all CTEP and CTSU (Cancer 
Trials Support Unit) websites and applications, including the CTSU members’ website. 
 
Additional information can be found on the CTEP website at 
<http://ctep.cancer.gov/branches/pmb/associate_registration.htm>.  For questions, please 
contact the CTEP Associate Registration Help Desk by email at 
<ctepreghelp@ctep.nci.nih.gov>. 
 
8.1.1 Investigator Registration Requirements  
 
Prior to the recruitment of a patient for this study, investigators must be registered 
members of a Lead Protocol Organization.  Food and Drug Administration (FDA) 
regulations and National Cancer Institute (NCI) policy require all investigators 
participating in any NCI-sponsored clinical trial to register and to renew their 
registration annually. Registration requires the submission of: 
 a completed Statement of Investigator Form (FDA Form 1572) with an original signature; 
 a current Curriculum Vitae (CV); 
 a completed and signed Supplemental Investigator Data Form (IDF); 
 a completed Financial Disclosure Form (FDF) with an original signature. 
 
 Fillable PDF forms and additional information can be found on the CTEP website at 
<http://ctep.cancer.gov/investigatorResources/investigator_registration.htm>.  For questions, 
please contact the CTEP Investigator Registration Help Desk by email at 
<pmbregpend@ctep.nci.nih.gov>. 


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8.1.2 Requirements for NRG-GY008 Site Registration (01/09/2017) (05/01/2017) 
Before patient enrollment, submit the following documents to the NRG Oncology Regulatory 
Department (See Section 8.1.2.2): 
• 
CTSU Transmittal Sheet (optional) 
• 
IRB approval letter (For sites not participating via the NCI CIRB; local IRB 
documentation, an IRB-signed CTSU IRB Certification Form, Protocol of Human Subjects 
Assurance Identification/IRB Certification/Declaration of Exemption Form, or a 
combination is accepted) 
• 
IRB-approved informed consent 
• 
IRB Membership list or IRB assurance number 
• 
FDA Form 1572 for institution PI (study-specific) 
• 
Current CV (signed and dated within 2 years) for institution PI and all sub-investigators 
listed on FDA Form 1572 
• 
Medical License for institution PI and sub-investigators listed on FDA Form 1572 
• 
Lab license, certificates, and Normal Lab Values (NLV) for labs listed on FDA Form 1572 
• 
Signed Investigator Signature Page  
• 
Signed Financial Disclosure Form for all investigators listed on FDA Form 1572 
• 
Pharmacy Information Form 
 
Screening Lab Kits (01/09/2017) 
Initial lab kit supplies must be ordered and all essential documents must be approved before a 
site can be activated to screen the first patient.   NRG Oncology will order the initial kit supply 
based on information provided on the online GY008 Lab Kit Registration Form. The delivery 
of kits can take at least 3 weeks after the initial kit order is placed.  After receipt of the initial 
kit supply, sites will be responsible for ordering all other biospecimen kits through the Q2 
Solutions Infosario™ website. Q2 Solutions will email the site designee with information about 
accessing the Q2 Solutions Infosario™ website.  
 
The NRG Oncology Regulatory Department Administrative Office will receive, review, and 
approve all regulatory documents. Please allow 7-10 days for review and approval of all 
documents prior to screening first patient. 
 
8.1.2.1 IRB Approval (01/09/2017) 
Each investigator or group of investigators at a clinical site must obtain IRB approval for this 
protocol and submit IRB approval and supporting documentation to the CTSU Regulatory 
Office before they can be approved to enroll patients.  Assignment of site registration status in 
the CTSU Regulatory Support system (RSS) uses extensive data to make a determination of 
whether a site has fulfilled all regulatory criteria including but not limited to: an active Federal 
Wide Assurance (FWA) number, an active roster affiliation with the Lead Network or a 
participating organization, a valid IRB approval, and compliance with all protocol specific 
requirements. 
 
Sites participating on the NCI CIRB initiative that are approved by the CIRB for this study are 
not required to submit separate IRB approval documentation to the CTSU Regulatory 
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applied to the RSS in an automated process.  Signatory Institutions must submit a Study 
Specific Worksheet for Local Context (SSW) to the CIRB via IRB Manager to indicate their 
intent to open the study locally.  The CIRB’s approval of the SSW is then communicated to the 
CTSU Regulatory Office.  In order for the SSW approval to be processed, the Signatory 
Institution must inform the CTSU which CIRB-approved institutions aligned with the 
Signatory Institution are participating in the study. (05/01/2017) 
 
8.1.2.2 Submitting Regulatory Documents:  
 
The required regulatory documents can be submitted electronically or via mail to the NRG 
Oncology Regulatory Department.   
 
NRG Oncology Regulatory Department 
ATTN: NRG-GY008 
1600 JFK Blvd., Suite 1020 
Philadelphia, PA 19103 
E-mail: NRG-GY-Regulatory@nrgoncology.org   
 
8.1.2.3 Checking Your Site’s Registration Status: (01/09/2017) 
You can verify your site registration status on the members’ section of the CTSU website. 
 Go to https://www.ctsu.org and log in to the members’ area using your CTEP-IAM 
username and password 
 Click on the Regulatory tab at the top of your screen 
 Click on the Site Registration tab 
 Enter your 5-character CTEP Institution Code and click on Go 
 
Note:  The status given only reflects compliance with IRB documentation and institutional 
compliance with protocol-specific requirements as outlined by the Lead Network.  It does not 
reflect compliance with protocol requirements for individuals participating on the protocol or 
the enrolling investigator’s status with the NCI or their affiliated networks. 
8.2 
Pre-registration Requirements 
 
8.2.1 Screening for PI3KCA Mutation Status (01/09/2017) 
Results of the Roche COBAS® PIK3CA Mutation Test (Q2 Solutions) are required at the time 
of step two of patient enrollment. 
 
Patient enrollment will be a two-step process in OPEN (See section 8.3.1). After the patient has 
signed the screening consent, step zero will initiate the patient in the enrollment process and 
assign a patient ID. Patients will have a representative primary or metastatic tumor sample 
screened for the PIK3CA mutation. Once the results of the PIK3CA mutation testing are 
provided to the site by Q2 Solutions and the patient is known to meet the PIK3CA eligibility 
criterion, the report is uploaded to the NRG website to undergo internal review. Once the 
PIK3CA mutation is confirmed internally, step 1 of the process is completed. Step 1 further 
assesses all eligibility criteria. Please see the “NRG-GY008 Prescreening Instructions” 
document for additional information. 
 


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(See sections 3.2.2, 4.1.1, 8.2.1, and 10.2 for details.) 
 
8.3 
Patient Enrollment 
Patient registration can occur only after evaluation for eligibility is complete, eligibility criteria 
have been met, and the study site is listed as ‘approved’ in the CTSU RSS.  Patients must have 
signed and dated all applicable consents and authorization forms.   
 
8.3.1 Oncology Patient Enrollment Network (OPEN) 
Patient enrollment will be facilitated using the Oncology Patient Enrollment Network (OPEN). 
OPEN is a web-based registration system available on a 24/7 basis. To access OPEN, the site 
user must have an active CTEP-IAM account (check at < https://eapps-
ctep.nci.nih.gov/iam/index.jsp >) and a 'Registrar' role on either the LPO or participating 
organization roster. 
 
All site staff will use OPEN to enroll patients to this study. It is integrated with the CTSU 
Enterprise System for regulatory and roster data and, upon enrollment, initializes the patient 
position in the Rave database. OPEN can be accessed at https://open.ctsu.org or from the 
OPEN tab on the CTSU members’ web site https://www.ctsu.org. 
 
Prior to accessing OPEN site staff should verify the following: 
 All eligibility criteria have been met within the protocol stated timeframes. 
 All patients have signed an appropriate consent form and HIPAA authorization form (if 
applicable).  
 Confirmation of PI3CKA mutation (See sections 3.2.2, 5.6, and 10.2 for details.) 
Note:  The OPEN system will provide the site with a printable confirmation of registration and 
treatment information.   Please print this confirmation for your records. 
 
Further instructional information is provided on the OPEN tab of the CTSU members’ side 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. 
 
 
In the event that the OPEN system is not accessible, participating sites can contact NRG web 
support for assistance with web registration: support@nrgoncology.org or call the NRG 
Registration Desk at 1-800-523-2917, Monday through Friday, 8:30 a.m. to 5:00 p.m. ET. The 
registrar will ask the site to fax in the eligibility checklist and will need the registering 
individual’s e-mail address and/or return fax number. This information is required to assure 
that mechanisms usually triggered by the OPEN web registration system (e.g. drug shipment 
and confirmation of registration) will occur.  
 
9. 
DRUG AND DEVICE INFORMATION  
 
9.1 
Investigational Study Agent 
 
Copanlisib (BAY 80-6946), NSC #784727, IND # 130822, IND Sponsor: NRG Oncology 
(01/09/2017) 
 
 


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9.1.1 Comprehensive Adverse Events and Potential Risks list (CAEPR) for 
Copanlisib dihydrochloride (BAY 80-6946 dihydrochloride, NSC 784727) 
(01/09/2017) (04/10/2017) 
 
The Comprehensive Adverse Events and Potential Risks list (CAEPR) provides a single list of reported and/or 
potential adverse events (AE) associated with an agent using a uniform presentation of events by body system. In 
addition to the comprehensive list, a subset, the Specific Protocol Exceptions to Expedited Reporting (SPEER), 
appears in a separate column and is identified with bold and italicized text. This subset of AEs (SPEER) is a list of 
events that are protocol specific exceptions to expedited reporting to NCI (except as noted below).  Refer to the 
'CTEP, NCI Guidelines: Adverse Event Reporting Requirements' 
http://ctep.cancer.gov/protocolDevelopment/electronic_applications/docs/aeguidelines.pdf for further clarification. 
Frequency is provided based on 425 patients. Below is the CAEPR for Copanlisib dihydrochloride (BAY 80-6946 
dihydrochloride).  
NOTE: Report AEs on the SPEER ONLY IF they exceed the grade noted in parentheses next to the AE in the 
SPEER.  If this CAEPR is part of a combination protocol using multiple investigational agents and has an AE listed on 
different SPEERs, use the lower of the grades to determine if expedited reporting is required. 
 
Version 2.1, January 21, 20171 
 
 Adverse Events with Possible  
 Relationship to Copanlisib dihydrochloride (BAY 80-6946 dihydrochloride) 
 (CTCAE 4.0 Term) 
[n= 425] 
 
 
 Specific Protocol Exceptions 
to Expedited Reporting 
(SPEER)  
 
Likely (>20%) 
Less Likely (<=20%) 
Rare but Serious (<3%) 
 
BLOOD AND LYMPHATIC SYSTEM DISORDERS 
  
 
Anemia 
 
 Anemia (Gr 2) 
 
 
Febrile neutropenia 
  
GASTROINTESTINAL DISORDERS 
  
Diarrhea 
  
 
 Diarrhea (Gr 2) 
 
Dry mouth 
 
  
 
Mucositis oral 
 
  
Nausea 
 
 
 Nausea (Gr 2) 
 
 
Pancreatitis 
  
 
Vomiting 
 
 Vomiting (Gr 2) 
GENERAL DISORDERS AND ADMINISTRATION SITE CONDITIONS 
  
Fatigue 
 
 
 Fatigue (Gr 2) 
INFECTIONS AND INFESTATIONS 
  
Infection2 
 
 
 Infection2 (Gr 2) 
INVESTIGATIONS 
  
 
Neutrophil count decreased 
 
 Neutrophil count decreased (Gr 2) 
 
Platelet count decreased 
 
 Platelet count decreased  
(Gr 2) 
 
White blood cell decreased 
 
  
METABOLISM AND NUTRITION DISORDERS 
  
 
Anorexia 
 
 Anorexia (Gr 2) 
Hyperglycemia 
 
 
 Hyperglycemia (Gr 2) 
MUSCULOSKELETAL AND CONNECTIVE TISSUE DISORDERS 
  
 
Musculoskeletal and connective 
tissue disorder - Other (muscle 
spasms) 
 
 Musculoskeletal and connective 
tissue disorder -  Other (muscle 
spasms) (Gr 2) 
NERVOUS SYSTEM DISORDERS 
  
 
Dysgeusia 
 
  
 
Paresthesia 
 
  


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 Adverse Events with Possible  
 Relationship to Copanlisib dihydrochloride (BAY 80-6946 dihydrochloride) 
 (CTCAE 4.0 Term) 
[n= 425] 
 
 
 Specific Protocol Exceptions 
to Expedited Reporting 
(SPEER)  
 
Likely (>20%) 
Less Likely (<=20%) 
Rare but Serious (<3%) 
 
RESPIRATORY, THORACIC AND MEDIASTINAL DISORDERS 
  
 
Pneumonitis3 
 
  
SKIN AND SUBCUTANEOUS TISSUE DISORDERS 
  
 
Rash maculo-papular 
 
 Rash maculo-papular (Gr 2) 
VASCULAR DISORDERS 
  
Hypertension 
 
 
 Hypertension (Gr 2) 
 
1This table will be updated as the toxicity profile of the agent is revised.  Updates will be distributed to all Principal 
Investigators at the time of revision.  The current version can be obtained by contacting PIO@CTEP.NCI.NIH.GOV.  Your 
name, the name of the investigator, the protocol and the agent should be included in the e-mail. 
 
2Infection includes all 75 sites of infection under the INFECTIONS AND INFESTATIONS SOC. 
 
3Pneumonitis is a group term that includes interstitial lung disease, dyspnea, dyspnea at rest, and dyspnea exertional. 
 
Adverse events reported on copanlisib dihydrochloride (BAY 80-6946 dihydrochloride) trials, but for which there is 
insufficient evidence to suggest that there was a reasonable possibility that copanlisib dihydrochloride (BAY 80-
6946 dihydrochloride) caused the adverse event: 
 
BLOOD AND LYMPHATIC SYSTEM DISORDERS - Blood and lymphatic system disorders - Other (eosinophilia, 
including eosinophil count decreased) 
CARDIAC DISORDERS - Atrial fibrillation; Cardiac arrest; Left ventricular systolic dysfunction; Myocardial infarction; 
Sinus tachycardia 
GASTROINTESTINAL DISORDERS - Abdominal pain; Colitis; Dyspepsia; Esophagitis; Flatulence; Gastritis; 
Gastroesophageal reflux disease; Oral dysesthesia; Oral pain; Upper gastrointestinal hemorrhage 
GENERAL DISORDERS AND ADMINISTRATION SITE CONDITIONS - Chills; Fever; General disorders and 
administration site conditions - Other (failure to thrive); Infusion related reaction; Non-cardiac chest pain 
IMMUNE SYSTEM DISORDERS - Allergic reaction; Autoimmune disorder 
INVESTIGATIONS - Activated partial thromboplastin time prolonged; Alanine aminotransferase increased; Alkaline 
phosphatase increased; Aspartate aminotransferase increased; Blood bilirubin increased; CPK increased; Ejection fraction 
decreased; Investigations - Other (blood insulin increased); Investigations - Other (electrocardiogram T wave abnormal); 
Lipase increased; Lymphocyte count decreased; Serum amylase increased 
METABOLISM AND NUTRITION DISORDERS - Dehydration; Hypertriglyceridemia; Hyperuricemia; 
Hypocalcemia; Hypokalemia; Hypomagnesemia; Hyponatremia; Hypophosphatemia 
MUSCULOSKELETAL AND CONNECTIVE TISSUE DISORDERS - Arthralgia; Musculoskeletal and connective 
tissue disorder - Other (psoriatic arthropathy); Myalgia 
NEOPLASMS BENIGN, MALIGNANT AND UNSPECIFIED (INCL CYSTS AND POLYPS) - Neoplasms benign, 
malignant and unspecified (incl cysts and polyps) - Other (tumor hemorrhage) 
NERVOUS SYSTEM DISORDERS - Dizziness; Headache; Peripheral sensory neuropathy; Presyncope; Reversible 
posterior leukoencephalopathy syndrome 
RENAL AND URINARY DISORDERS - Acute kidney injury 
RESPIRATORY, THORACIC AND MEDIASTINAL DISORDERS - Cough; Dyspnea3; Hypoxia; Pleural effusion; 
Pulmonary hypertension; Respiratory failure; Respiratory, thoracic and mediastinal disorders - Other (pulmonary 
congestion) 
SKIN AND SUBCUTANEOUS TISSUE DISORDERS - Alopecia; Dry skin; Pruritus; Rash acneiform; Stevens-Johnson 
syndrome 
VASCULAR DISORDERS - Vascular disorders - Other (circulatory collapse) 
 
 


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Note: Copanlisib dihydrochloride (BAY 80-6946 dihydrochloride) in combination with other agents could cause an 
exacerbation of any adverse event currently known to be caused by the other agent, or the combination may result in events 
never previously associated with either agent. 
 
9.1.2 Investigator Brochure 
To supplement the toxicity information contained in this document, investigators must obtain 
the current version of the investigator brochure (IB) for comprehensive pharmacologic and 
safety information.  
 
The IB can be requested by sending a request to NRG-GY-Regulatory@nrgoncology.org.  In 
the subject line, please state, “NRG-GY008 IB Request”.  The following information must be 
stated in the request: 
 
Institution Name 
CTEP Institution Code 
Principal Investigator 
 
9.1.3 Availability/Supply (01/09/2017) 
 
 
The following excipients are used to manufacture the medicinal product: mannitol, NaOH, and 
citric acid, and water for injection. The medicinal product is a freeze-dried product containing 
60 mg of copanlisib (equivalent to 69.12 mg BAY 84-1236) in a 6 mL injection vial. 
 
Copanlisib is supplied as a lyophilized preparation in a 6-mL injection vial.  After 
reconstitution with 4.4 mL of sodium chloride, the drug substance concentration amounts to 15 
mg/mL Copanlisib.  The labeled amount per vial is 60 mg Copanlisib, the nominal content due 
to the technically required overfill is 68.4 mg Copanlisib per vial.   
 
Copanlisib will be supplied by Bayer and distributed by Biologics, Inc. 
 
9.1.4 Reconstitution:  
 
Reconstitution medium for the lyophilisate: 
0.9% sodium chloride solution for injection 
(4.4 mL) 
 
Dilution medium for the reconstituted product: 0.9% sodium chloride solution for injection 
(100 mL) 
 
Colorless infusion bags (translucent), empty or filled with 100 mL 0.9% NaCl solution, made 
of polyethylene (PE), polypropylene (PP), or ethylene vinyl acetate (EVA) 
 
Colorless infusion tubes (translucent), made of polyethylene (PE), polypropylene (PP) or 
polyvinylchloride (PVC) (DEHP-free) or polyurethane (PU) 
 
9.1.5 Handling: For the handling of the study medication the following principles have to be 
followed: 


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 Use of sterile disposable gloves and hand hygiene as recommended for current 
clinical practice. 
 Disinfection of the septum of the injection stoppers using a swab with an 
appropriate disinfectant (e.g. based on ethanol or isopropanol) [applies to vials of 
Copanlisib and sodium chloride solution]. 
 To ensure product sterility the vial stopper must not be removed during handling. 
 
9.1.6 Dosage Preparation: These instructions are for the preparation of doses 30, 45, and 60 mg 
Copanlisib in 100 mL 0.9% NaCl bags. If starting with an empty bag, inject 100 mL of 0.9% 
NaCl into the bag to ensure a volume of not less than 100 mL. 
 
For reconstitution add 4.4 mL of sterile isotonic sodium chloride solution to the lyophilized 
mass of  one vial, leading to solutions with a drug substance concentration of 15 mg/mL. The 
appropriate volume of the reconstituted solution corresponding to the intended dose (see table 
below) is then withdrawn from the vial and diluted to the administration volume of 100 mL 
using physiological saline solution. 
 
Process 
 
Withdraw 4.4 mL of sterile isotonic chloride solution as reconstitution media by using a 
5 mL sterile syringe 
(Note: the dosing of the reconstituted lyophilisate may alternatively be performed by 
gravimetric means, provided the density of the reconstituted solution is taken into account: 
D20 4= 1.0222 g/mL) 
 
Inject the measured volume through the stopper into the 6 mL injection vials using a 
needle 
 
Shake the injection vial vigorously for 30 seconds, and then allow standing for 1 minute 
to let the bubbles rise to the surface 
 
Check if any undissolved substance is still seen. If yes, repeat the shaking and settling 
procedure. The reconstituted lyophilisate may only be diluted or withdrawn after the 
solution is clear 
 
Withdraw the required amount of the reconstituted lyophilisate with an unused sterile 
syringe: 
 
 
Copanlisib dose [mg] 
 
 
30  
45  
60 
___________________________________________________________ 
Volume of reconstituted Copanlisib   
2 
 3  
4 
solution to be withdrawn from the vial (ml) 
________________________________________________________________________ 
 
Connect the syringe to the 100 mL sodium chloride bag and transfer the required 
amount of the reconstituted lyophilisate into the bag 
 
Mix the dose well 
 
After administration the line is to be flushed to ensure patient gets the complete dose 
 
First Aid Measure in Case of Accidental Skin Contact 
Remove all contaminated clothes and shoes and wash off immediately with soap and plenty of 


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Water. 
 
9.1.7 Storage and Shelf Life:  The drug product has to be stored between +2ºC and +8ºC and should 
not be transported above +30ºC. 
Stability of the diluted solution 
The diluted solution is physically and chemically stable for 24 hours at room temperature. 
However, for microbiologic consideration, diluted solution should be stored between +2ºC and 
+8ºC if not administered immediately. 
 
9.1.8 Drug Interactions Encountered in Clinical Trials: Preliminary analysis of Study 16270 showed 
that the ACU of copanlisib was increased by 1.53% when copanlisib was coadministered with 
itraconazole (a strong CYP3A4 inhibitor). 
 
9.1.9 Agent Ordering and Agent Accountability 
 
9.1.9.1 Drug Distribution: Following submission and approval of all required regulatory documents, 
the Pharmacy Information Form will be forwarded to Biologics notifying them that an 
institution has been approved to receive drug/supplies. 
 
All study drug will be shipped with a protocol-specific label adhered to the outside of the 
packaging.  Each protocol-specific label includes the following information: 
 
 The Study Number (NRG-GY008) 
 Drug Identification 
 Lot # and Expiration Date 
 Dosing instructions (Administer as directed per Protocol NRG-GY008) 
 Storage instructions (Store at 2-8°C)  
 Emergency contact instructions 
 IND caution statement and/or local regulatory statements 
 
All drug orders are shipped via FedEx Priority Overnight delivery for shipments to US sites. 
Study Drug is shipped in a Biologics branded package with appropriate materials to maintain 
temperature stability.   
 
Institution Instruction upon Receipt of Study Drug: The designated site coordinator validates 
contents of package matches information provided on packing slip, signs off on the packing 
slip, and faxes completed form to Biologics at 919-256-0794 to validate shipment has been 
received and is accurate. 
 
9.1.9.2 Initial Supply: Sites are permitted to request study drug for up to 5 patients for 1 cycle of 
treatment per order (total of 15 vials).  To request drug, sites will need to submit a “Drug Order 
Request Form” to Biologics at 919-256-0794 or CRSorders@biologicsinc.com. (05/01/2017) 
 
9.1.9.3 Subsequent Supply: If additional drug is needed, sites will need to submit a “Drug Order 
Request Form” to Biologics at 919-256-0794 or CRSorders@biologicsinc.com. (05/01/2017) 
 


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9.1.9.4 Drug Accountability:  All study drug must be accounted for during the course of this study.  
Site must maintain an NCI Drug Accountability Record Form (DARF).  
 
9.1.9.5 Drug Destruction: At the conclusion of the study, remaining inventory is documented on the 
DARF and unused drug is to be destroyed as per institution policy and recorded on the DARF.  
The final DARF must be forwarded to the NRG Oncology Regulatory Department via email to 
NRG-GY-Regulatory@nrgoncology.org. 
  
9.2 
Glucometers, Lancets and Glucometer Test Strips (05/01/2017) 
 
Glucometers, lancets and glucometer test strips will be supplied and distributed by Biologics.  
Glucometers will be supplied in 1-ct boxes, lancets will be supplied in 100-ct boxes and 
glucometer test strips will be supplied in 25-ct boxes.  
 
9.2.1  Glucometer and Glucometer Test Strip Distribution: Following submission and approval of all 
required regulatory documents, the Pharmacy Information Form will be forwarded to Biologics 
notifying them that an institution has been approved to receive glucometers, lancets and 
glucometer test strips. 
 
The glucometers, lancets and glucometer test strips will be shipped with a protocol-
specific label adhered to the outside of the packaging.  Each protocol-specific label 
includes the following information: (05/01/2017) 
 
 The Study Number (NRG-GY008) 
 Device Identification 
 Lot # and Expiration Date 
 Device Instructions  
 Storage instructions (Store at 15-30°C)  
 Emergency contact instructions 
 IND caution statement and/or local regulatory statements 
 
All orders are shipped via FedEx Priority Overnight delivery for shipments to US sites and is 
shipped in a Biologics branded package with appropriate materials to maintain temperature 
stability.   
 
Institution Instruction upon Receipt of Study Supplies: The designated site coordinator 
validates contents of package matches information provided on packing slip, signs off on the 
packing slip, and faxes completed form to Biologics at 919-256-0794 to validate shipment has 
been received and is accurate. 
 
9.2.1.1 Initial Supply:  One glucometer will be supplied to each patient enrolled. Biologics will ship up 
to 5 boxes of lancets, 5 glucometers, and 5 boxes of test strips per order (for up to 5 patients). 
Study supplies will be shipped in the original manufacturer’s packaging. To request, sites will 
need to submit a “Drug Order Request Form” to Biologics at 919-256-0794 or 
CRSorders@biologicsinc.com. (05/01/2017) 
. 
 


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9.2.1.2 Subsequent Supply:  If additional glucometer test strips are needed, sites will need to submit a 
“Drug Order Request Form” to Biologics at 919-256-0794 or CRSorders@biologicsinc.com. 
(05/01/2017) 
 
9.2.1.3 Device Disposition:  Sites are to follow institutional standard operations procedures for 
recycling or destroying the device. 
 
10. 
PATHOLOGY/BIOSPECIMEN    
 
10.1 
Central Pathology Review Guidelines   
Stained pathology slides from the primary diagnosis are required for retrospective  review by 
the NRG Pathology Committee to confirm eligibility for the protocol.  At least one 
representative H&E stained slide (or slides) demonstrating primary site, histologic cell type, 
and grade, and one H&E stained slide showing the most advanced stage of disease will be 
required.  If the most advanced stage of disease is not documented by histology, the method of 
stage documentation needs to be stated (e.g. CT, MRI, etc.).  Slides from recurrence and/or 
persistent disease will be required only if recurrence/persistent disease is confirmed by 
histology or cytology.  
 
When submitting pathology material to the NRG Statistics and Data Management Center-
Buffalo Office individual slides must be labeled with NRG Patient ID, patient initials and the 
surgical / pathology accession number (e.g., S08-2355) and block identifier (e.g., A6).  Do not 
label the slides with disease site (e.g., right ovary) or procedure date.  Pack the labeled slides 
into plastic slide cassette(s).  Tape plastic slide cassettes shut and wrap in bubble wrap or 
another type of padded material prior to shipping.  Please include the NRG Patient ID, patient 
initials, and protocol number on all pages of the pathology report and black out the patient’s 
name.  Ship pathology slides, and the official pathology report in your own shipping container 
using postal mail at your own expense directly to the Pathology Materials Coordinator at 
the NRG Statistics and Data Management Center-Buffalo Office, Roswell Park Cancer 
Institute, Research Studies Center, Carlton and Elm Streets, Buffalo, New York, 14263; 
phone 716-845-5702.  
 
Retrospective Review  
Patients must have recurrent or persistent endometrial cancer (endometrioid, serous, 
undifferentiated,  mixed, and adenocarcinoma not otherwise specified [NOS] histologies are 
eligible).  Patients with mucinous, squamous, or clear cell histologies, carcinosarcoma, or 
sarcoma are ineligible.  Pathology slides will be reviewed retrospectively, semiannually by the 
NRG Pathology Committee, per the standard NRG Pathology Committee Central Review 
schedule. 
 
10.2 
Tissue Selection for Integral Marker Testing (01/09/2017) 
Six unstained sections (charged, 5μm) of formalin-fixed, paraffin-embedded (FFPE) primary or 
metatstatic tumor is required for the COBAS® PIK3CA Mutation Test at Q2 Solutions. 
Sections must contain at least 30% tumor. Tumor must be obtained by surgery or biopsy only 
(i.e., bone metastases, FNA, and cell blocks are not acceptable). 
 


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Note: Testing kits are typically received 7-10 business days after request. Typical testing 
turnaround time is five business days upon receipt of the sample. 
 
(See sections 3.2.2, 4.1.1, 5.6, 8.1.2 and 8.2.1 for details.) 
 
10.3 
Tissue Selection for Integrated Marker Testing 
FFPE primary or metatstatic tumor will be banked for retrospectively testing to evaluate PTEN 
status in all patients. 
 
Note: Testing of banked biospecimens will not occur until an amendment to this treatment 
protocol (or separate correlative science protocol) is reviewed and approved in accordance 
with National Clinical Trials Network (NCTN) policies. 
 
10.4 
Biospecimen Submission Tables 
 
A detailed description of biospecimen procedures can be found in Appendix VII.  
 
10.4.1 Mandatory Biospecimen Submissions (01/09/2017) 
The patient must give permission to participate in this mandatory study component. 
Participating sites are required to submit the patient’s biospecimens as outlined below. 
Required Biospecimen (Biospecimen Code) 
Collection Time Point 
Sites Ship Biospecimens To 
FFPE Primary Tumor (FP01)* 
1st Choice: block 
2nd Choice: 15 unstained slides (10 charged, 
5µm & 5 uncharged, 10µm) 
Prior to all treatment 
NRG Oncology 
Biospecimen Bank-
Columbus within 8 weeks of 
registration1 
FFPE Metastatic Tumor (FM01)* 
1st Choice: block 
2nd Choice: 15 unstained slides (10 charged, 
5µm & 5 uncharged, 10µm) 
Prior to all treatment (Optional 
if FP01 is submitted) 
* A copy of the corresponding pathology report must be shipped with all tissue biospecimens sent to the NRG BB-
Columbus 
1 NRG BB-Columbus / Protocol NRG-GY008, Nationwide Children’s Hospital, 700 Children’s Drive, WA1340, 
Columbus, OH 43205, Phone: (614) 722-2865, FAX: (614) 722-2897, Email: BPCBank@nationwidechildrens.org 
 
10.4.2 Optional Biospecimen Submissions 
Not applicable. 
 
10.5 
Laboratory Testing 
 
10.5.1 PTEN Mutation Testing (Integrated Biomarker) 
 
Note: Testing of banked biospecimens will not occur until an amendment to this treatment 
protocol (or separate correlative science protocol) is reviewed and approved in accordance 
with National Clinical Trials Network (NCTN) policies. 
 
Pending subsequent review and approval of assay details in accordance with NCTN policies, 
formalin-fixed, paraffin-embedded (FFPE) tissue specimens will be retrospectively tested to 
evaluate PTEN status in all patients. 
 


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11. 
SPECIAL STUDIES (NON-TISSUE) 
 
 
Not Applicable. 
 
12. 
MODALITY REVIEWS 
Not Applicable. 
 
13. 
ASSESSMENT OF EFFECT 
 
13.1 
Antitumor Effect – Solid Tumors  
Response and progression will be evaluated in this study using the 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 (uni-dimensional 
measurement) of the tumor lesions and the shortest diameter in the case of malignant lymph 
nodes are used in the RECIST criteria.  
  
13.1.1  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 ≥10 mm with CT scan, as ≥20 mm 
by chest x-ray, or ≥10 mm with calipers by clinical exam. All tumor measurements must be 
recorded in decimal fractions of centimeters. 
  
Note: Tumor lesions that are situated in a previously irradiated area will not be considered 
measurable unless progression is documented or a biopsy is obtained to confirm persistence at 
least 90 days following completion of radiation therapy. 
  
Malignant lymph nodes: To be considered pathologically enlarged and measurable, a lymph 
node must be ≥15 mm in short axis when assessed by CT scan (CT scan slice thickness 
recommended to be no greater than 5 mm). 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 or pathological lymph nodes with ≥ 10 to <15 mm short axis), are 
considered non-measurable disease. Leptomeningeal disease, ascites, pleural/pericardial 
effusions, lymphangitis cutis/pneumonitis, inflammatory breast disease, and abdominal/pelvic 
masses (identified by physical exam and not CT or MRI), are considered as non-measurable.  
 
Notes:  
Bone lesions: Lytic bone lesions or mixed lytic-blastic lesions, with identifiable soft tissue 
components, that can be evaluated by CT or MRI can be considered as measurable lesions if 
the soft tissue component meets the definition of measurability described above. Blastic bone 
lesions are non-measurable. 
 
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. 


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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, and 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. 
  
13.1.2  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. 
  
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 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 or less. If CT scans have slice 
thickness greater than 5 mm, 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), but NOT 
lung. 
  
Use of MRI remains a complex issue. MRI has excellent contrast, spatial, and temporal 


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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, subsequent image 
acquisitions should use the same type of scanner and follow the baseline imaging protocol as 
closely as possible. If possible, body scans should be performed with breath-hold scanning 
techniques. 
 
NRG will not allow PET-CT use for RECIST 1.1 response criteria.  
 
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. 
 
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. 
 
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. 
 
It is mandatory to obtain cytological confirmation of the neoplastic origin of any effusion that 
appears or worsens during treatment when measurable disease has met criteria for response or 
stable disease. This confirmation is necessary to differentiate response or stable disease versus 
progressive disease, as an effusion may be a side effect of the treatment. 
 
13.2  Response Criteria  
Determination of response should take into consideration all target (See 13.2.1) and non-target 
lesions (See 13.2.2). 
 
13.2.1 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. 
  
Partial Response (PR): At least a 30% decrease in the sum of the diameters of target lesions, 
taking as reference the baseline sum diameters. 


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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. (Note: the appearance of one or more new lesions is also 
considered progression). 
 
Stable Disease (SD): Neither sufficient shrinkage to qualify for PR nor sufficient increase to 
qualify for PD, taking as reference the smallest sum diameters (i.e. the nadir) while on study.  
 
13.2.2  Evaluation of Non-Target Lesions  
Complete Response (CR): Disappearance of all non-target lesions. All lymph nodes must be 
non-pathological in size (<10 mm short axis). 
  
Non-CR/Non-PD: Persistence of one or more non-target lesion(s) 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. 
  
Not evaluable (NE): When at least one non-target lesion is not evaluated at a particular time 
point. 
  
Although a clear progression of only “non-target” lesions 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). 
 
13.2.3 Evaluation of Best Overall (unconfirmed) Response  
 
The best overall response is the best time point response recorded from the start of the 
treatment until disease progression/recurrence (taking as reference for progressive disease the 
smallest sum recorded since baseline). The patient's best response assignment will depend on 
the achievement of both measurement and confirmation criteria in some circumstances. 
 
Time Point Response for Patients with Measurable Disease at baseline (i.e., Target 
Disease) 
 
Target 
Lesions 
Non-Target 
Lesions 
 
New 
Lesions* 
Time Point 
Response 
CR 
CR 
 
No 
CR 
CR 
Non-CR/Non-PD 
 
No 
PR 
CR 
NE 
 
No 
PR 
PR 
Non-PD or NE 
 
No 
PR 
SD 
Non-PD or NE 
 
No 
SD 
NE 
Non-PD 
 
No 
NE 
PD 
Any 
 
Yes or No 
PD 
Any 
PD** 
 
Yes or No 
PD 
Any 
Any 
 
Yes 
PD 


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*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. 
 
Time Point Response for Patients with only Non-Measurable Disease at baseline (i.e., 
Non-Target Disease) 
 
 
 
*See RECIST 1.1 manuscript for further details on what is evidence of a new 
lesion 
 
** ‘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 
 
13.2.4 Best Overall Confirmed Response  
 
Confirmation of CR and PR for determination of best overall response is required for 
studies with a primary endpoint that includes response.  
 
Confirmed CR and PR for best overall confirmed response 
 
Time Point 
Response 
First time point 
Time Point Response
Subsequent time 
point 
BEST overall 
confirmed 
response 
CR 
CR 
C
CR 
PR 
SD, PD or PR* 
CR 
SD 
SD provided minimum 
criteria for SD 
duration met, 
otherwise, PD 
CR 
PD 
SD provided minimum 
criteria for SD 
duration met, 
otherwise, PD 
Non-Target Lesions 
 
New Lesions* 
Time Point 
Response 
CR 
 
No 
CR 
CR 
 
No 
Non-CR/non-PD* 
Non-CR/non-PD 
 
No 
Non-CR/non-PD* 
NE 
 
No 
NE 
Unequivocal PD 
 
Yes or No 
PD 
Any 
 
Yes 
PD 


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CR 
NE 
SD provided minimum 
criteria for SD 
duration met, 
otherwise, NE 
PR 
CR 
P
PR 
PR 
P
PR 
SD 
S
PR 
PD 
SD provided minimum 
criteria for SD 
duration met, 
otherwise, PD 
PR 
NE 
SD provided minimum 
criteria for SD 
duration met, 
otherwise, NE 
NE 
NE 
NE 
 
 
*If a CR is truly met at first time point, then any disease seen at a subsequent time point, even 
disease meeting PR criteria relative to baseline, makes the disease PD at that point (since 
disease must have reappeared after CR).  However, sometimes ‘CR’ may be claimed when 
subsequent scans suggest small lesions were likely still present and in fact the patient had PR 
or SD, not CR at the first time point. Under these circumstances, the original CR should be 
changed to PR or SD and the best response is PR or SD. 
 
In non-randomized trials where response is part of the primary endpoint, confirmation of CR 
or PR is needed to deem either one the “best overall response.”   Responses (CR and PR) 
require confirmation at greater than or equal to 4 weeks from initial documentation. 
 
For this study, the minimum criteria for SD duration is 8 weeks. 
 
Patients with a global deterioration of health status requiring discontinuation of treatment or die 
without objective evidence of disease progression at that time should be reported to be off 
study treatment due to “symptomatic deterioration.”  Every effort should be made to document 
the objective progression even after discontinuation of treatment. 
 
13.3 
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). 
 
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 
date of study entry, including the baseline measurements. 


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13.4 
Progression-Free Survival 
Progression-Free Survival (PFS) is defined as the duration of time from study entry to time of 
progression or death, whichever occurs first, or date of last contact if neither progression nor 
death has occurred. 
 
13.5 
Survival 
Survival is defined as the duration of time from study entry to time of death or the date of last 
contact. 
 
14. 
DATA AND RECORDS 
 
14.1 
Data Management/Collection 
Data collection for this study will be done exclusively through Medidata Rave®. Access to the 
trial in Rave is granted through the iMedidata application to all persons with the appropriate 
roles in RSS (Regulatory Support System). To access iMedidata/Rave, the site user must have 
an active CTEP-IAM account and the appropriate Rave role (Rave CRA, Read-Only, Site 
Investigator) on either the LPO or participating organization rosters at the enrolling site. 
 
Upon initial site registration approval for the study in RSS, all persons with Rave roles 
assigned on the appropriate roster will be sent a study invitation e-mail from iMedidata 
(iMedidata-Notification@mdsol.com) to activate their account. To accept the invitation, site 
users must log into the Select Login (https://login.imedidata.com/selectlogin) using their 
CTEP-IAM user name and password, and click on the “accept” link in the upper right-corner 
of the iMedidata page. Please note, site users 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 will be listed in the upper right pane of the iMedidata 
screen. 
  
Users that have not previously activated their iMedidata/Rave accounts also will receive a 
separate invitation from iMedidata to activate their account. Account activation instructions are 
located on the CTSU website, Rave tab under the Rave resource materials (Medidata Account 
Activation and Study Invitation Acceptance). Additional information on iMedidata/Rave is 
available on the CTSU website under the Rave tab at www.ctsu.org/RAVE/ or by contacting 
the CTSU Help Desk at 1-888-823-5923 or by e-mail at ctsucontact@westat.com. 
 
 
14.2 
Summary of Data Submission 
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. Adverse events are reported in a routine manner at 
scheduled times during the trial using Medidata Rave®. Additionally, certain adverse events 
must be reported in an expedited manner for timelier monitoring of patient safety and care. See 
Section 7 for information about expedited and routine reporting.   
Summary of Data Submission: Refer to the CTSU member website for the table of Required 
Forms and Materials.  
 


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14.3 
Global Reporting/Monitoring 
 
This study will be monitored by the Clinical Data Update System (CDUS) Version 3.0. 
Cumulative protocol- and patient-specific CDUS data will be submitted electronically to CTEP 
on a quarterly basis, either by FTP burst of data or via the CDS web application. Reports are 
due January 31, April 30, July 31, and October 31. Instructions for submitting data using the 
CDUS can be found on the CTEP Web site (http://ctep.cancer.gov/reporting/cdus.html). 
 
15. 
STATISTICAL CONSIDERATIONS 
 
15.1 
Study Design 
The overall objectives of this study are to assess the activity and toxicity of BAY 80-6946 in 
patients with persistent or recurrent endometrial carcinoma harboring PIK3CA hotspot 
mutations. This is a single arm, two-stage, phase II study and no randomization is involved 
however mutation screening is required.  With appropriate consent and authorization, patients 
will be registered to the screening component of this study.  For those who meet all eligibility 
criteria and have also given an informed consent for the treatment, patient registration to the 
treatment component will be accomplished in the usual fashion; facilitated by Oncology 
Patient Enrollment Network (OPEN).  There are no treatment comparisons involved. If 
sufficient activity is noted, the experimental agent may be considered for a future randomized 
study since a single-arm study will not be able to distinguish between treatment effect and the 
prognostic effects of the PI3K mutations.  With a screen pass rate of 30% and two stages of 
accrual, 84 patients are expected to be screened and 28 will be enrolled. 
 
15.2 
Study Endpoints 
To assess the primary objective, the frequency of objective response (complete or partial best 
overall confirmed response) defined by RECIST 1.1 criteria will be estimated in patients with 
persistent or recurrent endometrial carcinoma treated with BAY 80-6946.  Confirmation of 
complete and partial responses in tumor evaluations at least 4 weeks apart is required. All 
registered and eligible patients who received the agent under study will be included in the 
analysis of the primary objective.   
 
Estimates of the distributions of progression-free survival (PFS) and overall survival (OS) will 
be estimated using Kaplan-Meier product-limit methods among all eligible patients who 
received the drug under study.   
 
The safety profile of BAY 80-6946 in recurrent endometrial cancer patients will be assessed 
using the maximum grade of reported adverse events by term and SOC defined by CTCAE 
version 4.0.  All patients will be evaluable for toxicity from the time of their first treatment 
with BAY 80-6946 until disease progression or non-protocol therapy is initiated. 
 
15.3 
Primary Objectives Study Design 
 
15.3.1 Primary Hypothesis and Endpoints 
The null hypothesis can be stated as the proportion responding, p, is no more than 5% versus 
the alternative that the proportion responding is greater than 5%. 


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15.3.2 How Primary Endpoints Will Be Analyzed 
Our general philosophy regarding Phase II trials of new drugs is to facilitate the prompt 
discovery of inactive agents, yet allow for a reasonable estimate of the response rates for those 
regimens demonstrating some degree of activity. However, excessive accrual to inactive study 
regimens to document precise response rates is to be avoided. The purpose of this study is to 
evaluate the activity and potential toxicity of BAY 80-6946 in patients with persistent or 
recurrent endometrial carcinoma harboring PIK3CA mutations previously treated with 
chemotherapy. Our accrual goal is complicated by the administrative logistics of managing the 
complexity of multi-center trial. Strict adherence to an exact two-stage sampling design with 
appropriate early stopping rules cannot be practically accomplished due to fluctuating rates of 
accrual, follow-up requirements, institutional IRB complexities, and the possibility of cases 
being declared ineligible following central reviews. Nevertheless, monthly decisions regarding 
the continuance or cessation of accrual will be guided by the following design: 
 
A flexible, minimax 2-stage design chosen for this study to test the null hypothesis that p≤5% 
with power and sample size calculated under the alternative that p≥25% has an average 
expected sample size of 18.5 and a probability of early termination of 55%.21  These average 
probabilities are computed from the individual probabilities averaged over all permitted accrual 
combinations and assuming each combination is equally likely. Between 10 and 17 patients 
(target of 15) will be enrolled onto the treatment component in the first stage of accrual. If the 
number responding is less than or equal to 0/(10-16) or 1/17, then the study would terminate 
early and the regimen declared uninteresting.  Otherwise, with medical judgment indicating, 
the study will accrue to a second stage with a cumulative sample size between 21 and 28 
(target of 25).  If the number of patients responding is less than or equal to 2/(21-22) or 3/(23-
28), then the regimen will be declared uninteresting to warrant further investigation.  All 
enrolled patients with recurrent endometrial tumors that are shown to harbor eligible PIK3CA 
mutations and that initiate study treatment will be included in the analysis of objective 
response.  Exact 95% confidence limits, accounting for the interim analysis, will be provided in 
the final report.   
 
The patient’s best response will be evaluated within the first 6 months on study.  Patients alive 
with a best response of stable disease that is sustained at 6 months but without disease 
progression will be considered as non-responders for the purpose of the interim and final 
analyses of the primary endpoint.  An additional 6 weeks can be allowed for the purposes of 
confirming an objective response.  Additional data beyond 6  months for these patients can be 
described in the final study report. (05/01/2017)    
 
15.3.3 Sample Size and Power Calculations:  
A design was chosen to allow for flexibility in accrual.  The target sample size for the first 
stage is 15 but allowed to vary between 10 and 17.  The target sample size for the second stage 
of accrual is 25 but allowed to vary between 21 and 28.  This design, described above, has an 
average expected sample size of 18.5 and a probability of early termination of 55%.  
Additionally, the design described above has 90% statistical power under the alternative 
specified.  Type I error is set at 0.05 (one-sided hypothesis test).   
 


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15.4 
Study Monitoring of Primary Objectives 
See section 15.3.2.  
  
15.5 
Accrual/Study Duration Considerations 
Screening:  Genomic analysis was performed on primary endometrial tumors of patients on 
two legacy GOG studies; 86P22  and 248.23 These analyses included identification of any 
PIK3CA mutations.  The studies included patients with advanced or metastatic disease that 
were either chemotherapy naïve (86P, 248) or had a recurrence following adjuvant 
chemotherapy (248).  For these studies the percentage of sequenced tumors that were identified 
to have a PIK3CA mutation was 29% (16 of 55) in GOG-0248 and 40% (88 out of 219) in 86P.  
The distribution of mutation across histologic groups was similar between these two studies.  
The expected rate of tumors with eligible PIK3CA mutations is expected to be between 20% 
and 30% among all tumors screened.  It is expected that tumors from 4-5 patients will be 
screened each month.     
 
Possible screening rate 
for tumors with PIK3CA 
mutations 
Number screened for 
first stage of accrual 
(accrual duration) 
Total number screened if second 
stage of accrual is necessary 
(accrual duration) 
20% 
75 (18 months) 
125 (28 months + interruption*) 
30% 
50 (12 months) 
84 (19 months + interruption*) 
*Possible interruption for interim analysis 
 
Treatment trial accrual:  Based on past trial experience, the annual accrual is anticipated to be 
10-15 patients.  The study accrual duration is expected to take 18 months for the first stage and 
10 months for the second stage.  An interruption in accrual between accrual stages could last as 
long as 6 months. 
 
Operationally, accrual and initiation of treatment will be monitored and, while there is a target 
of 15 patients, accrual will automatically be paused by OPEN when the 16th patient is enrolled.  
This allows for two patients to be enrolled on the same day. 
 
15.6 
Dose Level Guidelines 
 
Dose level guidelines are not applicable for this study. 
 
15.7 
Secondary or Exploratory Endpoints (including correlative science aims) 
 
15.7.1 Secondary Hypotheses and Endpoints:  
The secondary endpoints, progression-free survival, overall survival and adverse events, will 
be estimated as described in section 15.7.2.   
 
15.7.2 Definitions of Secondary Endpoints and How These Will Be Analyzed 
Disease progression will be defined using RECIST 1.1 criteria.  The duration of progression-
free survival and overall survival will be measured from date of study entry  onto the treatment 
component of the study and their distributions will be estimated using Kaplan-Meier product 
limit estimates.  CTCAE version 4.03 will be used to grade and categorize adverse events.  
Frequencies of maximum grade of adverse events by term or category will be reported.  Grade 


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5 adverse events will be individually reported. 
 
15.7.3 Study Monitoring of Secondary Objectives 
Data collected on this protocol will be reviewed by the study data manager and will also be 
reviewed by the Study Chairperson in conjunction with the Statistics and Data Management 
Center (SDMC). In some instances, because of unexpectedly severe toxicity, early closure of a 
study may be elected. 
 
The frequency and severity of all toxicities are tabulated from submitted case report forms and 
summarized for review by the study chairperson, Developmental Therapeutics Committee and 
the Safety Review Committee in conjunction with each semi-annual meeting. The initial 
overall review of toxicity is usually performed after completion of the first stage of accrual, at 
which point accrual is generally suspended pending formal analysis of response and toxicity. 
 
All serious adverse events (SAEs) are reported to the Study Chair, Sponsor, Pharmaceutical 
company, and regulatory agencies as mandated in the protocol. SAE reports are reviewed by 
the Study Chair (or designated co-chair) immediately for consideration of investigator 
notification of a suspected unexpected serious adverse reaction (SUSAR), protocol 
amendment, and/or immediate study suspension. All participating institutions will receive 
notification of the SUSAR from NRG as well as the reason for study suspension (if 
applicable). Under these circumstances, accrual cannot be re-activated until the study is 
reviewed by the Safety Review Committee. However, patients currently receiving treatment 
may continue to receive treatment in accordance with protocol guidelines at the discretion of 
their physicians, unless directed otherwise. 
 
Data collected on this protocol will be reviewed by the study data manager and will also be 
reviewed by the Study Chairperson in conjunction with the Statistics and Data Management 
Center (SDMC) on an ongoing basis. 
 
15.8 
Exploratory Hypothesis and Endpoints 
Associations between mutation subtypes and clinical outcomes will be explored using standard 
statistical methods for categorical and time to event data. 
   
 
 


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15.9 
Gender/Ethnicity/Race Distribution 
The accrual distribution by gender, ethnicity and race is provided for the target sample size for 
two stages.  International accrual is not expected. 
 
 
 
Racial Categories 
DOMESTIC PLANNED ENROLLMENT REPORT 
Ethnic Categories 
Not Hispanic or 
Latino 
Hispanic or Latino 
 
Total 
Female 
Male 
Female 
Male 
American Indian/Alaska 
Native 
0  
0 
0 
0 
0 
Asian 
1  
0 
0 
0 
1 
Native Hawaiian or Other 
Pacific Islander 
0  
0 
0 
0 
0 
Black or African American 
2 
0 
0 
0 
2 
White  
21 
0 
1 
0 
22 
More Than One Race 
0 
0 
0 
0 
0 
Total 
24 
0 
1 
0 
25 
 
 
 
 
Racial Categories 
INTERNATIONAL (including Canadian participants) 
PLANNED ENROLLMENT REPORT 
Ethnic Categories 
Not Hispanic or 
Latino 
Hispanic or Latino 
 
Total 
Female 
Male 
Female 
Male 
American Indian/Alaska 
Native 
0 
0 
0 
0 
0 
Asian 
0 
0 
0 
0 
0 
Native Hawaiian or Other 
Pacific Islander 
0 
0 
0 
0 
0 
Black or African American 
0 
0 
0 
0 
0 
White  
0 
0 
0 
0 
0 
More Than One Race 
0 
0 
0 
0 
0 
Total 
0 
0 
0 
0 
0 
 
16. 
REFERENCES 
1. 
Siegel RL, Miller KD, Jemal A. Cancer statistics, 2015. CA: a cancer journal for clinicians. 
2015;65:5-29. 
 
2. 
Bokhman, J. V. Two pathogenetic types of endometrial carcinoma. Gynecol. Oncol. 15, 10–17 
(1983). 
 


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3. 
Mutch, D. G. The more things change the more they stay the same. Gynecol. Oncol. 124, 3–4 
(2012). 
 
4. 
Zhao S. Choi M. Overton JD. Bellone S. Roque DM. Cocco E. Guzzo F. et al., Landscape of 
somatic single-nucleotide and copy-number mutations in uterine serous carcinoma. Proceedings 
of the National Academy of Sciences of the United States of America. 110(8):2916-21, 2013 
 
5. 
Integrated genomic characterization of endometrial carcinoma. The Cancer Genome Atlas 
Research Network. Nature. 497:67-73, 2013. 
 
6. 
Vanhaesebroeck, B., Guillermet-Guibert, J., Graupera, M. & Bilanges, B. The emerging 
mechanisms of isoform-specific PI3K signalling. Nat. Rev. Mol. Cell Biol. 11, 329–341 (2010). 
 
7. 
Pavlidou, A. & Vlahos, N. F. Molecular alterations of PI3K/Akt/mTOR pathway: a therapeutic 
target in endometrial cancer. ScientificWorldJournal 2014, 709736 (2014). 
 
8. 
English, D. P. et al. Oncogenic PIK3CA gene mutations and HER2/neu gene amplifications 
determine the sensitivity of uterine serous carcinoma cell lines to GDC-0980, a selective 
inhibitor of Class I PI3 kinase and mTOR kinase (TORC1/2). Am. J. Obstet. Gynecol. 209, 
465.e1–9 (2013). 
 
9. 
English, D. P. et al. HER2/neu gene amplification determines the sensitivity of uterine serous 
carcinoma cell lines to AZD8055, a novel dual mTORC1/2 inhibitor. Gynecol. Oncol. 131, 753–
758 (2013). 
 
10. 
Chresta, C. M. et al. AZD8055 is a potent, selective, and orally bioavailable ATP-competitive 
mammalian target of rapamycin kinase inhibitor with in vitro and in vivo antitumor activity. 
Cancer Res. 70, 288–298 (2010). 
 
11. 
Lopez, S. et al. Taselisib, a selective inhibitor of PIK3CA, is highly effective on PIK3CA-
mutated and HER2/neu amplified uterine serous carcinoma in vitro and in vivo. Gynecol. Oncol. 
(2014). doi:10.1016/j.ygyno.2014.08.024 
 
12. 
Dancey, J. E. Therapeutic targets: MTOR and related pathways. Cancer Biol. Ther. 5, 1065–
1073 (2006). 
 
13. 
Rodon, J., Dienstmann, R., Serra, V. & Tabernero, J. Development of PI3K inhibitors: lessons 
learned from early clinical trials. Nat. Rev. Clin. Oncol. 10, 143–153 (2013). 
 
14. 
Janku, F. et al. PI3K/AKT/mTOR inhibitors in patients with breast and gynecologic 
malignancies harboring PIK3CA mutations. J. Clin. Oncol. 30, 777–782 (2012). 
 
15. 
Llauradó, M. et al. Molecular bases of endometrial cancer: new roles for new actors in the 
diagnosis and the therapy of the disease. Mol. Cell. Endocrinol. 358, 244–255 (2012). 
 


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16. 
RuddML, et al., A unique spectrum of somatic PIK3CA (p110α) mutations within primary 
endometrial carcinomas Clin Cancer Res. 2011 March 15; 17(6): 1331–1340 
 
17. 
Bellone S., et al., Polymerase ε (POLE) ultra-mutated tumors induce robust tumor-specific CD4+ 
T cell responses in endometrial cancer patients. Gynecol Oncol. 2015 Jul;138(1):11-7. doi: 
10.1016/j.ygyno.2015.04.027. Epub 2015 Apr 27 
 
18. 
Liu N; Rowley BR; Bull CO; Schneider C; Haegebarth A; Schatz CA; Fracasso PR; Wilkie DP; 
Hentemann M; Wilhelm SM; Scott WJ; Mumberg D; Ziegelbauer K. BAY 80-6946 is a highly 
selective intravenous PI3K inhibitor with potent p110alpha and p110delta activities in tumor cell 
lines and xenograft models. Molecular Cancer Therapeutics. 12(11):2319-30, 2013 
 
19. 
Anonymous. Preliminary results of a phase II study of single agent Bay 80-6946, a Novel PI3K 
inhibitor, in patients with relapsed/refractory, indolent or aggressive lymphoma. Clinical 
Advances in Hematology & Oncology. 12(2 Suppl 5):14-6, 2014 
 
20. 
Pena C.L. et al., Biomarker analysis from a Phase I study of copanlisib with expansion cohorts 
in solid tumors with and without PIK3CA mutations and NHL. J Clin Oncol 33, 2015 (suppl; 
abstr 2548) 
 
21. 
Chen TT, NG T. Optimal flexible designs in phase II clinical trials, Statistics in Medicine. 
1998;17:2301-2312. 
 
22. 
Aghajanian C, Filiaci VL, Dizon DS, Carlson J, Powell MA, Secord AA, Tewari KS, Bender 
D, O'Malley DM, Stuckey A, Rotmensch J, Levine DA, Lankes HA, Moore KN.  A 
randomized phase II study of paclitaxel/carboplatin/bevacizumab, 
paclitaxel/carboplatin/temsirolimus and ixabepilone/carboplatin/bevacizumab as initial therapy 
for measurable stage III or IVA, stage IVB or recurrent endometrial cancer, GOG-86P ASCO 
2015 Abstract #144077. 
 
 23. 
Myers AP, Filiaci VL, Zhang Y, Pearl M, Behbakht K, Makker V, Hanjani P, Zweizig S, 
Burke JJ, Downey G, Leslie KK, Birrer MJ, Fleming GF.  Tumor mutational analysis of 
GOG248, a phase II study of temsirolimus or temsirolimus and alternating megestrol acetate 
and tamoxifen for advanced endometrial cancer (EC): An NRG Oncology/Gynecologic 
Oncology Group study ASCO 2015 Abstract #149616 
 
 


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APPENDIX I - 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 II - NYHA CLASSIFICATION 
Congestive Heart Failure – 
 
New York Heart Association Classification 
 
Class 
Definition 
I 
No limitation: Ordinary physical activity does not cause undue fatigue, 
dyspnea, or palpitation 
II 
Slight limitation of physical activity: Such patients are comfortable at rest. 
Ordinary physical activity results in fatigue, palpitations, dyspnea, or angina. 
III 
Marked limitation of physical activity: Although patients are comfortable at 
rest, less than ordinary physical activity will lead to symptoms. 
IV 
Inability to carry on physical activity without discomfort: Symptoms of 
congestive heart failure are present even with rest. With any physical activity, 
increased discomfort is experienced. 
 
Source: Criteria Committee, New York Heart Association, Inc. Diseases of the heart and blood 
vessels. Nomenclature and criteria for diagnosis. 6th ed. Boston, Little, Brown and Co, 1964: 114. 
 
 


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APPENDIX III – GLYCEMIC INDEX FOR COMMON FOODS 
 
The average Glycemic Index of common foods derived from multiple studies by different 
laboratories 
Foods are categorized as having a low-glycemic index if the glucose reference index is ≤ 55. High-
Glycemic Index foods have a glucose reference index >55. The summary table below contains glucose 
reference for common foods. 
 
 
GI = glycemic index. 
 
 
 
 
 
 
 
 
 
 


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APPENDIX IV – P-GP, BCRP AND MATE2K SUBSTRATES 
 
P-gp substrates, BCRP substrates and MATE2K-substrates 
A list of drugs to be used with caution. 
Copanlisib is an inhibitor of BCRP, P-gp and MATE2K in vitro. Therefore substrates, especially those 
with a narrow therapeutic range, should be used with caution. 
Pgp-Substrates 
Aliskiren, ambrisentan, colchicine, dabigatran etexilate, 
digoxinaa, everolimus, fexofenadine, imatinib, lapatinib, 
maraviroc, nilotinib, posaconazole, ranolazine, saxagliptin, 
sirolimus, sitagliptin, talinolol, tolvaptan, topotecan 
BCRP substrates 
 
Zidovudine, pantoprazole, cimetidine, sulfasalazine, 
nitrofurantoin, and several statins (lovastatin, simvastatin, 
cerivastatin, pitavastatin), mitoxantrone, methotrexate, 
topotecan, imatinib, and irinotecan 
MATE2K-substrates 
Metformin, cimetidine, procainamide and N methylnicotinamide 
BCRP = Breast cancer resistance protein; MATE2K = Multidrug and toxin extrusion protein 2,  
P-gp = Permeability glycoprotein 
a:Narrow therapeutic window 
 
 
 
 


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APPENDIX V – CYP3A4 INHIBITORS AND INDUCERS 
 
NOTE:  As stated in Section 3.3.4, only Strong CYP3A4 inhibitors and inducers should be excluded. 
 
A list of CYP3A4 inhibitors and inducers 
This list is not comprehensive. Please refer to a frequently-updated drug information reference for 
strong CYP3A4 inducers and inhibitors:   
http://www.uptodate.com/contents/image?imageKey=CARD/76992&topicKey=HEME%2F1370&sou
rce=outline_link&utdPopup=true 
 
Strong Inhibitors 
Moderate Inhibitors 
Strong Inducers 
Moderate Inducers 
Atazanavir 
Amiodarone¶ 
Carbamazepine 
Bexarotene 
Boceprevir 
Aprepitant 
Enzalutamide 
Bosentan 
Ceritinib 
Cimetidine¶ 
Fosphenytoin 
Dabrafenib 
Clarithromycin 
Conivaptan 
Lumacaftor  
Dexamethasone¶ 
Cobicistat and cobicistat 
containing coformulations 
Crizotinib 
Mitotane 
Efavirenz 
Darunavir 
Cyclosporine¶ 
Phenobarbital 
Eslicarbazepine 
Idelalisib 
Diltiazem 
Phenytoin 
Etravirine 
Indinavir 
Dronedarone 
Primidone 
Modafinil 
Itraconazole 
Erythromycin 
Rifabutin 
Nafcillin 
Ketoconazole 
Fluconazole 
Rifampin (rifampicin) St. John's wort 
Lopinavir 
Fosamprenavir 
Rifapentine 
 
Nefazodone 
Fosaprepitant¶ 
 
 
Nelfinavir 
Grapefruit juice 
 
 
Ombitasvir-paritaprevir-
ritonavir 
Imatinib 
 
 
Ombitasvir-paritaprevir-
ritonavir plus dasabuvir 
Isavuconazole 
(isavuconazonium 
sulfate) 
 
 
Posaconazole 
Mifepristone 
 
 
Ritonavir and ritonavir 
containing coformulations 
Netupitant 
 
 
Saquinavir 
Nilotinib 
 
 
Telaprevir 
Tibolone 
 
 
Telithromycin 
Verapamil 
 
 
Voriconazole 
 
 
 


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APPENDIX VI:  PATIENT DRUG INFORMATION HANDOUT AND WALLET CARD 
(01/09/2017) 
 
Information for Patients, Their Caregivers and Non-Study Healthcare Team on Possible 
Interactions with Other Drugs and Herbal Supplements  
 
The patient ____________________________ is enrolled on a clinical trial using the experimental 
study drug, copanlisib.  This clinical trial is sponsored by the National Cancer Institute.  This form is 
addressed to the patient, but includes important information for others who care for this patient.  
 
These are the things that you as a healthcare provided need to know: 
 
Copanlisib interacts with certain specific enzymes in your liver and certain transport proteins that help 
move drugs in and out of cells. 
 
 The enzymes in questions are CYP3A4 and 1A1.  Copanlisib is broken down by these 
enzymes and may be affected by other drugs that inhibit or induce these enzymes. 
 The proteins in question are P-gp, BCRP, MATE1, and MATE2K.  Copanlisib is moved in 
and out of cells/organs by P-gp and BCRP.  Copanlisib also inhibits P-gp, BCRP, MATE1, and 
MATE2K and may affect the clearance of other drugs that are dependent on these transport 
proteins. 
 
To the patient: Take this paper with you to your medical appointments and keep the attached 
information card in your wallet.   
 
 
Copanlisib  may interact with other drugs which can cause side effects. For this reason, it is very 
important to tell your study doctors of any medicines you are taking before you enroll onto this clinical 
trial.  It is also very important to tell your doctors if you stop taking any regular medicines, or if you 
start taking a new medicine while you take part in this study.  When you talk about your current 
medications with your doctors, include medicine you buy without a prescription (over-the-counter 
remedy), or any herbal supplements such as St. John’s Wort.  It is helpful to bring your medication 
bottles or an updated medication list with you. 
 
Many health care providers can write prescriptions.  You must tell all of your health care providers 
(doctors, physician assistants, nurse practitioners, pharmacists) you are taking part in a clinical trial.  
 
These are the things that you and they need to know:  
 
Copanlisib must be used very carefully with other medicines that use certain liver enzymes or 
transport proteins to be effective or to be cleared from your system.  Before you enroll onto the clinical 
trial, your study doctor will work with your regular health care providers to review any medicines and 
herbal supplements that are considered strong inducers/inhibitors of CYP3A4, 1A1, P-gp, and 
BCRP or substrates of P-gp, BCRP, MATE1, and MATE2K.  
 Please be very careful!  Over-the-counter drugs (including herbal supplements) may contain 
ingredients that could interact with your study drug.  Speak to your doctors or pharmacist to 


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determine if there could be any side effects. 
  Avoid smoking as copanlisib may not work as well in people who smoke. 
 Your regular health care provider should check a frequently updated medical reference or call 
your study doctor before prescribing any new medicine or discontinuing any medicine.  Your 
study doctor’s name is ___________________________________ 
 
 and he or she can be contacted at _________________________________________. 
 
 
 
 
 
 
 
 
 
 
STUDY DRUG INFORMATION WALLET CARD   
You are enrolled on a clinical trial using the experimental study drug 
copanlisib.  This clinical trial is sponsored by the NCI.  Copanlisib 
may interact with drugs that are processed by your liver or use certain 
transport proteins in your body.  Because of this, it is very important 
to: 
 Tell your doctors if you stop taking any medicines or if you start 
taking any new medicines. 
 Tell all of your health care providers (doctors, physician assistants, 
nurse practitioners, or pharmacists) that you are taking part in a 
clinical trial. 
 Check with your doctor or pharmacist whenever you need to use an 
over-the-counter medicine or herbal supplement. 
 Avoid smoking as copanlisib may not work as well in people who 
smoke. 
 
 
 
Copanlisib interacts with specific liver enzymes called CYP3A4 and 
1A1, transport proteins P-gp, BCRP, MATE1, and MATE2K, and 
must be used very carefully with other medicines that interact with 
these enzymes and transporters.  
 Before you enroll onto the clinical trial, your study doctor will 
work with your regular health care providers to review any 
medicines and herbal supplements that are considered “strong 
inducers/inhibitors of CYP3A4, 1A1, P-gp, and BCRP.” 
Copanlisib inhibits “P-gp, BCRP, MATE1, and MATE2K” and 
may affect how other medicines work in your body. 
 Before prescribing new medicines, your regular health care 
providers should go to a frequently-updated medical reference for a 
list of drugs to avoid, or contact your study doctor.   
 Your study doctor’s name is _____________________________ 
and can be contacted at _________________________________.  


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APPENDIX VII – TRANSLATIONAL SCIENCE BIOSPECIMEN PROCEDURES 
(01/09/2017) 
 
I. Obtaining a Bank ID for Translational Science Biospecimens 
Only one Bank ID (# # # # - # # - G # # #) is assigned per patient. All translational science 
biospecimens and accompanying paperwork must be labeled with this coded patient number. 
 
A Bank ID is automatically assigned once the Specimen Consent is completed and indicates that a 
patient has agreed to participate in the translational science component. If a patient has previously 
been assigned a Bank ID, please ensure the Bank ID appearing in Rave is the same as the previously 
assigned Bank ID. 
 
Please contact Support if you need assistance or have assigned more than one Bank ID to a patient 
(Email: support@nrgoncology.org; Phone: 716-845-7767). 
 
II. Requesting Translational Science Biospecimen Kits 
Kits are not provided for this protocol. 
 
III. FFPE Tissue Shipped to the NRG BB-Columbus 
Formalin-fixed, paraffin embedded (FFPE) tissue should be the most representative of the specimen 
type (e.g., primary tumor, metastatic tumor). 
 
Primary (FP01) and metastatic (FM01) tumor should be collected prior to all treatment. 
 
Only one block may be submitted per tissue type. 
 
All FFPE tissue should be submitted with the corresponding pathology report. 
 
Mandatory FFPE Biospecimen Requirement 
Every attempt should be made to provide a FFPE block; however, if a block cannot be provided on a 
permanent basis, then 15 unstained slides (10 charged, 5µm, and 5 uncharged, 10 µm) should be 
submitted.  All tissue sections should be cut sequentially from the same block.  
 
Completing Form TR for FFPE Biospecimens 
The type of specimen (block, slides) should be specified on Form TR. If submitting slides, the slide 
type, thickness, and count should also be specified. 
 
 
Labeling FFPE Tissue 
A waterproof permanent marker or printed label should be used to label each translational science 
tissue biospecimen with: 
 
Bank ID (# # # # - # # - G # # #) 
protocol number (NRG GY008) 
specimen code (see above) 
collection date (mm/dd/yyyy) 


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surgical pathology accession number 
block number 
 
Note: If labeling slides, only label on the top, front portion of the slide. Do not place a label on the 
back of the slide or over the tissue. The label must fit on the slide and should not be wrapped around 
the slide or hang over the edge. 
 
IV. Submitting Form TR 
An electronically completed copy of Form TR must accompany each biospecimen shipped to the NRG 
BB-Columbus. Handwritten forms will not be accepted. 
 
Note: A copy does not need to be sent to the NRG BB-Columbus if biospecimens are not collected. 
 
Form TR should be printed from the Translational Research Form screen in Rave using the “PDF 
File” link at the top of the form. Clicking this link will generate a PDF of Form TR in a “SEDES 
style” format. Do not use the “Printable Version” or “View PDF” links at the bottom of the form or 
any other method to print the form, as these formats will not be accepted.  
  
Retain a printout of the completed form for your records. 
  
Please contact Support if you need assistance (Email: support@nrgoncology.org; Phone: 716-845-
7767). 
 
V. Shipping Translational Science Biospecimens 
An electronically completed copy of Form TR must be included for each translational science 
biospecimen.  
 
A. FFPE Tissue 
FFPE tissue and a copy of the corresponding pathology report should be shipped using your own 
container at your own expense to: 
 
NRG BB-Columbus / Protocol NRG GY008 
Nationwide Children’s Hospital 
700 Children’s Dr, WA1340 
Columbus, OH 43205 
Phone: 614-722-2865 
FAX: 614-722-2897 
Email: BPCBank@nationwidechildrens.org 
 
Do not ship FFPE tissue for Saturday delivery. 
 
VI. Banking Translational Science Biospecimens for Future Research 
Biospecimens will remain in the NRG BB-Columbus and made available for approved research 
projects if the patient has provided permission for the use of her biospecimens for future health 
research. 
 


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Note: Testing of banked biospecimens will not occur until an amendment to this treatment protocol (or 
separate correlative science protocol) is reviewed and approved in accordance with National Clinical 
Trials Network (NCTN) policies. 
 
The patient’s biospecimen consent choices will be recorded on the signed informed consent document 
and electronically via the Specimen Consent form. At the time of biospecimen selection for project 
distribution, the most recent consent information will be used. 
 
Sites can amend a patient’s choices regarding the future use of her biospecimens at any time if 
the patient changes her mind. 
 
If the patient revokes permission to use her biospecimens, the NRG BB-Columbus will destroy or 
return any remaining biospecimens. The patient’s biospecimens will not be used for any further 
research; however, any biospecimens distributed for research prior to revoking consent cannot be 
returned or destroyed. In addition, the patient cannot be removed from any research that has been done 
with her biospecimens distributed prior to revoking consent. 
 
Note: If return of biospecimens is requested, shipping will be at the site’s expense. 
 
 


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APPENDIX VIII – BLOOD GLUCOSE DIARY 
 
Patient Name/ID:  _________________________________________________________ 
 
Please record your blood glucose levels as instructed by your doctor.  Return this diary to your doctor 
at your next visit. 
 
Date 
Wake-Up 
(pre-bkfst) 
Pre-Lunch 
Afternoon  
Pre-Dinner 
Bedtime (pre-
snack)