Phase 2 Study of PI3K Inhibitor Copanlisib in Combination With Fulvestrant in Selected ER+ and/or PR+ Cancers With PI3K (PIK3CA, PIK3R1) and/or PTEN Alterations
Phase: PHASE2
Conditions: Endometrial Cancer, Ovarian Cancer
Sponsor: M.D. Anderson Cancer Center

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TABLE OF CONTENTS 
MD ANDERSON IND SPONSOR COVER SHEET ................................................................................. 1 
TABLE OF CONTENTS ....................................................................................................................... 2 
LIST OF ABBREVIATIONS AND DEFINITION OF TERMS ..................................................................... 4 
CLINICAL STUDY SYNOPSIS .............................................................................................................. 8 
1 
BACKGROUND AND RATIONALE ............................................................................................ 19 
1.1 
Copanlisib ....................................................................................................................................................... 22 
1.1.1 
Non-Clinical Experience ............................................................................................................................. 23 
1.1.2 
Clinical Experience ..................................................................................................................................... 24 
1.1.3 
Safety ......................................................................................................................................................... 24 
1.2 
Fulvestrant ...................................................................................................................................................... 26 
1.2.1 
Safety ......................................................................................................................................................... 26 
1.3 
RATIONALE ..................................................................................................................................................... 27 
1.3.1 
Study Rationale and Purpose ..................................................................................................................... 27 
1.3.2 
The Rationale for Dose Selection ............................................................................................................... 28 
1.3.3 
The Rationale for Biomarker Assessments ................................................................................................. 28 
2 
STUDY OBJECTIVES ................................................................................................................. 29 
2.1 
Part 1: Dose confirmation: ............................................................................................................................. 29 
2.2 
Part 2: Dose expansion: .................................................................................................................................. 29 
3 
STUDY ENDPOINTS ................................................................................................................. 30 
3.1 
Efficacy endpoints: ......................................................................................................................................... 30 
3.2 
Safety endpoints: ............................................................................................................................................ 30 
3.3 
Exploratory endpoints: ................................................................................................................................... 31 
4 
INVESTIGATIONAL PLAN ......................................................................................................... 32 
4.1 
Study Design ................................................................................................................................................... 32 
4.1.1 
Screening/Baseline Phase .......................................................................................................................... 33 
4.1.2 
Treatment Phase ........................................................................................................................................ 33 
4.1.3 
Safety Follow-Up ........................................................................................................................................ 34 
4.1.4 
Follow-Up Visits .......................................................................................................................................... 34 
4.1.5 
Survival Follow-Up ..................................................................................................................................... 34 
4.1.6 
Pharmacodynamic Assessments ................................................................................................................ 34 
4.1.7 
Removal of Patients from the Study .......................................................................................................... 35 
4.1.8 
COVID-19 Pandemic Study Procedures ...................................................................................................... 35 
5 
STUDY POPULATION .............................................................................................................. 35 
5.1 
Patient Population .......................................................................................................................................... 35 
5.2 
Planned Number of Patients .......................................................................................................................... 36 
5.3 
Inclusion Criteria ............................................................................................................................................. 36 
5.4 
Exclusion Criteria ............................................................................................................................................ 37 
6 
STUDY TREATMENT ................................................................................................................ 39 
6.1 
Dosing and Administration ............................................................................................................................. 39 
6.1.1 
Copanlisib dosing requirements for pre-dose glucose levels ..................................................................... 40 
6.2 
Dose Modification .......................................................................................................................................... 41 
6.3 
Toxicity Management ..................................................................................................................................... 42 
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6.3.1 
Copanlisib toxicity management ................................................................................................................ 42 
6.3.2 
Fulvestrant toxicity management .............................................................................................................. 50 
6.3.3 
Other toxicities ........................................................................................................................................... 50 
6.3.4 
COVID-19/SARS-CoV-2 Infection ................................................................................................................ 51 
6.4 
Concomitant Therapy ..................................................................................................................................... 51 
6.4.1 
Prohibited Medications/Therapies ............................................................................................................ 51 
6.4.2 
Potential Drug Interactions ........................................................................................................................ 52 
6.5 
Supportive Care .............................................................................................................................................. 53 
6.6 
Contraception ................................................................................................................................................. 53 
6.6.1 
Female Patients .......................................................................................................................................... 54 
6.6.2 
Male Patients ............................................................................................................................................. 55 
6.7 
Use in Pregnancy ............................................................................................................................................ 55 
6.8 
Use in Nursing Women ................................................................................................................................... 55 
6.9 
Patient Withdrawal/Discontinuation Criteria ................................................................................................. 56 
6.10 
Length and End of Study ................................................................................................................................. 57 
7 
ASSESSMENT OF SAFETY ........................................................................................................ 57 
7.1 
Safety Parameters .......................................................................................................................................... 57 
7.1.1 
Definition of Adverse Event ....................................................................................................................... 57 
7.1.2 
Definition of Serious Adverse Event ........................................................................................................... 58 
7.2 
Adverse Event Reporting Period ..................................................................................................................... 58 
7.3 
Assessment of Adverse Events ....................................................................................................................... 59 
7.4 
Procedures for Eliciting, Recording, and Reporting Adverse Events .............................................................. 59 
7.4.1 
Eliciting Adverse Event Information ........................................................................................................... 59 
7.4.2 
Specific Instructions for Recording Adverse Events ................................................................................... 59 
7.5 
Assessment of Severity of Adverse Events ..................................................................................................... 61 
7.6 
Serious Adverse Event Reporting Requirements for MDACC Sponsor Single Site Investigational New Drug 
(IND) Protocols ............................................................................................................................................................ 62 
7.7 
Reporting of Adverse Events to Bayer Healthcare ......................................................................................... 63 
7.7.1 
Overdose .................................................................................................................................................... 63 
8 
DATA ANALYSIS AND STATISTICAL CONSIDERATIONS ............................................................ 63 
8.1 
Safety Analysis ................................................................................................................................................ 67 
8.1.1 
Clinical Laboratory Analyses ....................................................................................................................... 67 
8.2 
Efficacy Analysis .............................................................................................................................................. 68 
8.3 
Data Collection ............................................................................................................................................... 68 
8.3.1 
Data Protection and Confidentiality ........................................................................................................... 68 
9 
ETHICAL AND REGULATORY REQUIREMENTS ........................................................................ 69 
10 
REFERENCES ....................................................................................................................... 69 
APPENDIX A:  SCHEDULE OF ASSESSMENTS .................................................................................. 76 
APPENDIX B: RECIST V1.1 .............................................................................................................. 81 
APPENDIX C: NCI CTCAE V5.0 ........................................................................................................ 85 
APPENDIX D: ECOG PERFORMANCE STATUS SCALE ...................................................................... 86 
APPENDIX E: NEW YORK HEART ASSOCIATION FUNCTIONAL CLASSIFICATIONS ........................... 87 
APPENDIX F: STRONG INHIBITORS OR STRONG INDUCERS OF CYP3A4 ........................................ 88 
APPENDIX G: R CODE USED TO OBTAIN THE OPERATIONAL CHARACTERISTICS OF THE CBHM 
DESIGN. ......................................................................................................................................... 89 
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List of Abbreviations and Definition of Terms 
Abbreviation or 
special term 
Explanation 
AE 
Adverse event 
ALT 
Alanine transaminase 
ALP 
Alkaline phosphatase 
AST 
Aspartate transaminase 
AUC24h 
Area under the curve at 24 hours 
B.I.D 
Twice daily 
BOR 
Best overall response 
BP 
Blood pressure 
BCRP 
Breast cancer resistance protein 
CBC 
Complete blood count 
CBHM 
Calibrated bayesian hierarchical model 
CFR 
Code of Federal Regulations 
CI 
Confidence interval 
CLIA 
Clinical Laboratory Improvement Amendments 
CMV 
Cytomegalovirus 
Cmax 
Maximum concentration 
CNS 
Central nervous system 
CORe 
Clinical Oncology Research e-database 
COSMIC 
Catalogue of Somatic Mutations in Cancer 
CR 
Complete response 
CT 
Computed tomography 
CTCAE 
Common Terminology Criteria for Adverse Events 
ctDNA 
Circulating tumor DNA 
Ctrough 
Trough concentration 
CYP 
Cytochrome P450 
DLT 
Dose-limiting toxicity 
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Abbreviation or 
special term 
Explanation 
ECHO 
Echocardiogram 
ECOG 
Eastern Cooperative Oncology Group 
eCRF 
Electronic case report form 
EMR 
Electronic medical record 
ER+ 
Estrogen receptor-positive 
EOT 
End-of-treatment 
eSAE 
Electronic serious adverse event application 
FDA 
Food and Drug Administration 
GCP 
Good Clinical Practice 
HBV 
Hepatitis B virus 
HbcAb 
Hepatitis B core antibody 
HbsAg 
Hepatitis B surface antigen 
HCV 
Hepatitis C virus 
HR+ 
Hormone receptor-positive 
IB 
Investigator’s brochure 
IC50 
Half-maximal inhibitory concentration 
ICF 
Informed consent form 
ICH 
International Council on Harmonisation 
IHC 
Immunohistochemistry 
IM 
Intramuscular(ly) 
IND 
Investigational new drug 
IRB 
Institutional review board 
IV 
Intravenous(ly) 
Kd 
Dissociation constant 
MATE 
Multidrug and toxin extrusion protein 
MDACC 
MD Anderson Cancer Center 
MOCLIP 
Molecular and Clinical Data Integrated Platform 
MRI 
Magnetic resonance imaging 
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Abbreviation or 
special term 
Explanation 
mTOR 
Mammalian target of rapamycin 
MTD 
Maximum tolerated dose 
MUGA 
Multigated acquisition 
NCI 
National Cancer Institute 
NE 
Not evaluable 
NGS 
Next-generation sequencing 
NHL 
Non-Hodgkin’s lymphoma 
ORR 
Objective response rate 
OS 
Overall survival 
PCR 
Polymerase chain reaction 
PD 
Progressive disease 
PET 
Positron emission tomography 
PFS 
Progression-free survival 
P-gp 
P-glycoprotein 
PI 
Principal investigator 
PI3K 
Phosphatidylinositol-3 kinase 
PI3Ki 
Phosphatidylinositol-3 kinase inhibitor 
PR 
Partial response 
PR+ 
Progesterone receptor-positive 
PJP 
Pneumocystis jiroveci pneumonia 
RECIST 
Response Evaluation Criteria in Solid Tumors 
RNAseq 
RNA sequencing 
RP2D 
Recommended Phase 2 dose 
SAE 
Serious adverse event 
SD 
Stable disease 
SERD 
Selective estrogen receptor degrader 
SOC 
Standard of care 
TB 
Total bilirubin 
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Abbreviation or 
special term 
Explanation 
TCGA 
The Cancer Genome Atlas 
Treg 
Regulatory CD4+ T-cell 
ULN 
Upper limit of normal 
WBC 
White blood cell 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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CLINICAL STUDY SYNOPSIS 
 
Protocol Title: 
Phase 2 study of PI3K inhibitor copanlisib in combination with fulvestrant in selected ER+ 
and/or PR+ cancers with PI3K (PIK3CA, PIK3R1) and/or PTEN alterations 
 
IND Number: 
157719 
Protocol 
Number: 
21897/ 2020-1241 
Principal 
Investigator: 
 
Study Phase: 
Phase 2 
Investigational 
Products: 
Copanlisib and fulvestrant 
Study 
Indications: 
Solid tumors: ovarian cancer, endometrial cancer, breast cancer 
Study Centers: 
MD Anderson Cancer Center (single-center study) 
Length of 
study: 
2 years 
Objectives: 
The objective of this phase 2 basket study is to evaluate the efficacy and safety of 
copanlisib in combination with fulvestrant administered to subjects with selected 
estrogen receptor-positive (ER+) and/or progesterone receptor-positive (PR+) advanced 
or metastatic solid tumors with PI3K and/or PTEN alterations. The study will have two 
parts. 
 
Part 1: Dose confirmation:  
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Secondary Objectives: 
• To assess the efficacy of copanlisib administered in combination with fulvestrant 
as outlined in Part 2 by evaluating the objective response rate (ORR).  
• To evaluate additional efficacy measures such as progression-free survival (PFS) 
and overall survival (OS) of copanlisib in combination with fulvestrant. 
 
Exploratory Objective: 
• To investigate clonal evolution, and mechanisms of resistance using tissue and 
liquid biopsies utilizing circulating tumor DNA (ctDNA) as outlined in Part 2. 
 
 
Part 2: Dose expansion: 
Primary Objectives: 
• To assess the efficacy of copanlisib administered in combination with fulvestrant 
as outlined above by evaluating the objective response rate (ORR). Patients 
enrolled for Part 1 will be included in this efficacy analysis.  
 
Secondary Objectives: 
• To evaluate additional efficacy measures such as PFS and OS of copanlisib in 
combination with fulvestrant. 
• To evaluate the safety and tolerability of copanlisib in combination with 
fulvestrant. 
 
Exploratory Objective: 
• To investigate clonal evolution, and mechanisms of resistance using tissue and 
liquid biopsies utilizing ctDNA. 
 
 
Purpose/ 
Rationale:    
The purpose of this study is to evaluate the efficacy and safety of copanlisib in 
combination with fulvestrant in advanced hormone receptor-positive (HR+) solid tumors 
harboring alterations that activate the Phosphatidylinositol-3 kinase (PI3K) pathway. 
Copanlisib is a potent pan-PI3K inhibitor (PI3Ki) approved by the Food and Drug 
Administration (FDA) for the treatment of patients with relapsed follicular lymphoma. 
Fulvestrant is a selective ER degrader (SERD) and is FDA-approved to treat HR+ 
metastatic breast cancer. 
 
The Phase 3 SOLAR-1 trial demonstrated the efficacy of the PI3K-α specific inhibitor 
alpelisib in combination with fulvestrant in the treatment of PIK3CA-mutated, hormone 
receptor HR+ advanced or metastatic breast cancer refractory to hormone regimen (1). 
Given the findings of the SOLAR-1 trial, we hypothesize that the clinical benefit of the 
PI3K pathway inhibitors and endocrine therapy combination can be extended to other 
HR+ solid cancers harboring alterations that activate the PI3K pathway. Estrogen and/or 
progesterone receptors are commonly expressed in the ovarian, endometrial, salivary 
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gland, and other cancers (2). Furthermore, we and others found that PIK3CA mutations 
frequently co-occur in these HR-expressing cancers (3-8). Endocrine therapies, including 
fulvestrant, have been investigated for use in the treatment of gynecological 
malignancies and have demonstrated modest single-agent clinical activity (9-11). Similar 
to breast cancer, efficacy is limited by de novo and acquired endocrine resistance, and 
endocrine resistance can be overcome by PI3K pathway inhibition (12-14). In addition, 
our group and others have demonstrated that combinations of mammalian target of 
rapamycin (mTOR) inhibitors with hormone therapy can be effective in gynecological 
malignancies (14, 15). 
Study Design: 
We propose to conduct a multi-arm, open-label, phase 2 basket trial investigating the 
efficacy and safety of copanlisib in combination with fulvestrant in patients with selected 
HR+ advanced or metastatic solid cancers, harboring PI3K or PTEN alterations including 
ovarian cancer (cohort 1), endometrial cancer (cohort 2), and breast cancer (cohort 3). 
Study 
Population: 
The study population will consist of subjects with selected HR+ (ER+ or/and PR+) 
advanced or metastatic solid tumors with PI3K (PIK3CA, PIK3R1) and/or PTEN alterations 
with ovarian, endometrial and breast cancer. Patients must have no available standard 
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therapy known to prolong survival or are not candidates for such a therapy. The study 
Key Inclusion 
Criteria 
1. Histologically confirmed ER+ and/or PR+ advanced or metastatic solid cancer 
including ovarian cancer (cohort 1), endometrial cancer (cohort 2), or breast 
cancer (cohort 3) (Figure 1).  ER and/or PR positivity is defined as >10% 
immunohistochemical staining of any intensity. Cohort 3 will be enriched to 
include at least 7 patients naïve to any PI3Ki in Stage 1 and also in Stage 2.   
2. Presence of one or more PI3K and/or PTEN alterations in tumor tissue. Genetic 
alterations will include PIK3CA gain of function mutations, PIK3R1 loss of function 
mutations, PTEN loss of function mutations, and PTEN deletions. 
3. Measurable disease per the RECIST 1.1. 
4. The patient (or legally acceptable representative, if applicable) provides written 
informed consent for the study. 
5. Female or male >18 years of age on the day of informed consent signing. 
6. Patients have no available standard therapy known to prolong survival. For 
cohort 3 only, prior treatment with aPI3Ki or everolimus is not required and 
patients with or without prior PI3Ki or everolimus will be qualified for enrollment  
7. Adequate archived tumor tissue for the analysis for PI3K and PTEN alterations if 
available. 
8. Eastern Cooperative Oncology Group (ECOG) performance status of ≤2.  
9. Adequate organ and marrow function as defined below: 
a. Hemoglobin ≥9.0 g/dL  
b. Absolute neutrophil count ≥1.5 × 109/L  
c. Platelet count ≥100 × 109/L  
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d. Total bilirubin (TB) ≤1.5 × institutional upper limit of normal (ULN); 
Patients with known Gilbert’s disease who have TB ≤3 × ULN may be 
enrolled) 
e. Aspartate transaminase (AST)/ alanine transaminase (ALT) ≤3 × ULN. If 
patient has liver metastases, AST and ALT ≤5.0 × ULN.  
f. Creatinine ≤1.5 x ULN 
g. International normalized ratio ≤1.5. 
10. Fasting blood glucose ≤140 mg/dL and hemoglobin A1c ≤8.5% (both criteria have 
to be met). 
11. Cardiac ejection fraction ≥45%.  
12. Women of childbearing potential must have a negative serum or urine pregnancy 
test (minimum sensitivity 25 IU/L or equivalent units of human chorionic 
gonadotropin [HCG]) within 14 days prior to the initiation of treatment and/or 
postmenopausal women must be amenorrheic for at least 12 months to be 
considered of non-childbearing potential. Women of childbearing potential 
(WOCBP) must agree and commit to the use of 2 highly effective methods of birth 
control throughout the duration of the study until at least 150 days following the 
last dose of study drug. Acceptable methods are defined as those that result, 
alone or in combination, in a low failure rate (i.e., less than 1% per year) when 
used consistently and correctly, such as surgical sterilization, an intrauterine 
device, or hormonal contraception in combination with a barrier method. 
Women using systemically acting hormonal contraceptives should add a barrier 
method. In certain countries (if permitted by law), WOCBP may agree to abide 
by heterosexual sexual abstinence during the time of participation in this study. 
13. Male patients and their female partners of childbearing potential must agree and 
commit to use a barrier contraception (eg, condom with spermicidal 
foam/gel/film/cream/suppository) throughout the duration of the study until at 
least 90 days following the last dose of study drug, in addition to their female 
partners using either an intrauterine device or hormonal contraception and 
continuing until at least 90 days following the last dose of study drug. This 
criterion may be waived for male patients who have had a vasectomy > 6 months 
before signing the ICF. 
14. Willing and able to comply with the protocol for the duration of the study 
including undergoing treatment and scheduled visits and examinations. 
Key Exclusion 
Criteria 
1. The patient has central nervous system (CNS) involvement. If the patient fulfills 
the following 3 criteria, she/he is eligible for the study: 
a. Completed prior therapy (including radiation and/or surgery) for CNS 
metastases, and 
b. CNS tumor is radiologically stable for ≥28 days prior to study start, and 
c. The patient is not receiving steroids and enzyme-inducing antiepileptic 
medications for brain metastases. 
2. Patients with HER2 positive breast cancer. 
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3.  Patients must be ≥4 weeks or at least 5 half-lives beyond treatment with any 
chemotherapy or other investigational therapy including hormonal, biological, 
or targeted agents at the time of treatment initiation. 
-     NOTE:  If the patient received major surgery, she/he must have recovered 
adequately from the toxicity and/or complications from the intervention 
prior to starting the study treatment.   
4. Prior treatment with fulvestrant or any PI3Ki for cohorts 1 and 2. 
5. Known hypersensitivity to copanlisib or fulvestrant, or to any of the excipients 
of copanlisib or fulvestrant. 
6. Concomitant use of strong cytochrome P450 (CYP)3A4 inducers (e.g., rifampicin, 
phenytoin, carbamazepine, phenobarbital, St. John’s wort) or inhibitors (e.g., 
ritonavir, 
saquinavir, 
nelfinavir, 
boceprevir, 
telaprevir, 
ketoconazole, 
omeprazole). Use of strong inhibitors and/or inducers of CYP3A4 is not 
permitted from Day -14 of Cycle 1 until the start of the study intervention. 
7. The patient is currently receiving warfarin or other coumarin derived 
anticoagulants for treatment, prophylaxis, or otherwise. Therapy with heparin, 
low molecular weight heparin, fondaparinux, or direct oral anticoagulants such 
as rivaroxaban or apixaban is allowed. 
8. Known additional malignancy that is progressing or requires active treatment.  
9. History or current evidence of any condition, therapy, or laboratory abnormality 
that might confound the results of the study, interfere with the patient’s 
participation for the full duration of the study or is not in the best interest of the 
patient to participate, in the opinion of the treating investigator.   
10. Known psychiatric or substance abuse disorders that would interfere with 
cooperation with the requirements of the study. 
11. Known history of human immunodeficiency virus infection.  
12. History or current symptomatic pneumonitis. 
13. Has clinically significant, uncontrolled heart disease and/or recent cardiac 
events, including any of the following: 
a. History of angina pectoris, symptomatic pericarditis, or myocardial 
infarction within 12 months prior to study entry 
b. History of documented congestive heart failure (New York Heart 
Association functional classification III-IV) 
c. Documented cardiomyopathy 
d. History of any cardiac arrhythmias, e.g., ventricular, supraventricular, 
nodal arrhythmias, or conduction abnormality in the previous 12 months 
e. Uncontrolled hypertension defined by a systolic blood pressure (BP) 
≥140 mmHg and/or diastolic BP ≥90 mmHg, with or without 
antihypertensive medication over the course of one clinic visit at 
intervals of ≥30 minutes. Initiation or adjustment of antihypertensive 
medication(s) is allowed prior to screening. 
14. Type 1 diabetes mellitus. 
15. Uncontrolled type 2 diabetes mellitus. 
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16. Positive cytomegalovirus (CMV) polymerase chain reaction (PCR) test at 
baseline. 
17. Active hepatitis B virus (HBV; chronic or acute; defined as having a known 
positive hepatitis B surface antigen [HbsAg] test at the time of screening) or 
hepatitis C infection requiring treatment.  
• Participants with past HBV infection or resolved HBV infection (defined as 
the presence of hepatitis B core antibody [HbcAb] and absence of HbsAg) 
are eligible if HBV DNA is negative. 
• Participants with positive for hepatitis C virus (HCV) antibody are eligible 
only if PCR is negative for HCV RNA. 
 
Study 
endpoints: 
Efficacy endpoints: 
Radiographic tumor assessments (computed tomography [CT] scan or magnetic 
resonance imaging [MRI]) will be performed by RECIST 1.1. The endpoints of efficacy 
assessment include: 
• ORR described as the proportion of patients who achieve CR or PR by the 
combination therapy. 
• PFS described as the time from study treatment initiation to the date of disease 
progression or death due to any cause. Patients without progression will be 
censored at the time of the last follow up. 
• OS described as the time from study treatment initiation to the date of death 
due to any cause. Patients without progression will be censored at the time of 
the last follow up. 
 
Safety endpoints: 
• Incidence of AEs including but not limited to treatment-emergent AEs, serious 
AEs, deaths, and clinical laboratory abnormalities, as assessed by the National 
Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) 
v5.0.  
• DLT is defined as any of the following adverse reaction observed during first cycle 
of treatment, and assessed as possibly, probably or definitely related to 
treatment with copanlisib in combination with fulvestrant. NCI CTCAE v. 5.0 will 
be used for grading of AEs. 
o Non-hematological AEs: 
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 Grade ≥2 non-infectious pneumonitis 
 Laboratory abnormalities meeting Hy’s law criteria (AST or ALT >3 
× ULN with concomitant TB >2 × ULN).  (FDA 2009) 
 Any ≥Grade 3 AE, except: 
• 
Grade 3 fatigue lasting ≤5 days 
• 
Grade 3 nausea or vomiting that has resolved to grade 
≤ 2 within 3 days after standard antiemetic therapies 
• 
Grade 3 diarrhea that has resolved to grade ≤2 within 
3 days after standard antidiarrheal therapies 
• 
Isolated laboratory findings not associated with signs 
or symptoms and lasting less than 3 days, including but 
not limited to grade 3/4 alkaline phosphatase, uric 
acid, amylase, and lipase elevations, and grade 3 
electrolyte 
laboratory 
abnormalities 
hypophosphatemia, hypokalemia, hypocalcemia, or 
hypomagnesemia responsive to supplementation and 
grade 3/4 lymphopenia. 
• 
Grade 3 hyperglycemia lasting ≤7 days 
o Hematological AEs: 
 Grade 4 neutropenia lasting ≥7 consecutive days 
 Grade 3 and grade 4 febrile neutropenia 
 Grade 4 anemia (in the absence of disease progression in bone 
marrow) 
 Grade 3 anemia requiring blood transfusion 
 Grade 4 thrombocytopenia of any duration 
 Grade 3 thrombocytopenia lasting ≥7 consecutive days or 
associated with bleeding 
 
o The following event is classified as a DLT: 
 If a full cycle of copanlisib (3 doses) will not be completed due to 
any study intervention-related AE, the AE is considered as a DLT 
 A delay of over 1 week in initiating Cycle 2 of copanlisib and/or 
fulvestrant treatment occurs secondary to any study drug related 
AE, the AE will be considered a DLT 
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 Death not clearly attributed to underlying disease or alternative 
cause 
 
Note: Allergic reactions leading to discontinuation of study interventions will not be 
considered as a DLT and participant will be replaced. 
 
Exploratory endpoints: 
Biomarker-based studies will be conducted using tumor tissue and liquid biopsies to 
assess clonal evolution, and mechanisms of innate and adaptive resistance. 
 
Tumor biopsies, if medically feasible, will be obtained at screening (within 28 days of 
Cycle 1, Day 1), on-treatment after fulvestrant and copanlisib administration on Cycle 2 
Day 1, and at End-of-treatment (EOT). Tumor biopsies will be optional but encouraged, 
especially in patients with a response or prolonged disease control (Figure 2 and 
Appendix A:  Schedule of Assessments). Examples of studies include identification of 
genomic biomarkers of response and intrinsic or adaptive resistance by whole exome, 
targeted next-generation sequencing (NGS), Nanostring DSP,  or other similar methods.  
 
Mandatory blood samples to isolate plasma ctDNA will be collected at pre-treatment 
(Day -28 to Day 1 of Cycle 1), on-treatment (pre-dose -at the same time as the on 
treatment biopsy- on Cycle 2 Day 1 as well as at the first two restaging visits), and post-
treatment at EoT. (Figure 2 and Appendix A:  Schedule of Assessments).  
 
Plasma ctDNA samples will be used to evaluate changes in ctDNA quantity and clonal 
evolution by selected molecular methods that may include targeted NGS, methylation 
sequencing, and droplet digital polymerase chain reaction.. 
 
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1 BACKGROUND AND RATIONALE 
Hormone receptor (HR) expression is a common feature of gynecological cancers similar to breast 
cancer. Among the most common gynecological cancers, 60%- 87% of endometrial and 20%-98% 
of ovarian cancers are ER+ and/or PR+ depending on the specific subtype (2, 17-23). The 
recommended treatment for patients with HR+ cancers includes endocrine therapy, alone or 
combination with chemotherapy or targeted therapy (24-26). However, resistance develops, and 
disease progression eventually happens (27).  
 
The PI3K/AKT/mTOR signaling pathway is one of the most frequently dysregulated pathways in 
human cancer (28-33). PI3K/AKT/mTOR pathway regulates critical cellular activities such as 
proliferation, metabolism, and motility that promote the growth and survival of cancer cells (34). 
The PI3K/AKT/mTOR pathway can be aberrantly activated by multiple factors, including diverse 
oncogenic genomic alterations in PIK3CA, PIK3R1, PTEN, AKT, TSC1, TSC2, LKB1, mTOR, and other 
critical genes (5, 35-44). PTEN negatively regulates PI3K pathway by converting phosphatidyl-
inositol-3,4,5-trisphosphate (PIP3) to phosphatidyl-inositol-4-5-bisphosphate (PIP2) (45, 46). 
PI3Kβ isoform is the driver of PTEN-null cancers (47). Pan-Class I PI3K or PI3Kβ-specific inhibitors 
can be used to target PTEN-deficient tumors. Loss of PTEN and increased PI3K signaling have been 
implicated in resistance to endocrine therapies in ER+ breast cancer, indicating that alterations 
in PI3K/AKT/mTOR pathway might also contribute to resistance in other HR+ gynecological 
cancers to endocrine therapies (3, 48-51).   
 
Endometrial cancer is the leading gynecological cancer in the United States and is characterized 
by an activated PI3K pathway as a result of PTEN inactivating and/or PIK3CA-activating and 
PIK3R1-inactivating alterations (52). 63%, 39%, and 33% of endometrial cancers harbor 
inactivating PTEN alterations according to The Cancer Genome Atlas (TCGA) studies, Catalogue 
of Somatic Mutations in Cancer (COSMIC) database, and a study from our group, respectively. 
PIK3CA and PIK3R1 mutations were identified in 25-52% and 22-28% of endometrial cancers, 
respectively (28, 53, 54).  Interestingly, PIK3CA and PTEN are frequently mutated simultaneously 
in endometrial cancers (28, 52).  
 
Ovarian cancer is the most lethal gynecological malignancy in the United States and other 
developed countries. According to the TCGA study, PIK3CA is altered in 21% of ovarian cancers. 
More than 90% of the PIK3CA alterations in ovarian cancers are gene amplifications. Alterations 
in PTEN and PIK3R1 are also identified in ovarian cancers at lower rates (6% and 3%, respectively) 
(54). 
 
Investigations of the therapeutic targeting of the PI3K/AKT/mTOR pathway have resulted in the 
development of several distinct classes of pathway inhibitors, including PI3K and AKT inhibitors, 
as well as allosteric mTOR and catalytic mTOR kinase inhibitors (28). Despite the significant effort 
invested in the preclinical and clinical development of compounds targeting the PI3K/AKT/mTOR 
pathway, only a few have been approved for clinical use. There are several possible reasons for 
this lack of headway (55-59). Most inhibitors of the oncogenically activated PI3K/AKT/mTOR 
pathway have low ORRs when used as monotherapy (55, 56). The relatively modest activity is 
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1.2 Fulvestrant 
Fulvestrant (Faslodex®) is a competitive ER antagonist that causes degradation of ER upon 
binding. Fulvestrant significantly down-regulates ER protein and also PR expression consistent 
with a lack of intrinsic estrogen agonist effects. It is approved for use in the following indications: 
 
• HR+, human epidermal growth factor receptor 2-negative (HER2-) advanced breast cancer 
in postmenopausal women not previously treated with endocrine therapy. 
• HR+ advanced breast cancer in postmenopausal women with disease progression 
following endocrine therapy. 
• HR+, HER2- advanced or metastatic breast cancer in postmenopausal women in 
combination with ribociclib, as initial endocrine-based therapy or following disease 
progression on endocrine therapy. 
• HR+, HER2- advanced or metastatic breast cancer in combination with palbociclib or 
abemaciclib in women with disease progression after endocrine therapy. 
For more information, refer to the prescribing information. 
 
1.2.1 Safety 
The most common, clinically significant adverse reactions occurring in ≥5% of patients receiving 
Fulvestrant 500 mg were: injection site pain, nausea, bone pain, arthralgia, headache, back pain, 
fatigue, pain in extremity, hot flash, vomiting, anorexia, asthenia, musculoskeletal pain, cough, 
dyspnea, and constipation. 
 
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Increased hepatic enzymes (ALT, AST, ALP) occurred in >15% of Fulvestrant patients and were 
not dose-dependent. 
 
There may be overlapping toxicity when combining copanlisib with fulvestrant, based on current 
clinical experience: gastrointestinal disorders (e.g., nausea), asthenia, and rash have been 
observed with both copanlisib and fulvestrant.  
 
Increased exposure to fulvestrant is observed in the case of hepatic impairment. Therefore, 
caution is required when administering the combination of fulvestrant and copanlisib to patients 
with impaired liver function.  
 
1.3 RATIONALE 
 
1.3.1 Study Rationale and Purpose 
The purpose of this study is to evaluate the efficacy and safety of copanlisib in combination with 
fulvestrant in advanced HR+ solid tumors harboring alterations that activate the PI3K pathway. 
Copanlisib is a potent pan-PI3Ki approved by the FDA for the treatment of patients with relapsed 
follicular lymphoma. Fulvestrant is a SERD and is FDA-approved to treat HR+ metastatic breast 
cancer in addition to other cancers. 
Estrogen and/or progesterone receptors are commonly expressed in the ovarian, endometrial, 
salivary gland, and other cancers (2). Furthermore, we and others found that PIK3CA-activating, 
PTEN-inactivating and PIK3R1-inactivating mutations frequently occur in these HR-expressing 
cancers (3-8, 54). Functional inactivation of PTEN by mutations, loss of copy number and 
epigenetic silencing leads to aberrant activation of PI3K/AKT/mTOR pathway, increasing growth, 
invasion and metastasis of a diverse set of tumors including breast, endometrial, prostate, renal 
cell, hepatocellular, glioblastoma and colorectal cancers (75-77).  
 
Endometrial cancer is the leading gynecological cancer in the United States and is characterized 
by an activated PI3K pathway as a result of PTEN-inactivating and/or PIK3CA-activating and 
PIK3R1-inactivating alterations (52). 63%, 39%, and 33% of endometrial cancers harbor 
inactivating PTEN alterations according to The Cancer Genome Atlas (TCGA) studies, Catalogue 
of Somatic Mutations in Cancer (COSMIC) database, and a study from our group, respectively. 
PIK3CA and PIK3R1 mutations were identified in 25-52% and 22-28% of endometrial cancers, 
respectively (28, 53, 54).  Interestingly, PIK3CA and PTEN are frequently mutated simultaneously 
in endometrial cancers (28, 52). Ovarian cancer is the most lethal gynecological malignancy in the 
United States and other developed countries. According to the TCGA study, PIK3CA is altered in 
21% of ovarian cancers. More than 90% of the PIK3CA alterations in ovarian cancers are gene 
amplifications. Alterations in PTEN and PIK3R1 are also identified in ovarian cancers at lower rates 
(6% and 3%, respectively) (54). 
 
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Activation of PI3K/AKT/mTOR pathway has also been implicated in resistance to endocrine 
therapies in ER+ breast cancer, indicating that alterations in PI3K/AKT/mTOR pathway might also 
contribute to resistance in other HR+ gynecological cancers to endocrine therapies (3, 48, 49). 
Endocrine therapies, including fulvestrant, have been investigated for use in the treatment of 
gynecological malignancies and have demonstrated modest single-agent clinical activity (9-11). 
Similar to breast cancer, efficacy is limited by de novo and acquired endocrine resistance, and 
endocrine resistance can be overcome by PI3K pathway inhibition (12-14). Also, our group and 
others have demonstrated that combinations of mTOR inhibitors with hormone therapy can be 
effective in gynecological malignancies (14, 15).  
 
PI3K blockade, in combination with hormone therapy, demonstrated clinical activity in different 
gynecological and breast cancers. Specifically, the Phase 3 SOLAR-1 trial demonstrated the 
efficacy of the PI3K-α specific inhibitor alpelisib in combination with fulvestrant in the treatment 
of PIK3CA-mutated, hormone receptor HR+ advanced or metastatic breast cancer refractory to 
hormone regimen (1). Given the findings of the SOLAR-1 trial, we hypothesize that the clinical 
benefit of the PI3K pathway inhibitors and endocrine therapy combination can be extended to 
other HR+ solid cancers harboring alterations that activate the PI3K pathway.  
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2 STUDY OBJECTIVES 
The objective of this phase 2 basket study is to evaluate the efficacy and safety of copanlisib in 
combination with fulvestrant administered to subjects with selected ER+ and/or PR+ advanced 
or metastatic solid tumors with PI3K and/or PTEN alterations 
 
2.1 Part 1: Dose confirmation:  
Primary Objective: 
• To evaluate the safety, tolerability, and DLTs of copanlisib 60 mg administered IV on Days 
1, 8 and 15 in combination with fulvestrant 500 mg administered IM on Day 1 and Day 15 
of Cycle 1, and then on Day 1 of each subsequent 28-day cycle to confirm the RP2D of the 
combination therapy.  
 
Secondary objectives: 
• To assess the efficacy of copanlisib administered in combination with fulvestrant as 
outlined in Part 2 by evaluating the ORR. 
• To evaluate additional efficacy measures such as PFS and OS of copanlisib in combination 
with fulvestrant. 
 
Exploratory Objective: 
• To investigate clonal evolution, and mechanisms of resistance using tissue and liquid 
biopsies utilizing ctDNA as outlined in Part 2. 
 
 
2.2 Part 2: Dose expansion: 
Primary objective: 
• To assess the efficacy of copanlisib administered in combination with fulvestrant as 
outlined above by evaluating the ORR. Patients enrolled for Part 1 will be included in this 
efficacy analysis.  
 
Secondary Objectives: 
• To evaluate additional efficacy measures such as PFS and OS of copanlisib in combination 
with fulvestrant. 
• To evaluate the safety and tolerability of copanlisib in combination with fulvestrant. 
 
Exploratory Objective: 
• To investigate clonal evolution, and mechanisms of resistance using tissue and liquid 
biopsies utilizing ctDNA. 
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3 STUDY ENDPOINTS 
3.1 Efficacy endpoints: 
Radiographic tumor assessments (CT scan or MRI) will be performed by RECIST 1.1. The endpoints 
of efficacy assessment include: 
• ORR described as the proportion of patients who achieve CR or PR by the combination 
therapy. 
• PFS described as the time from study treatment initiation to the date of disease 
progression or death due to any cause. Patients without progression will be censored at 
the time of the last follow up. 
• OS described as the time from study treatment initiation to the date of death due to any 
cause. Patients without progression will be censored at the time of the last follow up. 
 
3.2 Safety endpoints: 
• Incidence of AEs including but not limited to treatment-emergent AEs, serious AEs, 
deaths, and clinical laboratory abnormalities, as assessed by the NCI CTCAE v5.0.  
• DLT is defined as any of the following adverse reaction observed during first cycle of 
treatment, and assessed as possibly, probably or definitely related to treatment with 
copanlisib in combination with fulvestrant. NCI CTCAE v. 5.0 will be used for grading of 
AEs. 
o Non-hematological AEs: 
 Grade ≥2 non-infectious pneumonitis 
 Laboratory abnormalities meeting Hy’s law criteria (AST or ALT >3 × ULN 
with concomitant TB >2 × ULN). (FDA 2009) 
 Any ≥Grade 3 AE, except: 
• 
Grade 3 fatigue lasting ≤5 days 
• 
Grade 3 nausea or vomiting that has resolved to grade ≤2 within 
3 days after standard antiemetic therapies 
• 
Grade 3 diarrhea that has resolved to grade ≤2 within 3 days 
after standard antidiarrheal therapies 
• 
Isolated laboratory findings not associated with signs or 
symptoms and lasting less than 3 days, including but not limited 
to grade 3/4 alkaline phosphatase, uric acid, amylase, and 
lipase elevations, and grade 3 electrolyte laboratory 
abnormalities 
hypophosphatemia, 
hypokalemia, 
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hypocalcemia, 
or 
hypomagnesemia 
responsive 
to 
supplementation and grade 3/4 lymphopenia. 
• 
Grade 3 hyperglycemia lasting ≤7 days 
o Hematological AEs: 
 Grade 4 neutropenia lasting ≥7 consecutive days 
 Grade 3 and grade 4 febrile neutropenia 
 Grade 4 anemia (in the absence of disease progression in bone marrow) 
 Grade 3 anemia requiring blood transfusion 
 Grade 4 thrombocytopenia of any duration 
 Grade 3 thrombocytopenia lasting ≥7 consecutive days or associated with 
bleeding 
 
o The following event is classified as a DLT: 
 If a full cycle of copanlisib (3 doses) will not be completed due to any study 
intervention-related AE, the AE is considered as a DLT 
 A delay of over 1 week in initiating Cycle 2 of copanlisib and/or fulvestrant 
treatment occurs secondary to any study drug related AE, the AE will be 
considered a DLT 
 Death not clearly attributed to underlying disease or alternative cause 
 
Note: Allergic reactions leading to discontinuation of study interventions will not be considered 
as a DLT and participant will be replaced. 
 
3.3 Exploratory endpoints: 
Biomarker-based studies will be performed using tumor tissue and liquid biopsies to assess clonal 
evolution, and mechanisms of innate and adaptive resistance. 
 
Tumor biopsies, if medically feasible, will be obtained at screening (within 28 days of Cycle 1, Day 
1) on-treatment after fulvestrant and copanlisib administration on Cycle 2 Day 1 and at EOT. 
Biopsies will be optional but encouraged, especially in patients with a response or prolonged 
disease control. Examples of studies include identification of genomic biomarkers of response 
and intrinsic or adaptive resistance by whole exome, targeted NGS, and Nanostring DSP or other 
similar methods.  
 
 
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Mandatory blood samples to isolate plasma ctDNA will be collected at pre-treatment (Day -28 to 
Day1 of Cycle 1), on-treatment (pre-dose -at the same time as the on treatment biopsy- on Cycle 
2 Day 1 as well as at the first two restaging visits), and post-treatment at EoT.  
Plasma ctDNA samples will be used to evaluate changes in ctDNA quantity and clonal evolution 
by selected molecular methods that may include targeted NGS, methylation sequencing, and 
droplet digital polymerase chain reaction.  
 
4 INVESTIGATIONAL PLAN 
 
4.1 Study Design 
We propose to conduct a multi-arm, open-label, phase 2 basket trial investigating the efficacy 
and safety of copanlisib in combination with fulvestrant in patients with selected HR+ advanced 
or metastatic solid cancers, harboring PI3K or PTEN alterations including ovarian cancer (cohort 
1), endometrial cancer (cohort 2), and breast cancer (cohort 3). Cohort 3 will be enriched to 
include at least 7 patients naïve to any PI3Ki in Stage 1 and also in Stage 2. 
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and will be contacted by telephone every 12 weeks (±14 days) for survival status until death, 
withdrawal of consent, or lost to follow-up.  
Exploratory biomarker studies using pre-treatment, on-treatment, and post-progression tumor 
biopsy tissues and serially collected blood liquid biopsies will investigate clonal evolution, and 
mechanisms of innate and adaptive resistance. 
The study will consist of a screening/baseline phase, treatment phase, safety follow-up, follow-
up visits, and survival follow-up.  
 
4.1.1 Screening/Baseline Phase 
Written informed consent is required before performing any study-specific tests or procedures. 
The signing of the informed consent form (ICF) can occur outside the 28-day screening period. All 
screening evaluations must be completed and reviewed to confirm that patients meet all 
eligibility criteria before study entry. Results of the standard of care (SOC) tests or examinations 
performed before obtaining informed consent and within 28 days prior to study entry may be 
used for screening assessments rather than repeating such tests. The investigator or designee 
will maintain a screening log to record details of all patients screened and to confirm eligibility or 
record reasons for screening failure, as applicable. 
 
ICFs for enrolled patients and for patients who are not subsequently enrolled will be maintained 
at the study site. 
 
The use of remote consenting to obtain informed consent from clinical trial participants using 
paper or electronic consent forms is allowed in this study. 
 
Evaluations for PI3K and/or PTEN alterations and hormone receptor status will be performed by 
a U.S. Clinical Laboratory Improvement Amendments (CLIA)-certified and College of American 
Pathologists-accredited clinical laboratory.  
 
Baseline assessments will be performed within 28 days of study treatment initiation unless 
specified otherwise. 
 
4.1.2 Treatment Phase 
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treatment in the opinion of the investigator, the patient is clinically asymptomatic, and 
continuation of study treatment is approved by the sponsor.  
Assessments will be performed at the time points specified in the Schedule of Assessments 
(Appendix A).  
 
4.1.3 Safety Follow-Up 
The safety follow-up visit should be conducted 30 (+ 5) days after the last dose of study treatment 
or before the initiation of a new anticancer therapy, whichever comes first. AEs that occur prior 
to the safety follow-up visit will be recorded as per the NCI Adverse Events Recording Guidelines 
for Phase II trials. Patients with an AE of > Grade 1 will be followed until the resolution of the AE 
to ≤Grade 1 or baseline. Serious AEs (SAEs) that occur within 30 days of EOT should also be 
followed and recorded.   
 
4.1.4 Follow-Up Visits 
Patients who discontinue study treatment for a reason other than disease progression will move 
into the follow-up phase. Patients will be monitored for disease status by tumor imaging (CT scan 
or MRI, as appropriate) every 8 weeks (±7 days) until PD, death, initiation of new anticancer 
therapy, withdrawal of consent, or lost to follow-up. 
 
4.1.5 Survival Follow-Up 
Patients who experience confirmed disease progression or initiate a new anticancer therapy will 
move into the survival follow-up phase. Patients will be contacted by telephone every 12 weeks 
(±14 days) for survival status until death, withdrawal of consent, or lost to follow-up. 
 
 
4.1.6 Pharmacodynamic Assessments 
In patients with accessible tumor, tumor biopsies may be obtained at Screening (within 28 days 
of Cycle 1 Day 1) on-treatment after fulvestrant and copanlisib administration on Cycle 2 Day 1, 
and at EOT. Tumor biopsies will be optional but encouraged, especially in patients with a 
response or prolonged disease control. Tumor biopsies will be used to evaluate genomic 
biomarkers of response and intrinsic and adaptive resistance. 
 
Mandatory blood samples to isolate plasma ctDNA will be collected at pre-treatment (Day -28 to 
Day 1 of Cycle 1), on-treatment (pre-dose -at the same time as the on treatment biopsy- on Cycle 
2 Day 1 as well as at the first two restaging visits), and post-treatment at EOT. Tissue and plasma 
ctDNA will be used to evaluate molecular and genetic biomarkers of response and resistance to 
study treatment. ctDNA analyses may include genomic profiling, concordance of ctDNA and 
tumor findings, and evolution of genomic profile with treatment upon serial samples. Genomic 
DNA will be used for the determination of somatic changes in the tumor and genomic variations 
that may affect the response. Since the ctDNA and biopsy analyses are performed exclusively for 
research purposes, the results will be used to increase the clinical experience to help move the 
field forward, but they will not be made available to patients. 
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4.1.7 Removal of Patients from the Study 
Every effort within the bounds of safety and patient choice should be made to have each patient 
complete the treatment period of the study. Patients who have treatment discontinued due to 
PD may be treated with any additional therapy deemed appropriate by the investigator. Patients 
with disease progression per RECIST can continue on therapy for clinical benefit if deemed 
appropriate by the investigator. 
Patients may be discontinued from the study for any of the following reasons: 
• Investigator recommends discontinuation and documents the reason(s) 
• There is a need for any treatment not allowed by the protocol  
• Patient’s decision to withdraw consent or discontinue for any reason 
• There is an unacceptable AE thought to be related to study medication 
 
Any patient who discontinues during the treatment period should return to complete safety and 
disease assessments (see Appendix A:  Schedule of Assessments). 
 
4.1.8 COVID-19 Pandemic Study Procedures 
During the COVID-19 pandemic, alternative methods for conducting study assessments should 
be considered when compliance, feasibility, and safety could be assured. These methods may 
include telemedicine visits (e.g., via telephone/video using compliant video-conference tools as 
permitted by health authority regulations) and use of primary care centers and local laboratories 
for blood draws and imaging/radiographs.   
 
If alternative methods are used, local laboratory reference ranges will be documented. Local 
laboratory test results, laboratory accreditation, and reports of tumor assessments should be 
retrieved and documented in the patient’s study records. The principal investigator (PI)/treating 
physician will review labs, determine clinical significance and sign/date results. 
 
The use of remote consenting to obtain informed consent from clinical trial participants using 
paper or electronic consent forms is allowed in this study. 
 
5 STUDY POPULATION 
5.1 Patient Population 
The study population will consist of subjects with selected HR+ (ER+ or/and PR+) advanced or 
metastatic solid tumors with PI3K (PIK3CA, PIK3R1) and/or PTEN alterations. Patients must have 
no available standard therapy known to prolong survival or are not candidates for such a therapy. 
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all patients complete the first 28 days, the study will advance to Part 2 (dose expansion), provided 
there is no more than 1 DLT observed. Patients will be considered evaluable for Part 1 once they 
have completed at least 1 cycle of treatment or they experience DLTs in the first treatment cycle. 
Cohort 1: Ovarian cancer (ER+ and/or PR+, PI3K or PTEN altered). 
Cohort 2: Endometrial cancer (ER+ and/or PR+, PI3K or PTEN altered). 
Cohort 3: Breast cancer (ER+ and/or PR+, PI3K or PTEN altered). Cohort 3 will be enriched to 
include at least 7 patients naïve to any PI3Ki in Stage 1 and also in Stage 2. 
Patients will be considered evaluable for Part 2 once they have completed at least 2 cycles of 
treatment and have at least one efficacy assessment. 
 
5.3 Inclusion Criteria 
Patients eligible for inclusion in this study have to meet all of the following criteria: 
1. Histologically confirmed ER+ and/or PR+ advanced or metastatic solid cancer including 
ovarian cancer (cohort 1), endometrial cancer (cohort 2), or breast cancer (cohort 3).  
Cohort 3 will be enriched to include at least 7 patients naïve to any PI3Ki in Stage 1 and 
also in Stage 2. ER and/or PR positivity is defined as >10% immunohistochemical staining 
of any intensity. 
2. Presence of one or more PI3K and/or PTEN alterations in tumor tissue. Genetic alterations 
will include PIK3CA gain of function mutations, PIK3R1 loss of function mutations, PTEN 
loss of function mutations, and PTEN deletions. 
3. Measurable disease per RECIST 1.1. 
4. The patient (or legally acceptable representative, if applicable) provides written informed 
consent for the study. 
5. Female or male >18 years of age on the day of informed consent signing. 
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6. Patients have no available standard therapy known to prolong survival. For cohort 3 prior 
treatment with a PI3Ki and everolimus is not required. The patients with or without prior 
treatment with PI3Ki and everolimus will qualify for enrollment 
7. Adequate archived tumor tissue for the analysis for PI3K and PTEN alterations if available. 
8. ECOG performance status of ≤2.  
9. Adequate organ and marrow function as defined below: 
a. Hemoglobin ≥9.0 g/dL  
b. Absolute neutrophil count ≥1.5 × 109/L  
c. Platelet count ≥100 × 109/L  
d. TB ≤1.5 × institutional ULN; Patients with known Gilbert’s disease who have TB ≤3 
× ULN may be enrolled) 
e. AST/ ALT ≤3 × ULN. If patient has liver metastases, AST and ALT ≤5.0 × ULN.  
f. Creatinine ≤1.5 x ULN 
g. International normalized ratio ≤1.5. 
10. Fasting blood glucose ≤140 mg/dL and hemoglobin A1c ≤8.5% (both criteria have to be 
met). 
11. Cardiac ejection fraction ≥45%.  
12. Women of childbearing potential must have a negative serum or urine pregnancy test 
(minimum sensitivity 25 IU/L or equivalent units of human chorionic gonadotropin [HCG]) 
within 14 days prior to the initiation of treatment and/or postmenopausal women must 
be amenorrheic for at least 12 months to be considered of non-childbearing potential. 
Women of childbearing potential (WOCBP) must agree and commit to the use of 2 highly 
effective methods of birth control throughout the duration of the study until at least 
4 months following the last dose of study drug. Acceptable methods are defined as those 
that result, alone or in combination, in a low failure rate (i.e., less than 1% per year) when 
used consistently and correctly, such as surgical sterilization, an intrauterine device, or 
hormonal contraception in combination with a barrier method. Women using 
systemically acting hormonal contraceptives should add a barrier method. In certain 
countries (if permitted by law), WOCBP may agree to abide by heterosexual sexual 
abstinence during the time of participation in this study. 
13. Male patients and their female partners of childbearing potential must agree and commit 
to 
use 
a 
barrier 
contraception 
(eg, 
condom 
with 
spermicidal 
foam/gel/film/cream/suppository) throughout the duration of the study until at least 
60 days following the last dose of study drug, in addition to their female partners using 
either an intrauterine device or hormonal contraception and continuing until at least 
4 months following the last dose of study drug. This criterion may be waived for male 
patients who have had a vasectomy > 6 months before signing the ICF.  
14.  Willing and able to comply with the protocol for the duration of the study, including 
undergoing treatment and scheduled visits and examinations. 
 
5.4 Exclusion Criteria 
Patients eligible for this study must not meet any of the following criteria: 
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1. The patient has CNS involvement. If the patient fulfills the following 3 criteria, she/he is 
eligible for the study: 
a. Completed prior therapy (including radiation and/or surgery) for CNS metastases, 
and 
b. CNS tumor is radiologically stable for ≥28 days prior to study start, and 
c. The patient is not receiving steroids and enzyme-inducing antiepileptic 
medications for brain metastases. 
2. Patients with HER2 positive breast cancer. 
3. Patients must be ≥4 weeks or at least 5 half-lives beyond treatment with any 
chemotherapy or other investigational therapy including hormonal, biological, or 
targeted agents at the time of treatment initiation. 
-   NOTE: If the patient received major surgery, she/he must have recovered 
adequately from the toxicity and/or complications from the intervention prior to 
starting the study treatment.   
4. For cohorts 1 and 2 prior treatment with fulvestrant or any PI3Ki. 
5. Known hypersensitivity to copanlisib or fulvestrant, or any of the excipients of copanlisib 
or fulvestrant. 
6. Concomitant use of strong CYP3A4 inducers (e.g., rifampicin, phenytoin, carbamazepine, 
phenobarbital, St. John’s wort) or inhibitors (e.g., ritonavir, saquinavir, nelfinavir, 
boceprevir, telaprevir, ketoconazole, omeprazole). Use of strong inhibitors and/or 
inducers of CYP3A4 is not permitted from Day -14 of Cycle 1 until the end of the study 
treatment. (See Appendix F: Strong Inhibitors or Strong Inducers of CYP3A4) 
7. The patient is currently receiving warfarin or other coumarin derived anticoagulants for 
treatment, prophylaxis, or otherwise. Therapy with heparin, low molecular weight 
heparin, fondaparinux, or direct oral anticoagulants such as rivaroxaban or apixaban is 
allowed. 
8. Known additional malignancy that is progressing or requires active treatment.  
9. History or current evidence of any condition, therapy, or laboratory abnormality that 
might confound the results of the study, interfere with the patient’s participation for the 
full duration of the study or is not in the best interest of the patient to participate, in the 
opinion of the treating investigator.   
10. Known psychiatric or substance abuse disorders that would interfere with cooperation 
with the requirements of the study. 
11. Known history of human immunodeficiency virus infection. 
12. History or current symptomatic pneumonitis. 
13. Has clinically significant, uncontrolled heart disease and/or recent cardiac events, 
including any of the following: 
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a. History of angina pectoris, symptomatic pericarditis, or myocardial infarction 
within 12 months prior to study entry 
b. History of documented congestive heart failure (New York Heart Association 
functional classification III-IV) 
c. Documented cardiomyopathy 
d. History of any cardiac arrhythmias, e.g., ventricular, supraventricular, nodal 
arrhythmias, or conduction abnormality in the previous 12 months 
e. Uncontrolled hypertension defined by a systolic blood pressure (BP) ≥140 mmHg 
and/or diastolic BP ≥90 mmHg, with or without antihypertensive medication over 
the course of one clinic visit at intervals of ≥30 minutes. Initiation or adjustment 
of antihypertensive medication(s) is allowed prior to screening. 
14. Type 1 diabetes mellitus. 
15. Uncontrolled type 2 diabetes mellitus. 
16. Positive cytomegalovirus (CMV) polymerase chain reaction (PCR) test at baseline. 
17. Active hepatitis B virus (HBV; chronic or acute; defined as having a known positive 
hepatitis B surface antigen [HbsAg] test at the time of screening) or hepatitis C infection 
requiring treatment.  
• Participants with past HBV infection or resolved HBV infection (defined as the 
presence of hepatitis B core antibody [HbcAb] and absence of HbsAg) are eligible 
if HBV DNA is negative. 
• Participants with positive for hepatitis C virus (HCV) antibody are eligible only if 
PCR is negative for HCV RNA. 
 
6 STUDY TREATMENT 
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consent, or discontinuation from the study treatment for any other reason. Patients who develop 
disease progression as centrally assessed according to the RECIST v1.1 criteria, as appropriate, 
may be allowed to continue treatment if the patient is benefitting from the study treatment in 
the opinion of the investigator, the patient is clinically asymptomatic, and continued study 
treatment is approved by the sponsor. 
 
Dose escalation will not be allowed for progressive disease. 
 
6.1.1 Copanlisib dosing requirements for pre-dose glucose levels 
Copanlisib should be administered if pre-glucose level is <160 mg/dL for fasting, or <200 mg/dL 
for non-fasting participants. Fasting status refers to a ≥ 8 hours fast. Non-fasting status includes 
any caloric intake, such as meals, as well as juice, snacks, and other caloric intake not consistently 
called a meal. 
For diabetic participants, who take insulin treatment at any cycle visit, timing and content of meal 
intake will be managed by the investigator. Consultation with treating physician or 
endocrinologist is advised. 
Because of inhibitory effect on PI3K α-isoform, which is implicated in insulin metabolism, 
copanlisib infusions may be associated with temporary increase in blood glucose. Addition of a 
meal in close proximity to copanlisib infusion may exacerbate glucose increase.  
On infusion days, a low calorie or low carbohydrate diet is recommended. The timing and content 
of caloric meal intake and additional glucose testing (if clinically indicated) is managed and 
monitored by the investigators based on glucose response patterns during prior intervention 
days. Consultation with endocrinologist is advised. 
All glucose measurements done at the site, oral glucose lowering medication and/or insulin 
administration, if applicable, fasting/non-fasting status and meal intake timing on infusion days 
will be collected as part of the clinical source documentation. 
 
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6.2 Dose Modification 
Any toxicity observed during the study can be managed by interruption of the dose of study 
treatments or dose reductions. Repeated dose interruptions are allowed as required, for a 
maximum of 4 weeks on each occasion. Where toxicity recurs following re-challenge with study 
drugs, and where further dose interruption is considered inadequate for toxicity management, 
then withdrawal is indicated.  
 
If either of the study drugs or both drugs need to be held due to AEs, then the study drug deemed 
to be responsible for the AE will be held until AE resolves to grade 1 or baseline. When copanlisib 
or fulvestrant dosing is interrupted, either the patient must recover completely, or the toxicity 
must revert to NCI CTCAE ≤Grade 1 or baseline before restarting study treatment. Patients whose 
NCI CTCAE Grade 3 or 4 event does not resolve to ≤1Grade or baseline within 4 weeks should be 
withdrawn from the study. When a patient withdraws prior to study completion, all applicable 
activities scheduled for the final study visit should be performed at the time of withdrawal. Any 
AEs that are present at the time of withdrawal should be followed until ≤Grade 1 or baseline.  
 
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6.3 Toxicity Management 
All dose modifications should be documented, including the approach taken and a clear rationale 
for the need for modification. For dose modification, the investigator must first assess if the 
toxicity is considered at least possibly related to the study treatment and must then apply the 
dose modification guidelines accordingly. Below are dose delay and management tables for the 
study drugs. These algorithms should be followed unless there are specific clinical circumstances 
for which the treating physician decides an alternative treatment approach is clinically 
appropriate. Consultation with the study chair is recommended. 
 
6.3.1 Copanlisib toxicity management 
 
Table 5: Management of Nausea/vomiting 
Toxicity 
Action to be Taken 
CTCAE Grade 1  
No change in dose  
CTCAE Grade 2  
Hold* until ≤Grade 1. No change in dose 
CTCAE Grade 3 
Hold* until ≤Grade 2. Resume at one dose 
level lower, if indicated.** 
CTCAE Grade 4 
Off copanlisib treatment 
*Patients requiring a delay of >2 weeks may go off protocol therapy. 
**Patients requiring >2 dose reductions should go off protocol therapy. 
Recommended management: Antiemetics 
 
Table 6: Management of Diarrhea 
Toxicity 
Action to be Taken 
CTCAE Grade 1  
No change in dose  
CTCAE Grade 2  
Hold* until ≤Grade 1. No change in dose 
CTCAE Grade 3 
Hold* until ≤Grade 2. Resume at one dose 
level lower, if indicated.** 
CTCAE Grade 4 
Off copanlisib treatment 
*Patients requiring a delay of >2 weeks may go off protocol therapy. 
**Patients requiring >2 dose reductions should go off protocol therapy. 
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Recommended management: Loperamide antidiarrheal therapy 
Dosage schedule: 4 mg at the first onset, followed by 2 mg with each loose motion until diarrhea-free for 12 hours (maximum dosage: 
16 mg/24 hours) 
Adjunct anti-diarrheal therapy is permitted and should be recorded when used. 
 
Table 7: Management of thrombocytopenia 
Toxicity 
Action to be Taken 
CTCAE Grade 1  
No change in dose  
CTCAE Grade 2  
No change in dose 
CTCAE Grade 3 
Hold* until ≤Grade 1. Resume at one dose 
level lower, if indicated. ** 
CTCAE Grade 4 
Off copanlisib treatment 
*Patients requiring a delay of >2 weeks may go off protocol therapy. 
**Patients requiring >2 dose reductions should go off protocol therapy. 
 
Table 8: Management of Neutropenia 
Toxicity 
Action to be Taken 
CTCAE Grade 1  
No change in dose  
CTCAE Grade 2  
No change in dose 
CTCAE Grade 3 
Hold* until ≤Grade 2. Resume at one dose 
level lower, if indicated.** 
CTCAE Grade 4 
Off copanlisib treatment 
*Patients requiring a delay of >2 weeks may go off protocol therapy. 
**Patients requiring >2 dose reductions should go off protocol therapy. 
 
6.3.1.1 Dose Modification Rules for Transient Post-Infusion Hyperglycemia 
Patients who develop transient post-infusion glucose >250 mg/dL after study drug administration 
may continue treatment. However, the next infusion must be delayed until the patient’s pre-
infusion glucose levels return to <160 mg/dL (fasting) or <200 mg/dL (non-fasting). Guidelines for 
the management of transient glucose increases are given in the tables below. The continuing 
occurrence of post-infusion blood glucose >500 mg/dL, based on repeated laboratory analysis 
despite optimal glucose-lowering therapy after 2 infusions of copanlisib, will require dose 
reduction by one dose level. 
• Further dose reduction (where appropriate per study design/population) is allowed as 
long as discontinuation criteria were not met. 
• Dose re-escalation is allowed when a patient has achieved controlled glucose levels per 
investigator’s judgment. 
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• Persistent occurrence of post-infusion blood glucose >500 mg/dL based on laboratory 
analysis, which occurred at the lowest dose level despite optimal glucose-lowering 
therapy (after at least one cycle of treatment) with the consultation of a diabetes 
specialist requires permanent discontinuation of the study drug. 
 
Table 9: Management of post-infusion glucose increase 
Toxicity 
Action to be Taken 
Glucose increase of CTCAE Grade 1 
(abnormal glucose level above baseline with 
no medical intervention) 
• Continue study treatment 
Glucose increase of CTCAE Grade 2 (change 
in daily management, from baseline for a 
diabetic; oral antiglycemic agent is initiated; 
workup for diabetes) 
• Hydration as clinically indicated 
• When planning next infusion 
prophylaxis with oral glucose-
lowering medication per local SOC is 
recommended 
• Consultation with an endocrinologist 
for diabetic patients is recommended 
Glucose increase of CTCAE ≥Grade 3 (insulin 
therapy initiated; hospitalization or urgent 
intervention indicated; life-threatening 
consequences) 
• Hydration as clinically indicated 
(orally, IV) 
• Insulin therapy per local SOC 
• When planning next infusion consider 
prophylaxis with oral glucose-
lowering medication per local SOC 
• Consultation with an endocrinologist 
is recommended 
 
Table 10: Management of Transient Glucose Increase on the Day of Copanlisib Infusion 
Criteria 
Recommendations 
Asymptomatic glucose increases to a value 
≤250 mg/dL 
• Does not generally require treatment 
with glucose-lowering medication. 
Asymptomatic glucose increases to a value 
>250 mg/dL 
• Should have repeated laboratory 
glucose determination. 
• If the repeated glucose value is 
decreasing, the glucose may be 
followed without glucose-lowering 
medication treatment if hydration 
status is normal as clinically assessed. 
• Consultation with an endocrinologist 
is recommended. 
• Hydration, if appropriate. 
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• When planning the next infusion, 
consider prophylaxis with oral 
glucose-lowering medication. 
Symptomatic or persisting glucose increases 
to a value >250 mg/dL 
• Hydration status should be clinically 
assessed. 
• If the clinical assessment is consistent 
with dehydration, fluids should be 
given as clinically appropriate (orally 
or IV). 
• Laboratory tests confirming increase 
should be repeated. If the repeated 
glucose value is persistent and/or the 
patient is symptomatic and/or the 
hydration status indicates the need 
for hydration, glucose-lowering 
medication should be administered. 
• Prompt input from a diabetes 
specialist should be obtained. 
• Hydration if appropriate 
• Rapid/short-acting insulin may be 
given for glucose persisting at 
>250 mg/dL or if the patient is 
symptomatic during the infusion day. 
• Rapid/short-acting insulin. 
• According to the institution sliding 
scale coverage of glucose persisting at 
>250 mg/dL is recommended, with 
oral or IV hydration as clinically 
appropriate. When planning the next 
infusion, consider prophylaxis with 
oral glucose-lowering medication. 
 
Table 11: Management of Transient Glucose Increase on Subsequent Days Following Copanlisib 
Infusion 
Criteria 
Recommendations 
Grade 2 Max post infusion glucose 
>200 mg/dL noted on subsequent days 
• Oral glucose-lowering medication 
recommended on subsequent days. 
• Consultation with an endocrinologist 
is recommended. 
• The use of 
sulphonylurea/metaglinides, insulin 
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secretagogues medications to manage 
increased glucose levels post drug 
infusions is not recommended. 
• Treatment with glucose-lowering 
medication suggested according to 
the local standards of practice. 
•  
 
The need for glucose monitoring at home should be determined by the investigator based on the 
post-infusion glucose profile and clinical status of the patient. 
6.3.1.2 Monitoring of diabetic patients 
If the patient already monitors his/her blood glucose as part of routine anti-diabetic care, the 
routine measurements should not be replaced by the study-specific measurements. 
6.3.1.3 Management 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 BP increases following copanlisib will need to be individualized for 
each patient, but experience from a Bayer-sponsored phase 1 study with copanlisib has 
suggested the benefit of dihydropyridine calcium channel blockers (i.e., amlodipine, felodipine). 
Topical nitrates should also be considered. Verapamil and diltiazem (non-dihydropyridine 
calcium channel blockers and moderate inhibitors of CYP3A4) should be used with caution due 
to a potential CYP3A4 interaction. In general, it is advisable for investigative teams to be 
prepared, so that anti-hypertensive medication is readily available in case of need. 
In the event of the occurrence of arterial hypertension ≥150/90 mmHg during infusion of 
copanlisib at any cycle, antihypertensive treatment is suggested as indicated in the Dose 
Modification of Copanlisib for Arterial Hypertension Table 13 below. In the event of the 
occurrence of grade 3 arterial hypertension (≥160/100 mmHg) during infusion of copanlisib, the 
infusion should be interrupted, and anti-hypertensive treatment, as suggested above, is 
administered. The infusion can be resumed when BP has returned to <150/90 mmHg. 
Table 12: Management of Blood Pressure 
Toxicity (CTCAE) 
Study Drug action 
Recommendation 
Pre-dose measurements 
BP ≥150/90 mmHg 
No dose should be given until 
recovery to <150/90 mmHg 
Consider BP-lowering 
medication. Dosing can 
proceed on the scheduled 
day if, after at least 2 
consecutive measurements, 
BP returns to 
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<150/90 mmHg. If BP 
doesn’t return to 
<150/90 mmHg, delay 
dosing until the next visit. 
During infusion: CTCAE 
hypertension of grade 3 
or ≥160/100 mmHg 
The infusion can be 
interrupted or slowed down, 
and the administration of BP-
lowering therapy should be 
initiated. 
The infusion may be 
resumed when BP has 
returned to <150/90 mmHg 
at the investigator’s 
discretion or skipped. 
Subsequent study drug 
administrations may be 
reduced by 1 dose level at 
the investigator’s 
discretiona. 
Post-dose: 
Drug-related CTCAE 
hypertension of grade 3 
or ≥160/100 mmHgb 
 
Administration of BP-
lowering therapy should be 
initiated according to the 
local SOC. 
Additional measurements 
to be performed as clinically 
indicated until recovery to 
<150/90 mmHg. 
Subsequent study drug 
administrations may be 
reduced by 1 dose level at 
the investigator’s 
discretionb. 
CTCAE hypertension of 
grade 4 
Permanent discontinuation 
 
a: The lowest dose level is 45 mg. 
b: Not manageable despite optimal antihypertensive treatment. 
 
6.3.1.3.1 Blood pressure measurement on treatment days 
BP will be measured every 5-10 minutes prior to each copanlisib dose (no more than 4 
measurements) until there are two consecutive results <150/90 mmHg. If BP is ≥150/90 mmHg, 
the investigator can consider a medical intervention or delaying the infusion of the study drug. 
The patient should rest for 5-10 min before BP is recorded. 
On infusion days, BP will be measured at 0 hour (pre-dose), 30 minutes (mid-infusion), 
60 minutes (end of infusion), and 1 hour after the end of infusion 
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NOTE: A window of ±10 minutes is allowed for all BP measurements, except for pre-dose (0 hour) 
measurement. 
6.3.1.4 Dermatologic toxicity 
The recommendations for dose modifications in cases of dermatologic toxicity are outlined in 
Table 14. If these recommendations are not followed, the rationale for other measures will be 
documented in detail in the participant’s medical record. 
 
Table 13: Dose modification of copanlisib for dermatologic toxicity 
Toxicity 
(CTCAE grade) 
Occurrence 
For current course of 
therapy 
For next course of therapy 
Grade 1 and 2 Any appearance No change 
No change 
Grade 3 a  
1st appearance 
Interruption until Grade ≤2 
Decrease by one dose level b 
 
2nd appearance 
Interruption until Grade ≤2 
Decrease by one dose level b 
 
3rd appearance 
Permanent discontinuation 
– 
Grade 4 
1st appearance 
Permanent discontinuation 
–  
Abbr.: CTCAE = Common terminology criteria of adverse events. 
a. Despite maximum supportive therapy. 
b. 
The lowest dose level is 30 mg; if a participant is already on the 30 mg dose level study intervention and 
meets criteria for further decrease of dose, copanlisib will be discontinued permanently. 
 
If dermatologic changes occur, the participant should be treated quickly and aggressively. Table 
15 can be used as guidance. 
 
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Table 14: Guidance on treatment of skin toxicities 
MILD (CTCAE Grade 1) 
Dry Skin / 
Fissures 
Emollients, - Eucerin or Aquaphor plus gentle soaps  
(Dove, Cetaphil, Basis), use fragrance free detergents 
Rash 
Topical hydrocortisone 2.5% and/or clindamycin 1% gel plus doxycycline 
100 mg b.i.d. or Minocycline 100 mg b.i.d. 
Nail Changes 
Moisturizers 
Pruritus 
Pramoxine 1% cream or Sarna Ultra Cream 
MODERATE (CTCAE Grade 2) 
Dry Skin / 
Fissures 
Emollients and topical as above plus Ammonium lactate or Urea 20% 
Rash 
Topical hydrocortisone 2.5% and/or clindamycin 1% gel plus doxycycline 
100 mg b.i.d. or Minocycline 100 mg b.i.d.  
Nail Changes 
Vinegar soaks (dilute 1:1 white vinegar in water and soak fingers for 10 
min 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 pack 
Nail Changes 
Topical antibacterial / antifungal (ciclopirox) cream or Topical high 
potency steroids (clobetasol ointment)  
Consider dermatology consult for nail avulsion 
Pruritus 
Pregabalin 50-100 mg b.i.d.  
Abbr.: b.i.d. = Twice daily, CTCAE = Common terminology criteria for adverse events. 
 
6.3.1.5 Management of Infections 
Serious, including fatal, infections occurred in 8.9% of 558 patients treated with copanlisib 
monotherapy. The most common serious infection was pneumonia. Monitor patients for signs 
and symptoms of infection and withhold copanlisib for Grade 3 and higher infection. 
Serious pneumocystis jiroveci pneumonia (PJP) occurred in 0.9% of 558 patients treated with 
copanlisib monotherapy. Before initiating treatment with copanlisib, consider PJP prophylaxis for 
populations at risk. Withhold copanlisib in patients with suspected PJP infection of any grade. If 
confirmed, treat infection until resolution, then resume copanlisib at previous dose with 
concomitant PJP prophylaxis 
6.3.1.6 Management of Non-Infectious Pneumonitis 
The investigator is requested to differentiate between non-infectious pneumonitis, and 
infectious pneumonitis (viral, bacterial, or fungal), aspiration pneumonitis, or other pneumonitis 
clearly not due to a potential hypersensitivity reaction to the copanlisib infusion; and provide the 
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basis for his/her assessment that it is infectious or other, as appropriate. The investigator is 
requested to report with the most specific clinical terms to describe the condition, not simple 
“pneumonitis”. 
In the event of suspected non-infectious pneumonitis, modify copanlisib treatment as per Table 
16 below. 
Table 15: Management of Non-Infectious Pneumonitis 
Suspected or confirmed 
NIP per CTCAE 
Action taken 
Re-treatment dose after 
recovery 
Grade 1 
No Change 
N/A 
Grade 2 
Dose Interruption Until 
recovery to ≤Grade 1 
Decrease dose to the next 
lowest dose levela.  
Grade 2 second re-
occurrence 
Permanent Discontinuation 
N/A 
Grade 3 
Permanent discontinuation 
N/A 
Grade 4 
Permanent discontinuation 
N/A 
NA = Not applicable; NIP = Non-infectious pneumonitis;  
a: Not applicable for 45 mg dose level. No re-escalation is allowed after the dose reduction. The lowest dose 
level is 45 mg; if a patient is already on the 45 mg dose level and cannot tolerate treatment study treatment will 
be discontinued permanently. 
 
6.3.2 Fulvestrant toxicity management 
6.3.2.1 
Management of Hepatic Impairment 
A Fulvestrant dose of 250 mg is recommended for patients with moderate hepatic impairment 
(Child-Pugh class B) to be administered IM into the buttock slowly (1 - 2 minutes) as one 5 mL 
injection on Day 1 and Day 15 of the first and  Day 1 of each subsequent 28-day cycle. Fulvestrant 
has not been evaluated in patients with severe hepatic impairment (Child-Pugh class C). 
 
6.3.3 Other toxicities 
Other toxicities that are not clearly attributable to copanlisib or fulvestrant, including overlapping 
toxicities, should be initially managed as follows: 
 
- 
Treatment interruption or dose modification for Grade 1 or grade 2 AEs per CTCAE would 
be implemented at the investigator and patient’s discretion.  
- 
Both agents should be interrupted for Grade 3 AEs per CTCAE until the AEs have reached 
grade 1 or have returned to baseline. Following the resolution of toxicity, copanlisib may 
be resumed at the same dose level or at one or more dose levels lower, at the 
investigator’s discretion. Fulvestrant should be resumed at the same dose level. 
Sequential reintroduction of each agent should be considered if clinically appropriate. 
- 
Both agents should be interrupted for Grade 4 AEs per CTCAE until the AEs have reached 
grade 1 or have returned to baseline. For AEs that are not life-threatening and that can 
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be managed, treatment with copanlisib may be resumed at a lower dose level, but 
fulvestrant should be resumed at the same dose level. Otherwise, patients must 
discontinue treatment. Sequential reintroduction of each agent should be considered if 
clinically appropriate.  
 
6.3.4 COVID-19/SARS-CoV-2 Infection 
The following guidelines apply to patients with confirmed (positive by regulatory authority-
approved test) or presumed (test pending/clinical suspicion) coronavirus disease 2019 (COVID-
19)/severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection:  
• For patients with active SARS-CoV-2 infection, study treatment should be delayed for at 
least 14 days from the first positive COVID-19 test or start of symptoms, whichever is 
later.  
• Prior to restarting study treatment, patients should be afebrile for 72 hours and SARS-
CoV-2-related symptoms should have recovered to Grade ≤1 for a minimum of 72 hours. 
The sponsor should be informed when study treatment is resumed.  
 
The sponsor and/or the supporting company must be informed within 24 hours of awareness of 
a patient with COVID-19/ SARS-CoV-2 infection. 
6.4 Concomitant Therapy 
All medications that the investigator considers necessary for a patient’s welfare may be 
administered at the discretion of the investigator in keeping with the community standards of 
medical care. All concomitant medication received within 28 days before the first dose of study 
treatment and 30 days after the last dose of study treatment  -including all prescription, over-
the-counter, IV medications and fluids, supportive care drugs and the drugs used to treat AEs or 
chronic diseases, and non-drug supportive interventions- will be captured in the electronic 
medical record (EMR), but not in the electronic case report forms (eCRF). 
 
6.4.1 Prohibited Medications/Therapies 
Use of the following concomitant medications/therapies is prohibited during the study: 
 
• Any chemotherapy, radiation therapy, immunotherapy, hormone, or biologic therapy for 
cancer treatment other than that under investigation in this study.  
Exceptions include the following: 
o Palliative radiotherapy is allowed during the study if the patient is otherwise 
benefitting from the study treatment in the opinion of the investigator. Study 
treatment should be discontinued for a minimum of 3 days before a patient 
undergoes palliative radiation treatment. Study treatment should be restarted 
within 28 days as long as any bone marrow toxicity has recovered.   
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• Concomitant use of herbal preparations containing CYP3A4 inducers (e.g. St John’s Wort) 
is not permitted during the study. 
• Grapefruit and grapefruit juice (a CYP3A4 inhibitor) consumption is not permitted during 
the study. 
• 
The use of systemic corticosteroids or immunosuppressants after starting the study 
intervention should be avoided, except:  
o (1) If a participant is on chronic corticosteroid therapy, e.g. replacement therapy 
such as physiologic corticosteroid replacement therapy for adrenal or pituitary 
insufficiency (in dosing not exceeding 10 mg daily of prednisone equivalent) is not 
considered a form of systemic treatment. 
o (2) Systemic corticosteroids above 10 mg prednisolone or equivalent or other 
immunosuppressants may be allowed after starting the study intervention for the 
management of acute conditions (e.g. treatment of non-infectious pneumonitis) 
or as premedication for radiological contrast infusion as clinically indicated.  
Participants may be using inhaled or topical steroids. For more information about steroid 
use in management of skin toxicities, please refer to 6.3.1.4. 
If treatment with a prohibited medication/therapy is necessary, the patient will be withdrawn 
from the study after discussion with the sponsor. 
 
6.4.2 Potential Drug Interactions 
 
No drug-drug interaction (DDI) effect of copanlisib on fulvestrant metabolism is expected, 
because copanlisib is not an inhibitor or inducer of drug metabolizing enzymes involved in 
fulvestrant metabolism, and vice versa.  
 
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6.5 Supportive Care 
Patients should receive appropriate supportive care measures as deemed necessary by the 
investigator.  
 
Gastrointestinal Disorders  
Nausea, vomiting, and diarrhea have been very common in patients treated with copanlisib. 
Patients with these side effects may require supportive care, including antiemetics, antidiarrheal 
medications, and IV fluids. Patients should receive appropriate antiemetic treatment at the first 
onset of nausea or vomiting in accordance with local practice guidelines. As per international 
guidance on antiemetic use in cancer patients (European Society for Medical Oncology, National 
Comprehensive Cancer Network), generally, a single-agent antiemetic should be considered (e.g., 
dopamine receptor antagonist, antihistamine, or dexamethasone).  
 
Fatigue  
Fatigue has been very common in patients treated with copanlisib. Patients with fatigue may 
require symptomatic management as needed.  
Hematological Disorders  
Patients with anemia and/or thrombocytopenia may require supportive care, including 
transfusion of red blood cells and platelets and administration of hematological growth factors.  
 
Metabolism abnormalities 
Hypophosphatemia has occurred in patients treated with copanlisib. Phosphate replacement 
might be needed. 
 
Hyperglycemia 
Hyperglycemia has been very common in patients treated with copanlisib. Hydration and/or oral 
glucose-lowering medication or insulin might be needed depending on the severity of the blood 
glucose level and the study treatment stage.  
 
Vascular Disorders 
Hypertension (includes secondary hypertension) has been frequent in patients treated with 
copanlisib. Anti-hypertensive treatment might be needed to manage hypertension. 
 
Infections 
Lower respiratory tract infections have been very common in patients treated with copanlisib. 
Infections need to be treated until resolution before resuming the treatment with copanlisib. 
 
6.6 Contraception 
Both copanlisib and fulvestrant can cause fetal harm during embryonic development. In pregnant 
animal models, the administration of copanlisib or fulvestrant caused embryo-fetal death and 
fetal abnormalities. No information is available on the safety of copanlisib or fulvestrant in 
pregnant human females. Neither copanlisib nor fulvestrant should be administered to pregnant 
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women. Female patients of childbearing potential must either abstain from heterosexual 
intercourse or use a highly effective method of contraception for the course of the study through 
150 days after the last dose of copanlisib or fulvestrant. Males with female partners of 
reproductive potential must abstain from sexual intercourse. Alternatively, they and their 
partners must use a highly effective method of contraception when engaging in sexual 
intercourse for the course of the study through 90 days after the last dose of copanlisib or 
fulvestrant.  
 
Patients should be informed that taking the study medications may involve unknown risks to the 
fetus (unborn baby) if the pregnancy were to occur during the study. To participate in the study, 
they must adhere to the contraception requirement for the duration of the study and after the 
last day of treatment as described in the paragraph above. If there is any question that a patient 
will not reliably comply with the requirements for contraception, that patient should not be 
entered into the study. 
 
6.6.1 Female Patients 
Women in the following categories are not considered women of childbearing potential: 
• Premenopausal female with 1 of the following: 
o Documented tubal ligation 
o Documented hysterectomy 
o Documented bilateral salpingectomy 
o Documented bilateral oophorectomy 
• Postmenopausal female 
Postmenopausal is defined as ≥45 years of age, with at least 12 months of spontaneous 
amenorrhea.  
 
Female patients of childbearing potential are eligible to participate if they agree to use a highly 
effective method of contraception consistently and correctly, as described in Table 17 during the 
protocol-defined timeframe.  
 
Table16: Highly Effective Contraception Methods 
• Combined (estrogen and progestogen-containing) hormonal contraception 
o Oral 
o Intravaginal 
o Transdermal 
• Progestogen-only hormonal contraception 
o Oral 
o Injectable 
o Implantable 
• Intrauterine devices and intrauterine hormone-releasing system 
• Bilateral tubal occlusion (women) 
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• Vasectomized partner  
A vasectomized partner is a highly effective contraception method provided that the 
partner is the sole male sexual partner of the woman of childbearing potential and the 
absence of sperm has been confirmed. If not, an additional highly effective method of 
contraception should be used.  
• Sexual abstinence (men and women) 
Sexual abstinence is considered a highly effective method only if defined as refraining from 
heterosexual intercourse during the entire period of risk associated with the study 
treatment. The reliability of sexual abstinence needs to be evaluated in relation to the 
duration of the study and the preferred and usual lifestyle of the patient. Periodic 
abstinence (such as a calendar, symptothermal and post-ovulation methods, withdrawal 
(coitus interruptus), and the lactational amenorrhea method are not acceptable methods of 
contraception  
 
 
6.6.2 Male Patients 
Male patients of childbearing potential must use a male condom plus spermicide. In addition, if 
the male patient’s female partner is of childbearing potential, she should use a highly effective 
contraception method, as described in Table 17.  
 
6.7 Use in Pregnancy 
If a patient inadvertently becomes pregnant while on study treatment, the patient will 
immediately be removed from the study. The investigative team will contact the patient at least 
monthly and document the patient’s status until the pregnancy has been completed or 
terminated.  The investigator must notify the sponsor and/or supporting company within 
24 hours of awareness of any pregnancy occurring from study treatment initiation until 150 days 
after the last dose of study treatment. The outcome of the pregnancy will be reported to the 
sponsor and/or supporting company without delay and within 24 hours. Individual cases with an 
abnormal outcome such as death, abortion, congenital anomaly, or other disabling or life-
threatening complications to the mother or newborn are considered as SAEs and should be 
reported using the SAE form. The study investigator will make every effort to obtain permission 
to follow the outcome of the pregnancy and report the condition of the fetus or newborn to the 
sponsor and the supporting company.  If a male patient impregnates his female partner during 
the study or in 90 days after the last dose of the study treatment, the investigative team must be 
informed immediately, and the pregnancy reported to the sponsor and/or the supporting 
company. The study investigator will make every effort to obtain permission to follow the 
outcome of the pregnancy and report the condition of the fetus or newborn to the sponsor 
and/or supporting company.  
 
6.8 Use in Nursing Women 
It is not known if copanlisib, fulvestrant or their metabolites are excreted in human milk. 
Copanlisib and fulvestrant can be detected in rat milk if administered to lactating animals. Since 
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many drugs are excreted in human milk, and because of the potential for serious adverse 
reactions in the nursing infant, patients who are breastfeeding are not eligible for enrollment. 
 
6.9 Patient Withdrawal/Discontinuation Criteria 
Patients may withdraw consent at any time for any reason or be dropped from the study at the 
discretion of the investigator should any untoward effect occur. In addition, a patient may be 
withdrawn by the investigator if enrollment into the study is inappropriate, the study plan is 
violated, or for administrative and/or other safety reasons. 
 
A patient must be discontinued from the study for any of the following reasons: 
 
• The patient or legal representative withdraws consent. Every effort will be made to 
determine why any subject withdraws from the study prematurely. 
 
A patient must be discontinued from stud y treatment (but may continue to be monitored 
in the study) for any of the following reasons: 
 
• The patient or legal representative withdraws consent  
• Confirmed radiographic disease progression with the exception of patients who are 
benefitting from the study treatment in the opinion of the investigator, the patient is 
clinically asymptomatic, and continuation of study treatment is approved by the sponsor.  
• Unacceptable toxicity 
• An intercurrent illness that prevents further administration of study treatment 
• Investigator’s decision to withdraw the patient 
• The patient has a confirmed positive serum or urine pregnancy test 
• Non-compliance with study treatment or procedure requirements 
• Initiation of new anticancer therapy including another investigational agent 
• The patient is lost to follow-up. A genuine effort must be made to determine the reason(s) 
why a patient fails to return for the necessary visits. If the subject is unreachable by 
telephone, a registered letter, at the minimum, should be sent requesting him/her to 
contact the clinic 
• Death 
• Dose interruption that exceeds 4 weeks 
• Administrative reasons 
 
When a patient is permanently discontinued from receiving study treatment prior to study 
completion, all applicable activities scheduled for the final study visit should be performed at 
the time of withdrawal. The patient will continue to be followed for safety unless consent is 
withdrawn or the patient is lost to follow-up or initiation of a new anticancer therapy. Patients 
who discontinue for reasons other than disease progression will have post-treatment follow-up 
for disease status until PD, death, initiation of new anticancer therapy, withdrawal of consent, 
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or lost to follow-up. After confirmed disease progression, each patient will be followed for 
survival status until death, withdrawal of consent, or lost to follow-up. 
 
6.10 Length and End of Study 
The study begins when the first patient signs the ICF. Patients will receive study treatment until 
disease progression, unacceptable toxicity, death, withdrawal of consent, or discontinuation 
from the study treatment for any other reason. There is no maximum number of cycles a patient 
may receive if, in the opinion of the investigator, the patient is benefiting clinically from the study 
treatment.   
 
The overall end of the study is defined as the time point when the final analysis is completed 
after the data collection stops in all cohorts, Also, the investigator may decide to terminate the 
study at any time. 
 
7 ASSESSMENT OF SAFETY 
The investigator is responsible for ensuring that all AEs and SAEs that are observed or reported 
during the study are collected and reported to the sponsor, the FDA, and the institutional review 
board (IRB) in accordance with 21 Code of Federal Regulations (CFR) 312.32.  
7.1 Safety Parameters 
7.1.1 Definition of Adverse Event 
The International Council on Harmonisation (ICH) Guideline for Good Clinical Practice (GCP) E6 
defines an AE as “any untoward medical occurrence in a patient, or clinical investigation patient 
administered a pharmaceutical product and which does not necessarily have a causal relationship 
with this treatment”. An AE can, therefore, be any unfavorable and unintended sign (including 
an abnormal laboratory finding), symptom, or disease temporally associated with the use of a 
medicinal product, whether or not considered related to the medicinal product. 
 
An AE includes but is not limited to any clinically significant worsening of a patient’s preexisting 
condition. An abnormal laboratory finding that requires an action or intervention by the 
investigator, or a finding judged by the investigator to represent a change beyond the range of 
normal physiologic fluctuation, should be reported as an AE. 
 
AEs may be treatment-emergent (i.e., occurring after initial receipt of investigational product) or 
non-treatment-emergent. A non−treatment-emergent AE is any new sign or symptom, disease, 
or other untoward medical events that begin after the written informed consent has been 
obtained, but before the patient has received the investigational product.  
 
Elective treatment or surgery or preplanned treatment or surgery (that was scheduled prior to 
the patient being enrolled in the study) for a documented preexisting condition, that did not 
worsen from baseline, is not considered an AE (serious or non-serious). An untoward medical 
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event occurring during the prescheduled elective procedure or routinely scheduled treatment 
should be recorded as an AE or SAE. 
 
The term AE is used to include both SAEs and non-serious AEs. 
 
7.1.2 Definition of Serious Adverse Event 
An SAE is an AE occurring during any study phase (i.e., screening, run-in, treatment, and wash-
out, follow-up), at any dose of the study drugs that fulfills one or more of the following criteria: 
• Results in death 
• Is immediately life-threatening 
• Requires in-patient hospitalization or prolongation of existing hospitalization  
• Results in persistent or significant disability or incapacity  
• Is a congenital abnormality or birth defect in the offspring of the patient 
• It is considered a significant medical event by the investigator based on medical judgment 
(e.g., may jeopardize the patient or may require medical/surgical intervention to prevent 
one of the outcomes listed above). 
 
7.2 Adverse Event Reporting Period 
All AEs, SAEs, and other reportable safety events that occur after the ICF is signed but before 
study treatment initiation must be reported by the investigator if the event causes the patient to 
be excluded from the study, or is the result of a protocol-specified intervention, including but not 
limited to washout or discontinuation of usual therapy, diet, or a procedure.  
 
• The investigator must report all AEs from the time of first protocol-specific intervention 
through 30 days following cessation of study treatment.  
• All AEs meeting serious criteria from the time of first protocol-specific intervention 
through 30 days following cessation of study treatment or before the initiation of a new 
anticancer therapy, whichever comes first, must be reported by the investigator.  
• Additionally, any SAE brought to the attention of an investigator at any time outside of 
the period specified above must be reported immediately by the investigator if the event 
is considered related to the study treatment. These events must be followed until they 
are resolved or stabilized 
 
Information to be reported in the description of each AE includes: 
• AE (verbatim) 
• Severity grade (CTCAE Grade 1–5) 
• The date of onset and resolution of the AE  
• Whether the AE is serious or not, where an SAE is defined as in Section 7.1.2. 
• Investigator causality assessment with respect to the study treatment (yes or no)  
• Action taken with respect to the study treatment (none, temporarily interrupted, dose 
reduced, permanently discontinued, unknown, not applicable) 
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• Outcome (not recovered/not resolved, recovered/resolved, recovering/resolving, 
recovered/resolved with sequelae, fatal, unknown) 
 
7.3 Assessment of Adverse Events 
All AEs and SAEs, whether reported by the patient, discovered by study personnel during 
questioning, or detected through a physical exam, laboratory test, or other means will be 
reported appropriately. Each reported AE or SAE will be described by its duration (i.e., start and 
end dates), regulatory seriousness criteria if applicable, suspected relationship to the study 
treatment (see following guidance), and actions taken. 
 
AE Attribution:  
 
The investigator (or physician designee) is responsible for verifying and providing source 
documentation for all AEs and assigning the attribution for all AEs for patients enrolled. 
Attribution: The determination of whether an AE is related to a medical treatment or procedure.  
 
To ensure consistency of AE and SAE causality assessments, investigators should apply the 
following general guideline: 
Definite - the AE is clearly related to the investigational agent. 
Probable - the AE is likely related to the investigational agent. 
Possible - the AE may be related to the investigational agent. 
Unlikely - The AE is doubtfully related to the investigational agent. 
Unrelated - The AE is clearly NOT related to the investigational agent.  
 
Expected AEs are those AEs that are listed or characterized in the current United States Product 
Insert.  
 
Unexpected AEs are those not listed in the current IB or not identified. This includes AEs for which 
the specificity or severity is not consistent with the description in the IB.   
 
7.4 Procedures for Eliciting, Recording, and Reporting Adverse Events 
 
7.4.1 Eliciting Adverse Event Information 
A consistent methodology of non-directive questioning should be adopted for eliciting AE 
information at all patient evaluation time points.  
 
7.4.2 Specific Instructions for Recording Adverse Events 
AEs and SAEs will be recorded in the Molecular and Clinical Data Integrated Platform (MOCLIP).  
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7.4.2.2 Deaths 
All deaths that occur during the protocol-specified AE reporting period, regardless of attribution, 
will be reported to the appropriate parties. When recording a death, the event or condition that 
caused or contributed to the fatal outcome should be reported as the single medical concept. If 
the cause of death is unknown and cannot be ascertained at the time of reporting, report “Death 
of unknown cause”. 
 
7.4.2.3 Preexisting Medical Conditions 
A preexisting medical condition is one that is present at the start of the study. Such conditions 
should be reported as medical and surgical history. A preexisting medical condition should be re-
assessed throughout the study and reported as an AE or SAE only if the frequency, severity, or 
character of the condition worsens during the study. When reporting such events, it is essential 
to convey the concept that the preexisting condition has changed by including applicable 
descriptors (e.g., “more frequent headaches”). 
 
7.4.2.4 Hospitalizations for Medical or Surgical Procedures 
Any AE that results in hospitalization or prolonged hospitalization should be documented and 
reported as an SAE. If a patient is hospitalized to undergo a medical or surgical procedure as a 
result of an AE, the event responsible for the procedure, not the procedure itself, should be 
reported as the SAE.   
 
Hospitalizations for the following reasons do not require reporting: 
• Hospitalization or prolonged hospitalization for diagnostic or elective surgical procedures 
for preexisting conditions that were planned prior to the start of the safety reporting 
period  
• Hospitalization or prolonged hospitalization required to allow efficacy measurement for 
the study  
• Hospitalization or prolonged hospitalization for scheduled therapy of the target disease 
of the study 
 
7.5 Assessment of Severity of Adverse Events 
The severity of the AEs will be graded according to the NCI CTCAE V.5.0.  Events not included in 
the NCI CTCAE will be scored as follows: 
General grading: 
• Grade 1: Mild: discomfort present with no disruption of daily activity, no treatment 
required beyond prophylaxis. 
• Grade 2: Moderate: discomfort present with some disruption of daily activity, require 
treatment. 
• Grade 3: Severe: discomfort that interrupts normal daily activity, not responding to first-
line treatment.  
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• Grade 4: Life-threatening: discomfort that represents an immediate risk of death 
 
7.6 Serious Adverse Event Reporting Requirements for MDACC Sponsor Single Site 
Investigational New Drug (IND) Protocols 
An adverse event or suspected adverse reaction is considered “serious” if, in the view of either 
the investigator or the sponsor, it results in any of the following outcomes: 
• Death 
• A life-threatening  adverse event 
• Inpatient hospitalization or prolongation of existing hospitalization 
• A persistent or significant incapacity or substantial disruption of the ability to conduct 
normal life functions 
• A congenital anomaly/birth defect 
• Important medical events that may not result in death, be life-threatening, or require 
hospitalization may be considered a serious adverse drug experience when based upon 
appropriate 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. Examples of such medical events include allergic bronchospasm requiring 
intensive treatment in an emergency room or at home, blood dyscrasias or convulsions 
that do not result in inpatient hospitalization, or the development of drug dependency or 
drug abuse (21 CFR 312.32). 
• Important medical events, as defined above, may also be considered serious adverse 
events. Any important medical event can and should be reported as an SAE if deemed 
appropriate by the PI or the IND sponsor, MDACC IND office. 
• All events occurring during the conduct of a protocol and meeting the definition of an SAE 
must be reported to the IRB following the timeframes and procedures outlined in “The 
University of Texas M. D. Anderson Cancer Center Institutional Review Board Policy on 
Reporting Adverse Events for Drugs and Devices”. 
• SAEs will be captured from the time of the first protocol-specific intervention, until 
30 days after the last dose of the drug or protocol-specific timeline, unless the participant 
withdraws consent.  
• SAEs must be followed until clinical recovery is complete, and laboratory tests have 
returned to baseline, the progression of the event has stabilized, or there has been 
acceptable resolution of the event. 
• All SAEs, expected or unexpected/ initial or follow up, must be reported to the IND office 
within 5 working days of knowledge of the event regardless of the attribution. 
• Death or life-threatening events that are unexpected, possibly, probably, or definitely 
related to the study treatment must be reported (initial or follow up) to the IND office 
within 24 hours of knowledge of the event.  
• Additionally, any SAEs that occur after the 30-day time period or protocol-specific 
timeline that is related to the study treatment must be reported to the IND office. This 
may include the development of a secondary malignancy. 
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• The electronic SAE application (eSAE) will be utilized for safety reporting to the IND office 
and MDACC IRB.  
• All events reported to the supporting company must also be reported to the IND office. 
Reporting to the FDA: 
•  Serious Adverse Events will be forwarded to the FDA by the IND sponsor (MDACC IND 
office) according to 21 CFR 312.32. 
 
It is the responsibility of the PI and the research team to ensure serious AEs are reported 
according to the CFR, GCP, protocol guidelines, sponsor’s guidelines, and IRB policy. 
 
7.7.1 Overdose 
Overdose includes only clinically symptomatic doses that are at least twice the intended dose. 
Any instance of overdose (suspected or confirmed and irrespective of whether or not it involved 
study drugs) must be communicated to the sponsor and supporting company within 24 hours 
and be fully documented as an SAE. Details of any signs or symptoms and their management 
should be recorded, including details of any antidote(s) administered. 
 
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Cohort 1: Ovarian cancer (ER+ and/or PR+, PI3K or PTEN altered) 
Cohort 2: Endometrial cancer (ER+ and/or PR+, PI3K or PTEN altered) 
Cohort 3: Breast cancers (ER+ and/or PR+, PI3K or PTEN altered). This cohort will be enriched to 
include at least 7 patients naïve to any PI3Ki in Stage 1 and in Stage 2. 
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8.1 Safety Analysis 
All patients who received at least 1 dose of both copanlisib and fulvestrant will be included in a 
descriptive safety analysis. The safety profiles will be assessed through summaries of AEs, serious 
AEs, AEs leading to treatment discontinuation, and treatment-related death. The safety analysis 
will report the frequency, severity, and duration of all treatment related AEs and laboratory 
abnormalities, 
dose 
interruptions, 
dose 
reductions, 
and 
toxicity-related 
treatment 
discontinuation. The worst per-patient toxicity according to NCI CTCAE grade will be used. The 
Bayesian Beta-Binomial model will be used to quantify the statistical inference of AE rates.  
The MDACC IND Office Medical and Safety Group will be provided with a copy of the safety and 
efficacy analysis when available. 
8.1.1 Clinical Laboratory Analyses 
All clinical laboratory values will be listed individually and tabulated in a manner to identify safety 
concerns on a per-patient basis. Listing tables will be prepared for each laboratory measure and 
will be structured to permit review of the patient data as they progress on treatment. The tables 
will list the cycle of treatment, copanlisib and fulvestrant doses for dose confirmation data, and 
the associated NCI CTCAE grade. Descriptive summary statistics will be generated per laboratory 
parameter.  
Summary tables will be prepared to examine the distribution of these toxicities per cycle. 
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Graphic displays and shift tables may be provided to illustrate results over time on study. 
Assessment of cumulative toxicities may be made. 
8.2 Efficacy Analysis  
The ORR is defined as the proportion of patients who achieve CR or PR by the combination 
therapy per RECIST 1.1. Bayesian beta-binomial model and the CBHM will be used to model the 
data observed within each cohort. Bayesian 95% credible interval will be derived. Summary 
statistics will be given for secondary efficacy endpoints without borrowing information across 
cohorts.  Time-to-event methodology will be used to assess mortality outcomes. Specifically, a 
log-rank statistic (accompanied by a Kaplan-Meier plot) will be the primary method of analysis 
for the mortality endpoint. Model-based methods (e.g., Cox proportional hazards or other robust 
methods) may also be applied. 
8.3 Data Collection 
 
8.3.1 Data Protection and Confidentiality 
All patients who meet eligibility criteria and are enrolled in this study will be registered in Clinical 
Oncology Research e-Database (CORe) at MDACC. All study patients must be registered in the 
CORe. The date of the current ICF is displayed to ensure only the most current IRB-approved 
version is used. Consent date, registration date, off study date, and evaluability data are required 
for all registrants. 
 
The investigator agrees to keep all information and results concerning the study confidential. The 
confidentiality obligation applies to all personnel involved with this clinical study. The 
investigator must ensure that each study patient’s anonymity will be maintained in accordance 
with applicable laws. The investigator should keep a separate log of identification numbers, 
names, and addresses.  Documents that contain the names associated with these identification 
numbers (e.g., written consent/assent forms) should be maintained by the investigator in strict 
confidence except to the extent necessary to allow auditing by regulatory authorities, auditing 
or monitoring by the IRB. 
 
The investigator shall obtain all such permissions and authorizations as may be necessary or 
desirable to allow the collection and use of information protected under federal privacy laws and 
state privacy laws, including permission/authorization for monitoring and analysis (including re-
analysis in combination with results of other studies), for regulatory submission purposes and 
applicable reporting (if any). 
 
Protocol-specific data will be entered into MOCLIP/CORe (or other databases); MOCLIP/CORe (or 
other databases) will be used as the eCRF. 
 
 
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9 Ethical and regulatory requirements 
 
This study will be conducted in full conformance with the ICH E6 guideline for GCP and the 
principles of the Declaration of Helsinki. The study will comply with United States FDA regulations 
and applicable local, state, and federal laws. Details are described in the MD Anderson 
institutional standard operating procedures and policies. 
 
 
 
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f) 
All concomitant medication received within 28 days prior to study drug initiation and 30 days after the last dose of study drug will be recorded, including 
all prescription, over-the-counter, IV medications and fluids, supportive care drugs and the drugs used to treat AEs or chronic diseases, and non-drug 
supportive interventions. If changes occur during the study period, documentation of drug dosage, frequency, route, and date will also be recorded. 
g) Archival tissue will be collected if available.  
h) Radiographic tumor assessments, using CT scanning or MRI, will be performed at Screening, Cycle 3 Day 1 (±7 days), Day 1 (±7 days) of every 2nd cycle 
after that, and at EOT. 
i) 
Patients who discontinue study treatment for a reason other than disease progression will move into follow-up phase. Patients will be monitored for 
disease status by tumor imaging (CT scan or MRI, as appropriate) every 8 weeks (±7 days) until PD, death, initiation of new anticancer therapy, 
withdrawal of consent, or lost to follow-up. 
j) 
Copanlisib (60 mg IV) will be administered on Day 1, Day 8, and Day 15 of 28-day cycles until disease progression, unacceptable toxicity, death, 
withdrawal of consent, or discontinuation from the study drug for any other reason. 
k) Fulvestrant (500 mg IM) will be administered on Day 1 and Day 15 of Cycle 1 and only Day 1 of any subsequent 28-day cycle. 
l) 
Physical examination, performance status, vital signs and weight at baseline, weekly (D1, D8, D15, D22) during Cycle 1, twice during cycle 2 (D1 and 
D15), and then at the start of every cycle thereafter (within 3 days prior to treatment), or more frequently if clinically indicated. Finally at 
EOT/Progression. 
m) On copanlisib infusion days, blood pressure should be measured pre-dose, mid-infusion, end of infusion, and 1 and 2 hours after the end of infusion. 
Note: a window of ± 10 minutes is allowed for all BP measurements, except for pre-dose (0 hour) measurement 
n) MUGA scan or ECHO will be performed at screening and as clinically indicated. The same method should be used throughout the study. 
o) Hematology (CBC with platelet and differential WBC count) will be performed at baseline, weekly (D1, D8, D15, D22) during Cycle 1, twice during cycle 
2 (D1 and D15), and then at the start of every cycle thereafter (within 3 days prior to treatment), or more frequently if clinically indicated. Finally at 
EOT/progression. 
p) Clinical chemistry (total protein, albumin, indirect and TB, AST, ALT, ALP, electrolytes [sodium, potassium, calcium, and magnesium], serum phosphate, 
serum creatinine, creatinine clearance, uric acid, and bile salts) will be performed at baseline, weekly (D1, D8, D15, D22) during Cycle 1, twice during 
cycle 2 (D1 and D15), and then at the start of every cycle thereafter (within 3 days prior to treatment), or more frequently if clinically indicated. Finally 
at EOT/progression. 
q)  Mandatory blood samples to isolate plasma ctDNA will be collected at pre-treatment (Day -28 to Day 1 of Cycle 1), on-treatment (pre-dose on the same 
day as the on treatment biopsy on Cycle 2 Day 1, as well as during the first two restaging visits), and post-treatment at EoT. A maximum of 5 ctDNA 
samples will be collected per patient. 
r) 
Tumor biopsies, if medically feasible, will be obtained at Screening (within 28 days of Cycle 1 Day 1),on-treatment after fulvestrant and copanlisib 
administration on Cycle 2 Day 1 and at EOT. Tumor biopsies will be optional but encouraged, especially in patients with a response or prolonged disease 
control. Tumor biopsies will be used to evaluate genomic biomarkers of response and intrinsic and adaptive resistance, and to evaluate 
pharmacodynamic markers of engagement.  
s) 
Pregnancy tests will be only for women with childbearing potential. Only whole blood will be collected for the pregnancy test that will be performed in 
the Screening period (Day -28 to Day -1). 
t) 
Additional pregnancy tests will be performed at Day 1 of each Cycle only for women with childbearing potential. Whole blood or urine can be collected 
for the test. 
u) Pregnancy test for Cycle 1 Day 1 can be skipped if the test for the screening period is performed close to the 1st cycle.  

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v) FPG testing will be performed at Screening and before each copanlisib administration on Day 1, Day 8, and Day 15 of each Cycle from Cycle 1 to Cycle 4 
inclusive. Starting with Cycle 5, FPG testing will only be performed on Day 1 of each cycle. 
w) Patients who experience confirmed disease progression or initiate a new anticancer therapy will move into the survival follow-up phase. Patients will 
be contacted by telephone every 12 weeks (±14 days) for survival status until death, withdrawal of consent, or lost to follow-up. 

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APPENDIX B: RECIST V1.1 
Measurability of Tumor  
Tumor lesions/lymph nodes will be categorized as measurable or non-measurable. Measurable disease is 
defined by the presence of at least 1 measurable lesion. 
 
Measurable 
 
Tumor lesions: Measured in at least 1 dimension (longest diameter in the plane of measurement is to be 
recorded) with a minimum size of: 
• 
10 mm by CT or MRI scan (slice thickness ≤5 mm) 
• 
10 mm caliper measurement by clinical examination (non-measurable lesions if cannot be 
accurately measured with calipers) 
• 
20 mm by chest x-ray. 
 
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 thickness recommended to be ≤5 mm). 
 
Non-measurable 
All other lesions, including small lesions (longest diameter <10 mm or pathological lymph nodes with ≥10 
to <15 mm short axis) as well as truly non-measurable lesions. Lesions considered truly non-measurable 
include: leptomeningeal disease, ascites, pleural/pericardial effusions, lymphangitis cutis/pulmonis, 
inflammatory breast disease, lymphangitis involvement of skin or lung, abdominal masses/abdominal 
organomegaly identified by physical examination that is not measurable by reproducible imaging 
techniques. 
 
Special Considerations for Lesion Measurability 
 
Bone lesions: 
• 
Bone scan, PET scan, or plain films are not considered adequate imaging techniques to measure 
bone lesions. 
• 
Lytic bone lesions or mixed lytic-blastic lesions, with identifiable soft tissue components, that 
can be evaluated by cross sectional imaging techniques such as CT or MRI, can be considered 
measurable lesions if the soft tissue component meets the definition of measurability. 
• 
Blastic bone lesions are non-measurable. 
Cystic lesions: 
• 
Simple cysts should not be considered as malignant lesions (neither measurable nor 
non-measurable) 
• 
Cystic lesions thought to represent cystic metastases can be considered as measurable 
lesions, if they meet the definition of measurability. If non-cystic lesions are presented 
in the same patients, these are preferred for selection as target lesions. 
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Lesions with Prior Local Treatment: 
• 
Tumor lesions situated at a previously irradiated area, or in an area subjected to other 
locoregional therapy, are non-measurable unless there has been demonstrated 
progression in the lesion. 
Baseline Documentation of Target and Non-Target Lesions 
 
Target Lesions 
When more than 1 measurable lesion is present at baseline, all lesions up to a maximum of 5 lesions total 
(and a maximum of 2 lesions per organ), representative of all involved organs, should be identified as 
target lesions and will be recorded and measured at baseline. Non-nodal target lesions should be selected 
based on their size (lesions with the longest diameter), be representative of all involved organs, and 
should be able to be reproduced in repeated measurements. Measurable lymph nodes are target lesions 
if they meet the criteria of a short axis of ≥15 mm by CT scan. All measurements are to be recorded in the 
eCRF in millimeters (or decimal fractions of centimeters [cm]). 
 
Non-Target Lesions 
All other lesions (or sites of disease) are identified as non-target lesions (chosen based on their 
representativeness of involved organs and the ability to be reproduced in repeated measurements) and 
should be recorded at baseline. Measurement of these lesions are not required but should be followed 
as “present,” “absent,” or in rare cases “unequivocal progression.” In addition, it is possible to record 
multiple non-target lesions involving the same organ as a single item on the eCRF (for example, multiple 
liver metastases recorded as 1 liver lesion). 
 
Lymph nodes with short axis ≥10 mm but <15 mm should be considered non-target lesions. Nodes that 
have a short axis <10 mm are considered non-pathological and are not recorded or followed. 
 
Response Criteria 
 
Evaluation of Target Lesions 
Completed 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. Tumor marker results must have 
normalized. 
Partial Response (PR): At least a 30% decrease in the sum of diameter of target lesions, taking as 
reference the baseline sum diameters. 
 
Progressive Disease (PD):  At least a 20% increase in the sum of the diameters of target lesions, taking as 
reference the smallest sum on study (including the baseline sum if that is the smallest). In addition to the 
relative increase of 20%, the sum must also demonstrate an absolute increase of at least 5 mm. 
 
The appearance of 1 or more new lesions is also considered progression. 
 
For equivocal findings of progression (e.g., very small and uncertain new lesions; cystic changes or 
necrosis in existing lesions), treatment may continue until the next scheduled assessment. If at the next 
scheduled assessment, progression is confirmed, the date of progression should be the earlier date when 
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progression was suspected. 
 
Stable Disease (SD): Neither sufficient shrinkage to qualify for PR, nor sufficient increase to qualify for 
PD, taking as reference the smallest sum diameters while on study. 
 
Not Evaluable (NE): When an incomplete radiographical assessment of target lesions is performed or 
there is a change in the method of measurement from baseline that impacts the ability to make a reliable 
evaluation of response. 
 
Evaluation of Non-Target Lesions 
Complete Response:  Disappearance of all non-target lesions and normalization of tumor marker level. 
All lymph nodes must be non-pathological or normal in size (<10 mm short axis). 
 
Non-CR/Non-PD:  Persistence of 1 or more non-target lesions and/or maintenance of tumor marker level 
above the normal limits. 
 
PD:  Unequivocal progression of existing non-target lesions. The appearance of 1 or more new lesions is 
also considered progression. 
 
NE:  When a change in method of measurement from baseline occurs and impacts the ability to make a 
reliable evaluation of response. 
 
Evaluation of Best Overall Response 
The best overall response (BOR) is the best response recorded from the start of the study treatment until 
the earliest of objective progression or initiation of new anticancer therapy, taking into account any 
requirement for confirmation. The patient’s BOR assignment will depend on the findings of both target 
and non-target disease and will also take into consideration the appearance of new lesions. The BOR will 
be calculated via an algorithm using the assessment responses provided by the investigator over the 
course of the study. 
 
Time Point Response 
It is assumed that at each protocol-specified time point, a response assessment occurs. (When no 
imaging/measurement is conducted/made at all at a particular time point, the patient is NE at that time 
point.) Table 21 provides a summary of the overall response status calculation at each time point for 
patients who have measurable disease at baseline. 
  
Table 21: Time Point Response: Patients with Target (± Non-target) Disease 
Target Lesions 
Non-Target Lesions 
New Lesions 
Overall Response 
CR 
CR 
No 
CR 
CR 
Non-CR/non-PD 
No 
PR 
CR 
Not evaluated 
No 
PR 
PR 
Non-PD or not all evaluated 
No 
PR 
SD 
Non-PD or not all evaluated 
No 
SD 
Not all evaluated 
Non-PD 
No 
NE 
PD 
Any 
Yes or No 
PD 
Any 
PD 
Yes or No 
PD 
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Any 
Any 
Yes 
PD 
CR = complete response; PR = partial response; SD = stable disease; PD = progressive disease;  
NE = not evaluable. 
 
 
Confirmatory Measurement/Duration of Response 
 
Confirmation 
To be assigned a status of PR/CR, changes in tumor measurements must be confirmed by repeat 
assessments that should be performed 4 weeks (±3 days) after the criteria for response are first met. To 
confirm a response of CR, a full assessment of all target and non-target lesions that were present at 
baseline must occur, including those measured by bone scan. To confirm a PR or SD, a full assessment of 
target lesions that were present at baseline must occur; assessment of non-target lesions is not required. 
 
Duration of Overall Response 
The duration of overall response is measured from the time measurement criteria are first met for CR or 
PR (whichever is first recorded) until the first date that disease is recurrent or objective progression is 
observed (taking as reference for PD the smallest measurements recorded on study). 
 
The duration of overall CR is measured from the time measurement criteria are first met for CR until 
the first date that recurrent disease is objectively documented. 
 
Duration of Stable Disease 
SD is measured from the start of the treatment until the criteria for objective progression are met, taking 
as reference the smallest sum on study (if the baseline sum is the smallest, that is the reference for 
calculation of PD). 
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APPENDIX C: NCI CTCAE V5.0 
 
The descriptions and grading scales found in the revised NCI CTCAE version 5.0 will be utilized for AE 
reporting. 
(https://ctep.cancer.gov/protocolDevelopment/electronic_applications/docs/CTCAE_v5_Quick_Referen
ce_8.5x11.pdf) 
 
 
 
 
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APPENDIX D: ECOG PERFORMANCE STATUS SCALE 
 
Grade 
Description 
0 
Normal activity. Fully active, able to carry on all pre-disease performance 
without restriction. 
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). 
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. 
3 
In bed >50% of the time. Capable of only limited self-care, confined to bed 
or chair more than 50% of waking hours. 
4 
100% bedridden. Completely disabled. Cannot carry on any self-care. 
Totally confined to bed or chair. 
5 
Dead. 
Oken MM, et al. Toxicity and response criteria of the ECOG. Am J Clin Oncol 1982;5:649-55.  
 
 
 
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APPENDIX 
E: 
NEW 
YORK 
HEART 
ASSOCIATION 
FUNCTIONAL 
CLASSIFICATIONS 
 
Class 
Description 
I 
Patients with cardiac disease but without resulting limitations of physical 
activity. Ordinary physical activity does not cause undue fatigue, 
palpitation, dyspnea, or anginal pain. 
II 
Patients with cardiac disease resulting in slight limitation of physical 
activity. They are comfortable at rest. Ordinary physical activity results in 
fatigue, palpitation, dyspnea, or anginal pain. 
III 
Patients with cardiac disease resulting in marked limitation of physical 
activity. They are comfortable at rest. Less than ordinary physical activity 
causes fatigue, palpitation, dyspnea, or anginal pain. 
IV 
Patients with cardiac disease resulting in inability to carry on physical 
activity without discomfort. Symptoms of cardiac insufficiency or of angina 
syndrome may be present at rest. If any physical activity is undertaken, 
discomfort is increased. 
 
 
 
 
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