Conditions: Anatomic Stage IV Breast Cancer AJCC v8 Metastatic Breast Carcinoma Metastatic HER2-Negative Breast Carcinoma Metastatic Hormone Receptor-Positive Breast Carcinoma Recurrent Breast Carcinoma
Allocation: RANDOMIZED | Intervention model: SEQUENTIAL
Enrollment: 24
Healthy volunteers: no

Brief summary:
This phase I trial studies the effects (good and bad) of adding copanlisib to the usual therapy of fulvestrant and abemaciclib in treating patients with hormone receptor positive and HER2 negative breast cancer that has spread from where it first started (breast) to other places in the body (metastatic). Some breast cancer cells have receptors for the hormones estrogen or progesterone. These cells are hormone receptor positive and they need estrogen or progesterone to grow. This can affect how the cancer is treated. Hormone therapy using fulvestrant may fight breast cancer by blocking the use of estrogen by the tumor cells. Abemaciclib and copanlisib may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. Adding copanlisib to the usual therapy of fulvestrant and abemaciclib may work better than giving fulvestrant and abemaciclib alone in treating patients with breast cancer.

Detailed description:
PRIMARY OBJECTIVES:

I. To evaluate the safety profile of fulvestrant + abemaciclib + copanlisib hydrochloride (copanlisib) (FAC) and determine the recommended phase 2 dose (RP2D).

SECONDARY OBJECTIVES:

I. To assess the objective response rate (ORR = partial response \[PR\] + complete response \[CR\]) and clinical benefit rate (CBR = PR + CR + stable disease \[SD\] \>= 6 months) of FAC and medium progression free survival (PFS) with FAC.

EXPLORATORY OBJECTIVES:

I. To assess whether triplet therapy with FAC inhibits AKT phosphorylation, reduces cyclin D1, and inhibits Rb phosphorylation.

II. To assess whether the combination of abemaciclib and fulvestrant affect the copanlisib pharmacokinetics (PK).

III. To assess the objective response rate (ORR), clinical benefit rate (CBR) and median PFS in the following molecularly defined subgroups treated with FAC such as mutations in genes in the PI3K pathway (PIK3CA, AKT, PTEN etc), ESR1, TP53, or PTEN IHC loss vs not.

IV. To assess baseline and treatment induced changes in various cancer associated pathways, including but not limited to PI3K, MAPK, ER, cyclins, CDKs and CDK inhibitors; and to correlate with treatment response and progression.

V. To correlate baseline and treatment induced changes in breast cancer intrinsic subtypes (PAM50), and PI3K messenger ribonucleic acid (mRNA) signature and expression of candidate genes with treatment response and benefit from adding copanlisib.

VI. To evaluate ctDNA mutations at baseline and over time for response predictors at baseline, and clonal evolution associated with treatment.

VII. To correlate ctDNA mutation profiles with tumor sequencing, and correlate baseline ctDNA mutations, particularly in components of the PI3K pathway with treatment response, and correlate early changes in ctDNA variant allele frequencies (VAFs) with PFS, assess emergent resistant mutations at progression.

VIII. To assess resistance mechanisms to FAC at baseline and at disease progression.

IX. To examine the molecular effects of FAC on tumor and circulating markers. X. To analyze tumor infiltrating lymphocytes at baseline, during treatment, and at disease progression.

OUTLINE: This is a phase I two part, dose-escalation study of copanlisib hydrochloride and abemaciclib.

PHASE I (PART A): Patients receive copanlisib hydrochloride intravenously (IV) over 1 hour on days 1, 8, and 15 or days 1 and 15 (depending on dose level) and abemaciclib orally (PO) twice daily (BID) on on days 2-28 of cycle 1 and on days 1-28 of subsequent cycles. Patients also receive fulvestrant intramuscularly (IM) on days 2 and 16 of cycle 1, and on day 1 of subsequent cycles. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity. Patients undergo an echocardiography (ECHO) or multigated acquisition (MUGA) scan during screening. Patients also undergo blood sample collection pre-treatment, cycle 1 days 1, 8, 15, and 22, cycle 2 day 1, cycle 4 day 1, cycle 7 day 1, and then every 3 cycles thereafter and at time of progression. Patients undergo tissue biopsy pre-treatment and optionally on cycle 1 day 15 and at the time of progression. Patients also undergo imaging at screening and at the completion of cycle 3, then every 3 cycles thereafter.

PHASE I (PART B): Patients receive copanlisib hydrochloride IV over 1 hour on days 1, 8, and 15 or days 1 and 15 (depending on dose level) and abemaciclib PO twice daily BID for 5 days each week (2 days off). Patients also receive fulvestrant IM on days 2 and 16 of cycle 1, and on day 1 of subsequent cycles. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity. Patients undergo an ECHO or MUGA scan during screening. Patients also undergo blood sample collection pre-treatment, cycle 1 days 1, 8, 15, and 22, cycle 2 day 1, cycle 4 day 1, cycle 7 day 1, and then every 3 cycles thereafter and at time of progression. Patients undergo tissue biopsy pre-treatment and optionally on cycle 1 day 15 and at the time of progression. Patients also undergo imaging at screening and at the completion of cycle 3, then every 3 cycles thereafter.

After completion of study treatment, patients are followed up every 3 months for 5 years.

\* As of November 2023, Bayer has decided to voluntarily withdraw the NDA for copanlisib, phase II portion removed.

Arms:
arm 1: Patients receive 45 mg copanlisib hydrochloride IV over 1 hour on days 1 and 15 and 100 mg abemaciclib PO BID on days 2-28 of cycle 1 and on days 1-28 of subsequent cycles. Patients also receive 500 mg fulvestrant IM on days 2 and 16 of cycle 1, and on day 1 of subsequent cycles. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity. Patients undergo an ECHO or MUGA scan during screening. Patients also undergo blood sample collection pre-treatment, cycle 1 days 1, 8, 15, and 22, cycle 2 day 1, cycle 4 day 1, cycle 7 day 1, and then every 3 cycles thereafter and at time of progression. Patients undergo tissue biopsy pre-treatment and optionally on cycle 1 day 15 and at the time of progression. Patients also undergo imaging at screening and at the completion of cycle 3, then every 3 cycles thereafter. arm 2: Patients receive 45 mg copanlisib hydrochloride IV over 1 hour on days 1, 8, and 15 and 150 mg abemaciclib PO twice daily BID for 5 days each week (2 days off). Patients also receive f500 mg fulvestrant IM on days 2 and 16 of cycle 1, and on day 1 of subsequent cycles. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity. Patients undergo an ECHO or MUGA scan during screening. Patients also undergo blood sample collection pre-treatment, cycle 1 days 1, 8, 15, and 22, cycle 2 day 1, cycle 4 day 1, cycle 7 day 1, and then every 3 cycles thereafter and at time of progression. Patients undergo tissue biopsy pre-treatment and optionally on cycle 1 day 15 and at the time of progression. Patients also undergo imaging at screening and at the completion of cycle 3, then every 3 cycles thereafter. arm 3: Patients receive 45 mg copanlisib hydrochloride IV over 1 hour on days 1 and 15 and 100 mg abemaciclib PO twice daily BID for 5 days each week (2 days off). Patients also receive 500 fulvestrant IM on days 2 and 16 of cycle 1, and on day 1 of subsequent cycles. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity. Patients undergo an ECHO or MUGA scan during screening. Patients also undergo blood sample collection pre-treatment, cycle 1 days 1, 8, 15, and 22, cycle 2 day 1, cycle 4 day 1, cycle 7 day 1, and then every 3 cycles thereafter and at time of progression. Patients undergo tissue biopsy pre-treatment and optionally on cycle 1 day 15 and at the time of progression. Patients also undergo imaging at screening and at the completion of cycle 3, then every 3 cycles thereafter. arm 4: Patients receive 45 mg copanlisib hydrochloride IV over 1 hour on days 1, 8, and 15 and 100 mg abemaciclib PO twice daily BID for 5 days each week (2 days off). Patients also receive 500 mg fulvestrant IM on days 2 and 16 of cycle 1, and on day 1 of subsequent cycles. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity. Patients undergo an ECHO or MUGA scan during screening. Patients also undergo blood sample collection pre-treatment, cycle 1 days 1, 8, 15, and 22, cycle 2 day 1, cycle 4 day 1, cycle 7 day 1, and then every 3 cycles thereafter and at time of progression. Patients undergo tissue biopsy pre-treatment and optionally on cycle 1 day 15 and at the time of progression. Patients also undergo imaging at screening and at the completion of cycle 3, then every 3 cycles thereafter.

Interventions: intervention 1: Abemaciclib intervention 2: Biopsy intervention 3: Biospecimen Collection intervention 4: Copanlisib Hydrochloride intervention 5: Diagnostic Imaging intervention 6: Echocardiography intervention 7: Fulvestrant intervention 8: Multigated Acquisition Scan
Intervention descriptions: intervention 1: Given PO intervention 2: Undergo tissue biopsy intervention 3: Undergo blood sample collection intervention 4: Given IV intervention 5: Undergo imaging intervention 6: Undergo ECHO intervention 7: Given IM intervention 8: Undergo MUGA

Protocol document:
Prot_SAP_001.pdf: 
NCI Protocol #:  10287 
Version Date:  June 13, 2024 
 
i 
SUMMARY OF CHANGES – Protocol 
For Protocol Amendment # 8d: 
NCI Protocol #:  10287 
Local Protocol #:  201911082 
NCI Version Date: June 13, 2024 
Protocol Date:  June 13, 2024 
 
I. 
Disapproval Letter, 02/27/2024, P10287_A12PAMDREVW01 Amendment 
Review Letter* 
*Of note, protocol version dated 11/28/2023 was titled Amendment 8c. 
# 
Section 
Comments 
1. 
General Due to the pharma collaborator strategic development plan for copanlisib, the 
decision is made to close the study. 
PI Response: We acknowledge the notification. References to opening the 
Phase 2 portion of the study have been removed throughout the protocol. 
Section 2.7 was replaced with the study closure plan. 
II. 
Summary of Changes for Protocol Amendment 8d, dated June 13, 2024 
# 
Section 
Comments 
1. 
Title Page 
Added Protocol Amendment 8d, dated June 13, 2024 
2. 
Schema 
The schema for Phase 2 was removed. 
3. 
1.1 
The primary objectives (1.1.2 and 1.1.3) for Phase 2 were removed. 
4. 
1.2 
The secondary objective (1.2.2) for Phase 2 was removed, and secondary 
objective 1.1.3 was modified to be applicable only to Phase 1 and moved to 
exploratory. 
5. 
1.3 
The exploratory objective (1.3.10) for Phase 2 was removed and the 
remaining objectives modified to be applicable only to Phase 1. 
6. 
2.5.1.1 
Removed language regarding comparing PFS between 2 arms given the 
removal of Phase 2. 
7. 
2.5.2.4 
Replaced ULP-WGS with the TSO500 assay in the Approach section. 
8. 
2.7 
Replaced Section 2.7, previously added as rationale for RP2D, with study 
closure information. 


NCI Protocol #:  10287 
Version Date:  June 13, 2024 
 
ii 
# 
Section 
Comments 
9. 
5.1 
Removed footnote 6 reference to patients in the Phase 2 portion. 
10. 5.7 
Replaced references to the MoCha lab PI Dr. Mickey Williams with the new 
PI, Dr. Chris Karlovich, and updated the email address to 
chris.karlovich@nih.gov. 
Removed the Broad Institute from the ctDNA analysis and replaced with the 
MoCha lab. 
Removed footnote ** reference to patients in the Phase 2 portion. 
11. 5.8  
Replaced references to the MoCha lab PI Dr. Mickey Williams with the new 
PI, Dr. Chris Karlovich, and updated the email address to 
chris.karlovich@nih.gov. 
12. 5.9.2.2 
Removed Broad Institute and added that ctDNA will be performed at 
MoCha. 
13. 5.9.2.3 
Replaced Broad Institute shipping address with MoCha shipping address. 
14. 5.9.2.4 
Replaced Broad Institute shipping contact with MoCha shipping contact. 
15. 6 
Removed Phase 2 opening instructions. 
16. 6.1.2 
Removed Phase 2 randomization language for abemaciclib schedule. 
17. 7.2 
Removed FAC arm language. 
18. 8.1.3.1 
Removed treatment arm assignment language. 
19. 9.1 
Removed Phase 2 primary endpoint language. 
20. 9.1.2 
Added definition of PFS. Removed Phase 2 secondary endpoints. 
21. 9.4 
Removed Phase 2 accrual calculations. 
22. 9.5 and 9.6 
Removed endpoint analyses only applicable to Phase 2 and updated Phase 1 
analyses.  
Clarified that differences between 2 patients groups instead of 2 Phase 2 arms 
will be compared. 
Removed Section 9.6.2. and 9.6.3 as they were applicable to Phase 2 only. 
In the new Section 9.6.2 Correlative Biomarker Analysis, removed language 
for Phase 2 arm comparisons. Added that descriptive statistics will be 


NCI Protocol #:  10287 
Version Date:  June 13, 2024 
 
iii 
# 
Section 
Comments 
provided for candidate gene mutations and PTEN loss. Removed statement 
that Phase 1 data will be analyzed separately from Phase 2 data. 
23. 9.7 
Removed per protocol analysis set as a population for analysis. 
24. 9.8 and 9.9 
Removed sections as they were applicable only to Phase 2. 
25. 9.9 
(renumbered) 
Removed Phase 2 DSMB language. 
26. 11 
Removed Phase 2 language from footnotes 10 and 15. 
27. 13.6 and 13.7 Removed sections as MoCha will not provide incidental findings. 
 
 
III. 
CIRB Letter, 11/21/2023, CIRB Approval Pending Modification of Amendment 
Review 
# 
Section 
Comments 
28. 1.1.1 
Section 1.1.1, Primary Objectives still lists RP2D. Please revise this section to 
reflect the current goal. 
PI Response: This has been updated as requested. 
29. 2.8 
Incorporate language regarding the recent copanlisib FDA approval withdrawal 
into the Protocol and Consent Form. 
PI Response: This has been updated as requested. 
 
 
IV. 
Disapproval Letter, 09/27/2023, Review of Amendment #11 of Protocol #10287* 
*Of note, protocol version dated 09/07/2023 was titled Amendment 8a. 
# 
Section 
Comments 
30. 4.1, 
Investig
ator and 
Researc
h 
Associa
Please revise the excerpt below as indicated. 
 
Food and Drug Administration (FDA) regulations require sponsors to select 
qualified investigators.  National Cancer Institute (NCI) policy requires all 
individuals contributing to NCI-sponsored trials to register with their qualifications 
and credentials and to renew their registration annually.  To register, all 


NCI Protocol #:  10287 
Version Date:  June 13, 2024 
 
iv 
# 
Section 
Comments 
te 
Registr
ation 
with 
CTEP 
individuals must obtain a Cancer Therapy Evaluation Program (CTEP) credentials 
necessary to access secure NCI Clinical Oncology Research Enterprise (CORE) 
systems Identity and Access Management (IAM) account at 
https://ctepcore.nci.nih.gov/iam.  Investigators and clinical site staff who are 
significant contributors to research must register in the Registration and Credential 
Repository (RCR) at https://ctepcore.nci.nih.gov/rcr/. The RCR is a self-service 
online person registration application with electronic signature and document 
submission capability. 
PI Response: This has been updated as requested. 
31. 4.2.3, 
Submitt
ing 
Regulat
ory 
Docum
ents 
Please revise the excerpt below as indicated. 
 
Submit required forms and documents to the CTSU Regulatory Office via the 
Regulatory Submission Portal on the CTSU members’ website. 
 
To access the Regulatory Submission Portal, log on to the CTSU members’ website 
go to the Regulatory section, and select Regulatory Submission.  
 
Institutions with patients waiting that are unable to use the Regulatory Submission 
Portal should alert the CTSU Regulatory Office immediately by phone or email: 1-
866-651-CTSU (2878), or CTSURegHelp@coccg.org at 1-866-651-2878 in order 
to receive further instruction and support. 
PI Response: This has been updated as requested. 
32. 4.3.1, 
OPEN/I
WRS 
Please revise the excerpt below as indicated. 
 
 
• All patients have signed an appropriate consent form and Health Insurance 
Portability and Accountability Act (HIPAA)HIPAA authorization form (if 
applicable). 
PI Response: This has been updated as requested. 
33. 5.8.1.1 
To clarify that the germline control for WES will come from the pre-treatment 
Steck cfDNA tube, revise the last paragraph in Section 5.8.1.1 as follows: 
 
DNA and RNA will be co-extracted from tumor tissue.  DNA will be extracted 
from the whole blood collected in the EDTA tube.  The nucleic acids will be 
analyzed to determine concentration and quality.  Aliquots of DNA will be 
shipped to the central sequencing laboratory for analysis. 
 
Germline DNA will be extracted from blood collected in Streck cfDNA tubes at 
pre-treatment (baseline) following plasma processing.  DNA will be quantitated. 
An aliquot of germline DNA will be shipped to the central sequencing laboratory 
for analysis. 
PI Response: This has been updated as requested. 


NCI Protocol #:  10287 
Version Date:  June 13, 2024 
 
v 
# 
Section 
Comments 
34. 8.1.X 
**New Section – renumber subsequent section** 
Material Safety Data Sheets 
The current versions of the material safety data sheets (MSDS or SDS) for PMB-
distributed agents will be accessible to site investigators and research staff through 
the PMB AURORA application. Questions about MSDS access may be directed to 
the PMB at PMBAfterHours@mail.nih.gov or by using the dialog function in 
AURORA to communicate with PMB staff. 
PI Response: This has been updated as requested. 
35. 8.1.2.1, 
8.1.3 
Replace “establishment of a CTEP Identity and Access Management (IAM) 
account” and “establishment of a CTEP IAM account” with “establishment of 
credentials necessary to access secure NCI Clinical Oncology Research Enterprise 
(CORE) systems” 
PI Response: This has been updated as requested. 
36. 8.1.2.2 
Add the following as a second paragraph: 
 
Product Quality Complaint (PQC): A product quality complaint is defined as any 
suspicion of a product defect related to a potential quality issue during   
manufacturing, packaging, release testing, stability monitoring, dose preparation, 
storage or distribution of the product, or delivery system.  Not all PQCs involve a 
study subject.  Lot or batch numbers are of high significance and need to be 
provided where and when possible. PQC must be reported to the PMB as soon as 
the PQC is identified. Report PQC to PMB at PMBAfterHours@mail.nih.gov or 
by using the dialog function in AURORA to communicate with PMB staff. 
PI Response: This has been updated as requested. 
 
V. 
Disapproval Letter, 08/02/2023, Review of Amendment #10 of Protocol #10287* 
*Of note, protocol version reviewed was Amendment #8 dated July 10, 2023 
Comments Requiring a Response – Major Issues: 
# 
Section 
Comments 
2. 
Throughout 
Section 5 
Section 5.3.5.2 says that blood in EDTA should be processed to plasma and 
buffy coat; however, the protocol is not consistent about whether the buff coat 
samples should be sent to the EET Biobank.  If buffy coat from the blood in 
EDTA should be submitted to the EET Biobank then please make the updates 
outlined in the comments below. 
PI Response: Blood in EDTA will not be processed to buffy coat.  Rather, 
the blood collected in the Streck cfDNA tube at pre-treatment time point 
will also be processed to buffy coat for germline DNA at EET Biobank.  


NCI Protocol #:  10287 
Version Date:  June 13, 2024 
 
vi 
# 
Section 
Comments 
This is now clarified throughout Section 5. 
3. 
5.1  
cfDNA is not sent to the EET Biobank.  To prevent confusion, it is suggested to 
revise the 2nd sentence above the Specimen Collection Table to the following: 
Blood draws for EDTA (purple top), red top, and Streck cfDNA tubes could 
still be submitted on a day when treatment is held or delayed - do not discard 
samples. 
PI Response: This has been updated as requested. 
4. 
5.1 
Archival and Pre-treatment should be listed as separate time points in the 
Specimen Collection Table.  Please re-separate them as shown below.   
Also, please add the blue shading to the header as shown and update “cfDNA 
Streck tubes” to “Streck cfDNA tubes” throughout the Table. 
Time Point 
Specimen 
Send Specimens 
To: 
Archival 
 
• Archival tumor sample1: 
− 1 tumor-rich (more than 
50% tumor cellularity) 
FFPE block (preferred) 
 
If a block cannot be submitted, 
then submit: 
− 
1 H&E-stained slide at 3-5 
microns 
− 
15-20 unstained, 
uncharged, air-dried slides 
cut at 10 microns* 
− 
2 unstained, charged slides 
cut at 4-5 microns* 
EET Biobank 
Pre-treatment 


NCI Protocol #:  10287 
Version Date:  June 13, 2024 
 
vii 
# 
Section 
Comments 
 
• Fresh tumor biopsy2: 
− 1st and 2nd tumor cores snap-
frozen 
− 3rd and 4th tumor cores in 
formalin 
• 20 mL blood in Streck cfDNA 
tubes 
• 10 mL blood in EDTA (purple 
top) tube, processed for plasma 
and frozen3 
• 10 mL blood in red top tube, 
processed for serum and 
frozen4 
EET Biobank 
 
Section 5.3.5.2 says that blood in EDTA should be processed to plasma and 
buffy coat.  If this is correct, please update the bullets for this collection 
throughout the Table as follows to make it clear the EET Biobank will be 
receiving both specimens: 
• 10 mL blood in EDTA (purple top) tube, processed for plasma and 
buffy coat and frozen3 
 
Section 5.3.5.4 indicates that blood collected for PK should be proceeded to 
plasma at the collection site.  Update the bullets for this collection throughout 
the Table as follows to make this clear: 
• [5 or 7] x 4 mL blood in Li-Heparin BD vacutainers (green top), 
processed to plasma, and frozen for each PK time point before and after 
copanlisib infusion 
Also, is the 5 x 4 mL or 7 x 4 mL meant to indicate 20 or 28 mL per time point 
or 4 mL per time point for a total of 5 or 7 collections?  If the latter remove the 
“5 x” or “7 x” from the respective bullets as this could lead to over collection. 
 
Revise footnote #2 to remove the following sentence: 
When completed, upload the corresponding pathology report to Rave and send 
a copy to the EET Biobank. 
PI Response: The 5 x or 7 x have been removed to prevent over collection. 
Any mention of processing the EDTA tubes to buffy coat has been removed 
as well. Other updates were made as requested. 


NCI Protocol #:  10287 
Version Date:  June 13, 2024 
 
viii 
# 
Section 
Comments 
5. 
5.2.2 
Add bullets to the last two paragraphs in Section 5.2.2 as shown so the 
formatting of this section is consistent.   Also, will buffy coat from EDTA tubes 
will be submitted?  If yes, then retain the text below in yellow highlight.  If no, 
then remove the text in yellow highlight. 
• Frozen specimens, including processed serum, plasma, buffy coat, and 
frozen tissue, may be collected, processed, and shipped to the EET 
Biobank on Monday through Thursday, since the Biorepository does not 
need to perform additional processing.  In the event that frozen samples 
cannot be shipped immediately, they must be stored in a -80 °C freezer. 
Fresh blood specimens may be collected and shipped Monday through Friday. 
PI Response: The items were added to the bulleted list and buffy coat was 
removed from the collected specimens. 
6. 
5.3.4 
Replace the current language in Section 5.3.4 for the collection of frozen tissue 
with the following.  The updated language is recommended to help prevent the 
tissue from sticking to the side of the cryovial. 
 
5.3.4 Collection of Biopsy to Snap-Freeze 
 
1. Tissue should be frozen as soon as possible.  Optimally, freeze within 
30 minutes from resection. 
2. Prior to tissue collection: 
a. Label cryovial(s) according to instructions in Section 5.4.1.  
b. Place cryovial(s) on dry ice to freeze. The vials should appear 
frosty when ready.  
3. Immediately place tissue in foil and allow to completely freeze (using 
either direct contact with dry ice, or liquid nitrogen vapor).  
4. Gently remove the frozen tissue from the foil. If the tissue is sticking to 
the foil, then gently run a finger over the back of the foil to loosen the 
tissue.  
5. Using clean forceps place each tissue core in a separate pre-chilled 
cryovial. Tissue should move freely in the vial. 
 Place the tissue in a -70 to -80°C freezer.  Keep frozen until shipment to the 
EET Biobank. 
PI Response: This has been updated as requested. 
7. 
5.3.5 
Throughout this Section, revise ctDNA or cfDNA Streck tubes to Streck 
cfDNA tubes 


NCI Protocol #:  10287 
Version Date:  June 13, 2024 
 
ix 
# 
Section 
Comments 
PI Response: This has been updated as requested. 
8. 
5.4.1 
Revise the third sentence in the third paragraph the following.   
Do not redact SPID, block number, diagnosis or relevant dates (such as 
collection date), and include the UPID and patient study ID on each 
document (either by adding a label or hand writing).  
PI Response: This has been updated as requested. 
9. 
5.4.2 & 5.4.3.2 
Is collection time required on the specimen labels?  It is not indicated on the 
Specimen Collection labels in 5.4.2, but is indicated in Step 2 of Section 
5.4.3.2. 
 
If time is not required, remove “time” from the 1st bullet in Step 2 of Section 
5.4.3.2. 
 
If time is required, then please update the labeling instructions in 5.4.2 to 
indicate for which samples it is needed (e.g., blood).  If it is only required for a 
subset of samples (e.g., PK specimens only), please indicate that in parentheses 
both in the labeling instructions in Section 5.4.2 and in Step 2 of Section 
5.4.3.3.   
 
For example, for 5.4.2.2, 
• Collection date and time (only for PK specimens) (to be added by hand) 
 
For example, for Step 2 in Section 5.4.3.2 
Label specimen containers and write collection date and time (time only needed 
for PK samples) on each label. 
PI Response: Time has been removed from the instructions in Step 2 of 
Section 5.4.3.2. 
10. 
5.4.3.2 
Revise the last sentence of the final bullet in Step 2 as follows: 
Do not redact SPID, block number or relevant dates (such as collection date), 
and include the UPID and the patient study ID on each document.  
PI Response: No update has been made as the last sentence of Step 2 
already stated the above. 
11. 
5.5.1.1 
Revise the Required Forms for Specimen Submissions Table as shown below 


NCI Protocol #:  10287 
Version Date:  June 13, 2024 
 
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# 
Section 
Comments 
to: 
• Update Tissue to Specimen in the header 
• Update Surgical to Operative in the new biopsy row 
• Update blood to Blood in Streck Tubes, Plasma, Buffy Coat, and Serum 
in the blood row 
Note:  only include Buffy Coat, if buffy coat from EDTA tubes should be 
shipped to the EET Biobank. 
 
Specimen 
Required Forms 
Archival 
1. Shipping List 
2. Corresponding Pathology Report 
New Biopsy 
 
1. Shipping List 
2. Tissue Biopsy Verification Form 
3. Diagnostic Pathology Report  
4. Operative and/or Radiology Report 
Blood in Streck Tubes, 
Plasma, Buffy Coat and 
Serum 
1. Shipping List 
PI Response: This has been updated as requested. Buffy coat was not 
included. 
12. 
5.5.2.3 
If buffy coat from EDTA tubes is to be shipped to the EET Biobank, then revise 
the first sentence of Section 5.5.2.3 as follows: 
Serum, plasma, and buffy coat collected at time points that do not include the 
collection of frozen tissue must be submitted using institutional supplies. 
PI Response: Buffy coat from EDTA is not collected; this was not updated. 
13. 
5.8 
Replace the current Biomarker Table with revised Table below.  This will bring 
the table up to date with current formatting SOPs and make some additional 
changes for clarification including: 
• Separate tissue-based and blood-based assays. 
• The integrated and exploratory entries for WES and RRPA have been 
combined to make it clear that each assay is only to be performed once.  
It is not necessary to separate out exploratory purposes. 


NCI Protocol #:  10287 
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# 
Section 
Comments 
• The lab information has been updated to use the harmonized names for 
MoCha, the RRPA core, and the IHC lab. 
• The gene expression analysis biomarker name has been updated to 
RNAseq to match the harmonized name used across ETCTN Trials for 
this assay. 
• The PI and PI email information was added for the MoCha-based 
assays. 
• Collections for exploratory tissue-based biomarkers cannot be 
mandatory in the Biomarker Table.  The pre-treatment collections for 
RNAseq and TILs were updated to optional.  
• Additional formatting changes the specimens tested, collection time 
point, and M/O information. 
• For the Plasma and serum proteomics and metabolomics biomarker, if 
buffy coat is not required from the EDTA tube, then please remove the 
yellow highlighted text. 
Prio
Bio
mar
ker 
Na
me 
Assa
y and  
CLI
A: 
Y/N 
Use in the 
Trial  and 
Purpose 
Speci
mens 
Tested 
Collect
ion 
Time 
Points 
Mand
atory 
or 
Optio
nal 
Assay 
Laborato
ry, Lab 
PI, and 
Lab PI 
Email 
Tissue-based 
 
1 
Wh
ole 
exo
me 
sequ
enci
ng 
(WE
S) 
 
NGS 
CLIA
:  N 
 
Integrated 
Mutations 
in PIK3CA 
or PTEN as 
predictive 
markers for 
response to 
PI3K 
inhibitors 
Additional 
exploratory 
analyses:  
To assess 
mutations 
in in 
candidate 
DNA 
from 
FFPE 
Tumor 
Tissue 
Archiva
l, 
Pre-
treatme
nt 
(Baseli
ne) 
M 
M 
MoCha, 
Frederick 
National 
Laborator
y for 
Cancer 
Research 
(FNLCR) 
Dr. 
Mickey 
Williams 
mickey.wi
lliams@ni
h.gov 


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xii 
# 
Section 
Comments 
genes 
including 
ESR1, Rb, 
TP53, 
AKT1, 
PIK3R1, 
RAS, and 
others at 
baseline 
and 
progression 
and to 
correlate 
with 
response in 
each 
treatment 
arm. 
2 
PTE
N 
expr
essi
on 
IHC 
CLIA
:  N 
 
Integrated 
Loss of 
PTEN as 
predictive 
markers for 
response to 
PI3K 
inhibitors 
Unstai
ned 
slides 
from 
FFPE 
Tumor 
Tissue 
 
Archiva
l, 
Pre-
treatme
nt 
(Baseli
ne) 
M 
M 
Clinical 
Immunohi
stochemist
ry 
Laborator
y, MD 
Anderson 
Cancer 
Center 
(MDACC
) 
Dr. Wei-
Lien 
Wang 
wlwana@
mdanders
on.org 
 
3 
Rev
erse 
Phas
e 
Prot
RPP
A 
CLIA
:  N 
Integrated 
Levels of 
phosphoryl
ated Rb 
Snap-
frozen 
Tumor 
Tissue 
Pre-
treatme
nt, 
C1D15, 
M 
 
O 
Functional 
Proteomic
s RPPA 
Core 
Facility, 


NCI Protocol #:  10287 
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xiii 
# 
Section 
Comments 
ein 
arra
y 
(RP
PA) 
 
 
(pS807_S8
11), AKT 
(pS473), 
Cyclin D1:  
To test 
whether 
baseline 
AKT 
phosphoryl
ation 
correlates 
with PFS 
benefit 
from the 
addition of 
copanlisib 
and 
whether the 
triplet 
therapy 
with 
copanlisib/f
ulvestrant/a
bemaciclib 
inhibits 
AKT 
phosphoryl
ation, 
reduces 
cyclin D1 
expression, 
and is more 
effective in 
reducing 
Rb 
phosphoryl
ation than 
with the 
fulvestrant/
abemacicli
b doublet;  
Additional 
exploratory 
analyses: 
Disease 
progres
sion  
O 
MD 
Anderson 
Cancer 
Center 
(MDACC
) 
Dr. Yiling 
Lu  
yilinglu@
mdanders
on.org 
 
 


NCI Protocol #:  10287 
Version Date:  June 13, 2024 
 
xiv 
# 
Section 
Comments 
To assess 
baseline 
and 
treatment 
induced 
changes in 
in various 
cancer 
associated 
pathways, 
including 
but not 
limited to 
PI3K, 
MAPK, 
ER, 
cyclins, 
CDKs and 
CDK 
inhibitors,; 
to correlate 
with 
treatment 
response 
and 
progression 
4 
RN
Ase
q 
 
NGS 
 
Explorator
y 
Gene 
expression 
analysis:  
To 
correlate 
baseline 
and 
treatment 
induced 
changes in 
breast 
cancer 
intrinsic 
subtypes 
(PAM50), 
RNA 
from 
snap-
frozen 
tumor 
tissue 
Pre-
treatme
nt, 
C1D15, 
Disease 
progres
sion  
O 
 
O 
O 
MoCha, 
Frederick 
National 
Laborator
y for 
Cancer 
Research 
(FNLCR) 
Dr. 
Mickey 
Williams 
mickey.wi
lliams@ni
h.gov  


NCI Protocol #:  10287 
Version Date:  June 13, 2024 
 
xv 
# 
Section 
Comments 
and PI3K 
mRNA 
signature 
and 
expression 
of 
candidate 
genes with 
treatment 
response 
and benefit 
from 
adding 
copanlisib. 
5 
Tum
or 
imm
une 
micr
oen
viro
nme
nt 
(TIL
) 
Multi
-plex 
IHC 
(CD4
+, 
CD8+
, 
CD3+ 
T 
cells) 
Explorator
y 
To assess 
tumor 
immune 
microenvir
onment to 
correlate 
changes in 
infiltrating 
lymphocyte
s with 
treatment 
response 
Unstai
ned 
Slides 
from 
FFPE 
Tumor 
Tissue 
 
Pre-
treatme
nt, 
C1D15, 
Disease 
progres
sion  
O 
 
O 
O 
Washingt
on 
University 
Center for 
Human 
Immunolo
gy and 
Immunoth
erapy 
Programs 
(CHiiPs) 
Core 
Dr. 
Robert 
Schreiber 
rdschreibe
r@wustl.e
du 
Blood-based 


NCI Protocol #:  10287 
Version Date:  June 13, 2024 
 
xvi 
# 
Section 
Comments 
1 
Wh
ole 
exo
me 
sequ
enci
ng 
(WE
S) 
 
NGS 
CLIA
:  N 
 
Integrated 
Germline 
control for 
WES 
Germli
ne 
DNA 
from 
blood 
in 
Streck 
cfDN
A 
tubes 
Pre-
treatme
nt 
(Baseli
ne) 
M 
MoCha, 
Frederick 
National 
Laborator
y for 
Cancer 
Research 
(FNLCR) 
Mickey 
Williams 
mickey.wi
lliams@ni
h.gov 
2 
ctD
NA 
sequ
enci
ng 
(PI
K3C
A, 
PTE
N, 
ESR
1 
and 
othe
rs) 
NGS 
 
 
Explorator
y 
To 
correlate 
ctDNA 
mutation 
profiles 
with tumor 
sequencing
, and 
correlate 
baseline 
ctDNA 
mutations, 
particularly 
in 
component
s of the 
PI3K 
pathway 
with 
treatment 
response, 
and 
correlate 
early 
changes in 
ctDNA 
Plasm
a from 
blood 
in 
Streck 
cfDN
A 
tubes 
Pre-
treatme
nt 
C1D8,  
C1D15,  
C2D1,  
C4D1,  
C7D1 
and 
then 
every 3 
cycles 
after),  
Disease 
progres
sion 
M 
M 
M 
M 
M 
M 
 
M 
 
Broad 
Institute 
Dr. 
Gerburg 
Wulf  
gwulf@bi
dmc.harva
rd.edu 
 


NCI Protocol #:  10287 
Version Date:  June 13, 2024 
 
xvii 
# 
Section 
Comments 
VAFs with 
PFS, assess 
emergent 
resistant 
mutations 
at 
progression 
3 
Plas
ma 
and 
seru
m 
prot
eom
ics 
and 
met
abol
omi
cs 
Prote
omic 
Analy
sis 
 
Explorator
y 
To 
characteriz
e 
circulating 
markers 
before and 
after PI3K 
inhibitor 
therapy to 
predict 
treatment 
response 
and 
resistance 
mechanism
s 
Plasm
a from 
blood 
in 
EDTA 
tube  
& 
Serum 
from 
blood 
in red 
top 
tube 
Pre-
treatme
nt 
C1D8,  
C1D15,  
C2D1,  
C4D1,  
C7D1 
and 
then 
every 3 
cycles 
after),  
Disease 
progres
sion 
M 
M 
M 
M 
M 
M 
 
M 
 
Beth 
Israel 
Deaconess 
Medical 
Center 
Proteomic
s Core/ 
Broad 
Institute 
Dr. 
Gerburg 
Wulf  
gwulf@bi
dmc.harva
rd.edu 
 


NCI Protocol #:  10287 
Version Date:  June 13, 2024 
 
xviii 
# 
Section 
Comments 
4 
Cop
anlis
ib 
Phar
mac
okin
etics
** 
LC/M
S/MS 
 
Explorator
y 
To evaluate 
whether 
abemacicli
b impacts 
the PK of 
copanlisib 
Plasm
a from 
blood 
in Li-
Hepari
n BD 
vacuta
iners 
(i) 
C1D1  
(a) 
Prior to 
copanli
sib 
infusio
n and 
(b) 
After 
copanli
sib 
infusio
n (10 
min, 1 
hr, 2 hr, 
3 hr, 5 
hr, 24 
hr 
[before 
C1D2’s 
abemac
iclib 
and 
fulvestr
ant]) 
 
and (ii) 
C1D15(
a) Prior 
to 
copanli
sib 
infusio
n and 
(b) 
After 
copanli
sib 
infusio
n (10 
min, 1 
M 
 
 
 
 
 
 
 
 
 
 
 
M 
 
 
NorthEast 
Bioanalyti
cal 
Laboratori
es 
Dr. Vipin 
Agarwal 
vipin.agar
wal@nebi
olab.com 
 


NCI Protocol #:  10287 
Version Date:  June 13, 2024 
 
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# 
Section 
Comments 
hr, 2 hr, 
3 hr, 5 
hr, 24 
hr 
[before 
C1D16’
s 
abemac
iclib 
and 
fulvestr
ant]) 
5 
Abe
mac
iclib 
Phar
mac
okin
etics
** 
LC/M
S/MS 
 
Explorator
y 
 
To evaluate 
whether 
copanlisib 
impacts the 
PK of 
abemacicli
b 
Plasm
a from 
blood 
in Li-
Hepari
n BD 
vacuta
iners 
(i) 
C1D15: 
Use the 
blood 
collecte
d the 
same 
timepoi
nts for 
the 
copanli
sib PK. 
 
(ii) 
C1D22:  
Prior 
to, 1h, 
2h, 4h, 
23h 
post the 
M 
 
 
 
 
 
 
M 
NorthEast 
Bioanalyti
cal 
Laboratori
es 
Dr. Vipin 
Agarwal 
vipin.agar
wal@nebi
olab.com 
 


NCI Protocol #:  10287 
Version Date:  June 13, 2024 
 
xx 
# 
Section 
Comments 
mornin
g dose 
of 
abemac
iclib 
 
** PK samples are required for patients enrolled in the phase 1 portion and the 
first four patients enrolled to the FAC arm in the randomized phase 2 portion.   
PI Response: This has been updated as requested. The contact for CHiiPs 
has also been updated from Dr. Schreiber to Diane Bender, PhD. Shipping 
of the buffy coat was removed from the table. 
14. 
5.8.1 & 5.9.1 
• Revise the title for 5.8.1 PIK3CA/PTEN mutation status to 5.8.1 Whole 
Exome Sequencing (WES). 
• In 5.8.1.3, revise the Attn: information to: 
Attn: Alyssa Chapman or Ruth Thornton 
Remove Section 5.9.1 as all WES-related biomarkers have been combined into 
one biomarker 
PI Response: This has been updated as requested. 
15. 
5.8.2 
Add new subsections 5.8.2.3 and 5.8.2.4 as shown below: 
5.8.2.3 Shipment of Specimens from the EET Biobank to Site Performing 
Correlative Study  
Specimens will be shipped from the EET Biobank to: 
Add the shipping information for the MD Anderson Clinical 
Immunohistochemical Laboratory 
5.8.2.4   Contact Information for Notification of Specimen Shipment 
Add the contact information for notification of specimen shipments to the MD 
Anderson Clinical Immunohistochemical Laboratory 
PI Response: 
16. 
5.9.2  
Move current Section 5.9.2 RPPA to the Section 5.8.3 since it is an integrated 
biomarker. 
Add new subsections 5.8.3.3 and 5.8.3.4 as shown below: 
5.8.3.3 Shipment of Specimens from the EET Biobank to Site Performing 
Correlative Study  
Specimens will be shipped from the EET Biobank to: 


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# 
Section 
Comments 
Add the shipping information for the RPPA Core 
5.8.3.4   Contact Information for Notification of Specimen Shipment 
Add the contact information for notification of specimen shipments to the 
RPPA Core 
PI Response: This has been moved and updated as requested. 
17. 
5.9.3 
In 5.9.3.3, revise the Attn: information for RNAseq to: 
Attn: Alyssa Chapman or Ruth Thornton 
PI Response: This has been updated as requested. 
18. 
5.9.4 
Add new subsections 5.9.4.3 and 5.9.4.4 as shown below: 
5.9.4.3 Shipment of Specimens from the EET Biobank to Site Performing 
Correlative Study  
Specimens will be shipped from the EET Biobank to: 
Add the shipping information for the Broad Institute for ctDNA analysis 
5.9.4.4   Contact Information for Notification of Specimen Shipment 
Add the contact information for notification of specimen shipments to the for 
the Broad Institute for ctDNA analysis  
PI Response: 
19. 
5.9.7 
Add new subsections 5.9.7.3 and 5.9.7.4 as shown below: 
5.9.7.3 Shipment of Specimens from the EET Biobank to Site Performing 
Correlative Study  
Specimens will be shipped from the EET Biobank to: 
Add the shipping information for the Washington University CHiiP Core for 
TILs 
5.9.7.4   Contact Information for Notification of Specimen Shipment 
Add the contact information for notification of specimen shipments to the 
Washington University CHiiP Core for TILs 
PI Response: This has been updated as requested. 
20. 
11.1 and 11.2 
If buffy coat is to be sent to the EET Biobank, update the row in each study 
calendar for the EDTA tube to the following: 
Blood (EDTA purple top tube) for plasma and buff coat6 
PI Response: Buffy coat is processed from the Streck cfDNA tube, so this 
change was not made. 


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Version Date:  June 13, 2024 
 
xxii 
Comments Requiring a Response – Administrative and Editorial Issues: 
# 
Section 
Comments 
21. 
ICD -Optional 
Studies for 
Phase 1 and 
Phase 2 ICD 
Results will not be returned as stated under “Optional studies you can chose to 
take part in”  
Please delete the following language under “Samples for known future 
studies”  
 
I agree that my study doctor, or someone on the study team, may contact me or 
my doctor to see if I wish to learn about results from this study.  
YES        NO 
PI Response: This has been updated as requested. 
22. 
 9.4 
Please insert a Domestic Planned Enrollment Table for Phase 1 & Phase 2 
portions of the study. And also please add an “International Planned 
Enrollment Report” tables for Phase 1 & Phase 2 phases of the study since 
Princess Margaret Cancer Center is listed as a participant. 
PI Response: This has been updated as requested. 
23. 
 Both consents 
& 9.4 
Per 9.4 there will be 204 participants. Per the ICD “What is the purpose” there 
will be a total of 194 participants (Phase 1 n= 24; Phase 2  n=170). Please 
review and reconcile 
PI Response: Section 9.4 has been updated to clarify that Phase 1 is 
complete as of the time of Amendment 8, and enrollment was 24 patients. 
Recommendations: 
# 
Section 
Comments 
24. 
4.1, Investigator 
and Research 
Associate 
Registration 
with CTEP 
Please delete the information within this subsection and replace with the 
following language to reflect the current CTEP language template. 
 
4.1 
Investigator and Research Associate Registration with CTEP 
Food and Drug Administration (FDA) regulations require sponsors to select 
qualified investigators.  National Cancer Institute (NCI) policy requires all 
individuals contributing to NCI-sponsored trials to register with their 
qualifications and credentials and to renew their registration annually.  To 
register, all individuals must obtain a Cancer Therapy Evaluation Program 
(CTEP) Identity and Access Management (IAM) account at 
https://ctepcore.nci.nih.gov/iam.  Investigators and clinical site staff who are 
significant contributors to research must register in the Registration and 


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# 
Section 
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Credential Repository (RCR) at https://ctepcore.nci.nih.gov/rcr/. The RCR is 
a self-service online person registration application with electronic signature 
and document submission capability. 
RCR utilizes five person registration types. 
• Investigator (IVR):  MD, DO, or international equivalent, 
• Non Physician Investigator (NPIVR):  advanced practice providers 
(e.g., NP or PA) or graduate level researchers (e.g., PhD), 
• Associate Plus (AP):  clinical site staff (e.g., RN or CRA) with data 
entry access to CTSU applications such as the Roster Update 
Management System (RUMS), OPEN, Rave, acting as a primary site 
contact, or with consenting privileges, 
• Associate (A):  other clinical site staff involved in the conduct of NCI-
sponsored trials, and 
• Associate Basic (AB):  individuals (e.g., pharmaceutical company 
employees) with limited access to NCI-supported systems. 
RCR requires the following registration documents: 
 
Documentation Required 
I
V
R 
NPIV
R 
A
P 
A 
A
B 
FDA Form 1572 
✔ 
✔ 
 
 
 
Financial Disclosure Form 
✔ 
✔ 
✔ 
NCI Biosketch (education, training, 
employment, license, and certification) 
✔ 
✔ 
✔ 
GCP training 
✔ 
✔ 
✔ 
Agent Shipment Form (if applicable) 
✔ 
CV (optional) 
✔ 
✔ 
✔ 
 
IVRs and NPIVRs must list all clinical practice sites and Institutional Review 
Boards (IRBs) covering their practice sites on the FDA Form 1572 in RCR to 
allow the following: 
• Addition to a site roster, 
• Selection as the treating, credit, or drug shipment  investigator or 
consenting person in OPEN, 
•  Ability to be named as the site-protocol Principal Investigator (PI) on 
the IRB approval, and 
• Assignment of the Clinical Investigator (CI) task on the Delegation of 
Tasks Log (DTL).  
In addition, all investigators acting as the Site-Protocol PI (Investigator listed 


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xxiv 
# 
Section 
Comments 
on the IRB approval), consenting/treating/drug shipment investigator in 
OPEN, or as the Clinical Investigator (CI) on the DTL must be rostered at the 
enrolling site with a participating organization.  
Refer to the NCI RCR page on the CTEP website for additional information.  
For questions, please contact the RCR Help Desk by email at 
RCRHelpDesk@nih.gov. 
PI Response: This has been updated as requested. 
25. 
4.2, Site 
Registration 
Please delete the information within this subsection and replace with the 
following language to reflect the current CTEP language template. 
 
4.2 
Site Registration 
This study is supported by the NCI Cancer Trials Support Unit (CTSU). 
IRB Approval   
Sites participating with the NCI Central Institutional Review Board (NCI 
CIRB) must submit the Study Specific Worksheet (SSW) for Local Context to 
the CIRB using IRBManager to indicate their intent to open the study locally.  
The NCI CIRB’s approval of the SSW is automatically communicated to the 
CTSU Regulatory Office, but sites are required to contact the CTSU 
Regulatory Office at CTSURegPref@ctsu.coccg.org to establish site 
preferences for applying NCI CIRB approvals across their Signatory Network.  
Site preferences can be set at the network or protocol level.  Questions about 
establishing site preferences can be addressed to the CTSU Regulatory Office 
by email or calling 1-888-651-CTSU (2878). 
In addition, the Site-Protocol PI (i.e., the investigator on the IRB/REB 
approval) must meet the following criteria for the site to be able to have an 
Approved status following processing of the IRB/REB approval record: 
• Have an active CTEP status, 
• Have an active status at the site(s) on the IRB/REB approval (applies 
to US and Canadian sites only) on at least one participating 
organization’s roster, 
• If using NCI CIRB, be active on the NCI CIRB roster under the 
applicable CIRB Signatory Institution(s) record, 
• Include the IRB number of the IRB providing approval in the Form 
FDA 1572 in the RCR profile, 
• List all sites on the IRB/REB approval as Practice Sites in the Form 
FDA 1572 in the RCR profile; and 
• Have the appropriate CTEP registration type for the protocol.  
 


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# 
Section 
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Additional Requirements 
Additional site requirements to obtain an approved site registration status 
include: 
• An active Federal Wide Assurance (FWA) number, 
• An active roster affiliation with the Lead Protocol Organization (LPO) 
or a Participating Organization (PO),  
• An active roster affiliation with the NCI CIRB roster under at least one 
CIRB Signatory Institution (US sites only); and 
• Compliance with all applicable protocol-specific requirements (PSRs). 
PI Response: This has been updated as requested. 
26. 
4.2.1, 
Downloading 
Site 
Registration 
Documents 
Please delete the information within this subsection and replace with the 
following language to reflect the current CTEP language template. 
 
4.2.1 Downloading Site Registration Documents 
Download the site registration forms from the protocol-specific page located 
on the CTSU members’ website.  Permission to view and download this 
protocol and its supporting documents is restricted to institutions and their 
associated investigators and staff on a participating roster.  To view/download 
site registration forms:   
• Log in to the CTSU members’ website (https://www.ctsu.org), 
• Click on Protocols in the upper left of the screen 
o Enter the protocol number in the search field at the top of the 
protocol tree, or 
o Click on the By Lead Organization folder to expand, then select 
LAO-CT018, and protocol number 10287, 
• Click on Documents, Protocol Related Documents, and use the 
Document Type filter and select Site Registration to download and 
complete the forms provided.  (Note:  For sites under the CIRB, IRB 
data will load automatically to the CTSU.)  
PI Response: This has been updated as requested. 
27. 
4.2.2 
Requirements 
for 10287 Site 
Registration 
Please revise the excerpt below as indicated. 
 
o The training is a one-time only requirement per individual. If 
an individual has previously completed the training for another 
ETCTN study, the training does not need to be completed 
again nor does the certificate of completion need to be 
resubmitted to the CTSU.  However, new versions of the 


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# 
Section 
Comments 
Specimen Tracking System may require new training. Users 
are strongly encouraged to take a refresher of the training if 
they have not entered specimen data for an extended period of 
time. 
o This training will need to be completed before first/further 
patient enrollment at a given site. 
o Please contact STS Support at Theradex for the training 
(STS.Support@theradex.com; Theradex phone:  609-799-
7580).   
PI Response: This has been updated as requested. 
28. 
4.3.1, 
OPEN/IWRS 
Please revise the excerpt below as indicated. 
 
• A valid CTEP-IAM account. 
• Active CTEP registration with the credentials necessary to 
access secure NCI/CTSU IT systems. 
• To perform enrollments or request slot reservations:  Be Must be 
on an LPO roster, ETCTN Corresponding roster, or 
Participating Organization PO roster with the role of Registrar.  
Registrars must hold a minimum of an AP Associate Plus (AP) 
registration type. 
 
Please revise the excerpt below as indicated. 
 
• All patients have signed an appropriate consent form and 
HIPAA Health Insurance Portability and Accountability Act 
(HIPAA) authorization form (if applicable). 
PI Response: This has been updated as requested. 
29. 
10.3.1, Rave-
CTEP-AERS 
Please delete the information within this subsection and replace with the 
following language to reflect the current CTEP language template. 
 
10.3.1 Rave-CTEP-AERS Integration 
 
The Rave Cancer Therapy Evaluation Program Adverse Event 
Reporting System (CTEP-AERS) integration enables evaluation of 
Adverse Events (AEs) entered in Rave to determine whether they 
require expedited reporting and facilitates entry in CTEP-AERS for 
those AEs requiring expedited reporting.  Sites must initiate all AEs 


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xxvii 
# 
Section 
Comments 
for this study in Medidata Rave. 
 
Include the following (highlighted) paragraphs about pre-treatment 
AEs only if the study requires reporting of pre-treatment AEs and 
the CTSU standard Pre-Treatment AE form is used. Pre-existing 
medical conditions are not considered adverse events and therefore 
should not be reported on the Pre-Treatment Adverse Event form. 
 
Pre-treatment AEs:  AEs that occur after informed consent is signed 
and prior to start of treatment are collected in Medidata Rave using the 
Pre-treatment Adverse Event form.  
 
Pre-existing medical conditions (formerly referred to as baseline AEs) 
identified during baseline assessment are not considered AEs and 
therefore should not be reported on the Pre-treatment Adverse Event 
form. If these pre-existing conditions worsen in severity, the 
investigator must reassess the event to determine if an expedited 
report is required. Whether or not an expedited report is required, the 
worsened condition should be reported in Rave as a routine AE. 
 
Treatment-emergent AEs:  All AEs that occur after start of treatment 
are collected in Medidata Rave using the Adverse Event form, which 
is available for entry at each treatment course or reporting period and 
is used to collect AEs that start during the period or persist from the 
previous reporting period.  AEs that occur 30 days after the last 
administration of the investigational agent/intervention are collected 
using the Late Adverse Event form. 
 
Prior to sending AEs through the rules evaluation process, site staff 
should verify the following on the Adverse Event form in Rave: 
 
• The reporting period (course/cycle) is correct, and 
• AEs are recorded and complete (no missing fields) and the 
form is query free.  
 
The CRA reports AEs in Rave at the time the Investigator learns of 
the event.  If the CRA modifies an AE, it must be re-submitted for 


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xxviii 
# 
Section 
Comments 
rules evaluation. 
Upon completion of AE entry in Medidata Rave, the CRA submits the 
AE for rules evaluation by completing the Expedited Reporting 
Evaluation form (i.e., checking the box Send All AEs for Evaluation 
and save the form).  Both NCI and protocol-specific reporting rules 
evaluate the AEs submitted for expedited reporting.  A report is 
initiated in CTEP-AERS using information entered in Medidata Rave 
for AEs that meet reporting requirements.  The CRA completes the 
report by accessing CTEP-AERS via a direct link on the Medidata 
Rave Expedited Reporting Evaluation form.  Contact the CTSU Help 
Desk at 1-888-823-5923 or by email at ctsucontact@westat.com if 
you have any issues submitting an expedited report in CTEP-AERS. 
In the rare occurrence that internet connectivity is lost, a 24-hour 
notification is to be made to CTEP by telephone at 301-897-7497.  
Once internet connectivity is restored, the 24-hour notification that 
was phoned in must be entered immediately into CTEP-AERS using 
the direct link from Medidata Rave. 
Additional information about the CTEP-AERS integration is available 
on the CTSU members’ website: 
• Study specific documents:   Protocols > Documents> Protocol 
Related Documents> Adverse Event Reporting, and   
• Additional resources: Resources > CTSU Operations 
Information> User Guides & Help Topics. 
NCI requirements for SAE reporting are available on the CTEP 
website:  
• NCI Guidelines for Investigators:  Adverse Event Reporting 
Requirements is available at 
https://ctep.cancer.gov/protocolDevelopment/electronic_applic
ations/docs/aeguidelines.pdf. 
PI Response: This has been updated as requested. The Pre-treatment AE 
page is not utilized for this study so the highlighted text was omitted from 
the update. 
30. 
13.2, Data 
Reporting 
Please delete the information within this subsection and replace with the 
following language to reflect the current CTEP language template. 
 
13.2 
Data Reporting 
Medidata Rave is the clinical data management system being used for data 
collection for this trial/study.  Access to the trial in Rave is controlled through 


NCI Protocol #:  10287 
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xxix 
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Section 
Comments 
the CTEP-IAM system and role assignments.   
Requirements to access Rave via iMedidata: 
• 
Active CTEP registration with the credentials necessary to access 
secure NCI/CTSU IT systems, and 
• 
Assigned a Rave role on the LPO or PO roster at the enrolling site of:  
Rave CRA, Rave Read Only, Rave CRA (LabAdmin), Rave SLA, or 
Rave Investigator.   
Rave role requirements: 
o Rave CRA or Rave CRA (Lab Admin) role must have a 
minimum of an Associate Plus (AP) registration type, 
o Rave Investigator role must be registered as a Non-Physician 
Investigator (NPIVR) or Investigator (IVR), and 
o Rave Read Only or Rave SLA role must have at a minimum an 
Associate (A) registration type. 
• 
Refer to https://ctep.cancer.gov/investigatorResources/default.htm for 
registration types and documentation required. 
If the study has a DTL, individuals requiring write access to Rave must also 
be assigned the appropriate Rave tasks on the DTL. 
Upon initial site registration approval for the study in the Regulatory 
application, all persons with Rave roles assigned on the appropriate roster will 
be sent a study invitation email from iMedidata.  To accept the invitation, site 
staff must either click on the link in the email or log in to iMedidata via the 
CTSU members’ website  under Data Management > Rave Home and click to 
accept the invitation in the Tasks pane located in the upper right-corner of the 
iMedidata screen.  Site staff will not be able to access the study in Rave until 
all required Medidata and study specific trainings are completed.  Trainings 
will be in the form of electronic learnings (eLearnings) and can be accessed 
by clicking on the eLearning link in the Tasks pane located in the upper right 
corner of the iMedidata screen.  If an eLearning is required for a study and 
has not yet been taken, the link to the eLearning will appear under the study 
name in the Studies pane located in the center of the iMedidata screen; once 
the successful completion of the eLearning has been recorded, access to the 
study in Rave will be granted, and a Rave EDC link will replace the 
eLearning link under the study name.  
Site staff who have not previously activated their iMedidata/Rave account at 
the time of initial site registration approval for the study in the Regulatory 
application will receive a separate invitation from iMedidata to activate their 
account.  Account activation instructions are located on the CTSU website in 
the Data Management section under the Rave resource materials (Medidata 


NCI Protocol #:  10287 
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Section 
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Account Activation and Study Invitation Acceptance).  Additional information 
on iMedidata/Rave is available on the CTSU members’ website in the Data 
Management > Rave section or by contacting the CTSU Help Desk at 1-888-
823-5923 or by email at ctsucontact@westat.com.   
PI Response: This has been updated as requested. 
31. 
13.3, Data 
Quality Portal 
Please delete the information within this subsection and replace with the 
following language to reflect the current CTEP language template. 
 
13.3 
Data Quality Portal 
The Data Quality Portal (DQP) provides a central location for site staff to 
manage unanswered queries and form delinquencies, monitor data quality and 
timeliness, generate reports, and review metrics.  
The DQP is located on the CTSU members’ website under Data Management.  
The Rave Home section displays a table providing summary counts of Total 
Delinquencies and Total Queries.  DQP Queries, DQP Delinquent Forms, 
DQP Form Status and the DQP Reports modules are available to access 
details and reports of unanswered queries, delinquent forms, forms with 
current status, and timeliness reports.  Site staff should review the DQP 
modules on a regular basis to manage specified queries and delinquent forms. 
The DQP is accessible by site staff who are rostered to a site and have access 
to the CTSU website.  Staff who have Rave study access can access the Rave 
study data via direct links available on the DQP modules. 
CTSU Delinquency Notification emails are sent to primary contacts at sites 
twice a month. These notifications serve as alerts that queries and/or 
delinquent forms require site review, providing a summary count of queries 
and delinquent forms for each Rave study that a site is participating in. 
Additional site staff can subscribe and unsubscribe to these notifications using 
the CTSU Report and Information Subscription Portal on the CTSU 
members’ website. 
To learn more about DQP use and access, click on the Help Topics button 
displayed on the Rave Home, DQP Queries, DQP Delinquent Forms, DQP 
Form Status, and DQP Reports modules. 
 
Include the following paragraph only if study is not using the Calendaring 
functionality in Rave; otherwise, delete. 
This study does not use the Rave Calendaring functionality and 
therefore the DQP Delinquent Forms module will not include details 
for this study, and the DQP Summary table on the Rave Home page 


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# 
Section 
Comments 
will display N/A for the Total Delinquencies summary count. 
PI Response: This has been updated as requested. The calendaring 
function is not used so the language was kept. 
32. 
8.1.2.1, 8.1.3 
Please replace “Online Agent Order Processing (OAOP)” and “OAOP” with 
“AURORA” 
PI Response: This has been updated as requested. 
33. 
8.1.4 
Please replace: 
PMB Online Agent Order Processing (OAOP) application: 
https://ctepcore.nci.nih.gov/oaop 
With: 
PMB AURORA application: https://ctepcore.nci.nih.gov/aurora/login  
PI Response: This has been updated as requested. 
34. 
ICD  
Pg 19 
Study Calendar – remove the X for copanlisib on Day 8 as Day 8 and day 22 
are removed from cycles 2 and beyond. 
PI Response: This has been updated as requested. 
35. 
ICD  
Pg 19, 20 0f 19 
Please correct page numbers 
PI Response: This has been updated as requested. 
Company Comments – Requiring a Response: 
# 
Section 
Comments 
35. 
Schema page 3 
Schema (page 3): the old diagram is still in the protocol... it is still showing 
that the copa is dosed on D1, 8 and 15 in each cycle and abemaciclib as 
continuous dosing for 28 days. This figure should reflect the changes noted in 
the legend. 
PI Response: This has been updated as requested. 
 
VI. 
Summary of Changes in Amendment #8 of Protocol #10287, dated July 10, 2023 
 
# 
Section 
Comments 
36. 
Global 
Updated version date and table of contents. 
 
Minor typographical and formatting changes were made throughout the 
document. 


NCI Protocol #:  10287 
Version Date:  June 13, 2024 
 
xxxii 
# 
Section 
Comments 
37. 
Title page 
Updated University of Pittsburgh Cancer Institute to UPMC Hillman 
Cancer Center 
 
Added Amendment 8 / July 10, 2023 
38. 
Schema 
Added RP2D for Phase 2 FAC arm as determined by the Phase 1 portion 
of the study.  
 
Abemaciclib will be dosed at 100 mg BID PO Days 1-5 of each week 
during each 28-day cycle (Days 1-5, 8-12, 15-19, and 22-26). 
 
Copanlisib will be dosed at 45 mg IV on Days 1 and 15. 
 
Clarified that the first 2 doses of abemaciclib on C1D1 will be skipped for 
patients participating in the PKs. 
 
39. 
Section 2.7 
Added new Section 2.7 Rationale for Protocol Amendment #8 and RP2D. 
40. 
Section 4.3 
Clarified that information for the 10287 Study Portal is found in LPO 
Documents for the study on CTSU. 
 
41. 
Section 5.3.2 
Pre-treatment biopsies: Added that bone biopsies are acceptable and 
clarified that a minimum of 2 cores is required. 
 
C1D15 and Disease Progression biopsies: Corrected the biopsy collection 
time for patients on the FA regimen to at least 1 hour after abemaciclib, 
not copanlisib. Added that it is recommended to use the same site for both 
the pre-treatment and C1D15 biopsies, and clarified that a minimum of 2 
cores is required. 
 
42. 
Section 6 
Reworded the summary of the study design to clarify that the RP2D from 
the Phase 1 FAC regimen would be used for the randomized Phase 2 
portion, and that the RP2D is Dose Level 1b for the FAC arm. 
 
43. 
Section 6.1 
Added note to tables of potential dose levels for Part A and B stating: 
• Before initiating treatment with copanlisib, patients must initiate 
oral anti-histamine prophylaxis (i.e cetirizine) daily for rash 
prophylaxis to be continued throughout the course of protocol 
therapy. It is required that anti-histamine prophylaxis be initiated at 
least 3 days prior to Cycle 1 Day 1; however, if any issues arise 
that may necessitate a later start date for the anti-histamine 
prophylaxis, they must be discussed with the Principal 
Investigator. 


NCI Protocol #:  10287 
Version Date:  June 13, 2024 
 
xxxiii 
# 
Section 
Comments 
 
Added the RP2D dose of abemaciclib 100 mg BID on a 5 days on 2 days 
off schedule and copanlisib 45 mg IV Days 1 and 15 of a 28-day cycle to 
both paragraph and the regimen table. 
 
Added statement to Randomized Phase 2 portion in both paragraph and in 
the regimen table stating “Before initiating treatment with copanlisib, 
patients must initiate oral anti-histamine prophylaxis (i.e cetirizine) daily 
for rash prophylaxis to be continued throughout the course of protocol 
therapy. It is required that anti-histamine prophylaxis be initiated at least 3 
days prior to Cycle 1 Day 1; however, if any issues arise that may 
necessitate a later start date for the anti-histamine prophylaxis, they must 
be discussed with the Principal Investigator.” 
 
Clarified that for the first 4 patients randomized to the FAC arm and 
undergoing PKs, the C1D1 dose of abemaciclib is skipped. 
 
44. 
Section 6.1.1 
Added statement “Before initiating treatment with copanlisib, patients 
must initiate oral anti-histamine prophylaxis (i.e cetirizine) daily for rash 
prophylaxis to be continued throughout the course of protocol therapy. It 
is required that anti-histamine prophylaxis be initiated at least 3 days prior 
to Cycle 1 Day 1; however, if any issues arise that may necessitate a later 
start date for the anti-histamine prophylaxis, they must be discussed with 
the Principal Investigator.” 
 
Clarified that fasting is only required prior to the first C1D1 glucose 
measurement. 
 
Added an allowance for patients to have a low carbohydrate meal on 
C1D1 is their infusions are scheduled at a later hour, due to their age, or 
when medically indicated. 
 
45. 
Section 6.1.2 
Added the abemaciclib RP2D of 100 mg BID on Days 1-5, 8-12, 15-19, 
and 22-26 of each 28-day cycle. 
 
Clarified that for the first 4 patients enrolled to the FAC arm who are 
undergoing PKs, the first 2 doses of abemaciclib on C1D1 are skipped. 
 
46. 
Section 6.2.1 
Clarified that the DLT window is the first 28 days of treatment. 
 
Added a note stating that “patients who have major protocol deviations (as 
determined by the study chair and the study statistician) in the dose and/or 


NCI Protocol #:  10287 
Version Date:  June 13, 2024 
 
xxxiv 
# 
Section 
Comments 
schedule of the study drugs during Cycle 1 are not evaluable for DLT. 
These patients may be evaluable for overall AE and efficacy endpoints per 
statistical section.” 
 
47. 
Section 6.3 
Added requirement of daily oral antihistamine during copanlisib 
treatment. 
48. 
Section 7.1.2 
Clarified that an occurrence of hypertension consists of either systolic or 
diastolic reaching the 150/90 threshold, and that the infusion can be 
resumed once both systolic and diastolic BPs are less than 150/90. 
 
Added statement that “In patients who have not had any episodes of post 
infusion blood pressures ≥150/90 mmHg for at least 2 consecutive cycles 
of treatment, the blood pressure monitoring at 1h and 2h could be omitted 
at the discretion of the treating physician.” 
 
49. 
Section 7.1.6 
Clarified that a new cycle of treatment with copanlisib can only start if 
both systolic and diastolic BPs are less than 150/90. 
 
Added a note stating that “If dose interruption for copanlisib is necessary, 
it is preferred that the dose of copanlisib be delayed rather than missed to 
maximize copanlisib dosing.  However, copanlisib dosing schedule could 
be adjusted in subsequent cycles so to align with the fulvestrant 
administration, with the condition that no more than 2 consecutive weekly 
doses of copanlisib is administered.” 
 
Added that cycle length should be 28 days +/- 7 days, and that a 
maximum duration of holding copanlisib is 3 consecutive weeks. 
50. 
Section 7.2 
Added 50 mg BID continuously to Dose Level -1 to denote that the dosing 
schedule for the lowest dose reduction would be continuous irrespective 
of the initial dosing schedule. 
51. 
Section 9.1 
Added an interim toxicity analysis performed by the DSMB after the first 
10 patients are enrolled to the FAC arm in the Phase 2 portion of the 
study. 
52. 
Section 9.4.2 
Added an interim toxicity analysis performed by the DSMB after the first 
10 patients are enrolled to the FAC arm in the Phase 2 portion of the 
study. 
53. 
Section 11 
Renamed Baseline visit as Screening visit. 
 
Due to the schedule changes from Phase I to Phase II, a Phase II calendar 
was added. 
 
Phase I Calendar  Changes: 


NCI Protocol #:  10287 
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# 
Section 
Comments 
• Removed randomization row and subsequent cycles Day 22 column. 
• Added submission of genomic testing report at baseline if available. 
• Updated footnote 5 to include requirement for daily prophylactic 
antihistamine. 
• Updated footnote 7 to add a 14 day window for the tumor biopsy at 
baseline. 
• Updated footnote 15 to clarify that the first 2 doses of abemaciclib 
on C1D1 are skipped in patients undergoing PKs. 
• Updated footnote 17 with biopsy timing requirements relative to 
drug dosing. 
• Added footnote 22 clarifying where the genomic testing report 
should be uploaded if available. 
• Updated footnote ** to clarify that tumor imaging should be 
conducted at the end of cycle 3 and every 3 cycles after that, and 
removed the additional mention of every 12 weeks. 
 
 
 
 
 


NCI Protocol #:  10287 
Version Date:  June 13, 2024 
 
1 
NCI Protocol #: 
10287 
 
Local Protocol #: 
201911082 
 
ClinicalTrials.gov Identifier:  NCT03939897 
 
TITLE:  A randomized Phase I/II trial of fulvestrant and abemaciclib in combination with 
copanlisib (FAC) versus fulvestrant and abemaciclib alone (FA) for endocrine-resistant, 
hormone receptor positive, HER2 negative metastatic breast cancer (FAC vs FA) 
 
 
Corresponding Organization: 
 LAO-CT018 / Yale University Cancer Center LAO. 
  
 
Principal Investigator: 
Cynthia X. Ma, M.D., Ph.D. 
Washington University School of Medicine 
660 South Euclid Ave., CB 8056 
St. Louis, MO 63110 
Telephone: 314-362-9383 
E-mail:  cynthiaxma@wustl.edu 
 
Participating Organizations  
LAO-11030 / University Health Network Princess Margaret Cancer Center LAO 
LAO-CA043 / City of Hope Comprehensive Cancer Center LAO 
LAO-CT018 / Yale University Cancer Center LAO 
LAO-MA036 / Dana-Farber - Harvard Cancer Center LAO 
LAO-MD017 / JHU Sidney Kimmel Comprehensive Cancer Center LAO 
LAO-OH007 / Ohio State University Comprehensive Cancer Center LAO 
LAO-PA015 / UPMC Hillman Cancer Center LAO 
LAO-TX035 / University of Texas MD Anderson Cancer Center LAO 
LAO-NCI / National Cancer Institute LAO 
CATCHUP / Creating Access to Targeted Cancer Therapy for Underserved Populations 
 
 
Statistician: 
 
 
Study Coordinator: 
Jingqin (Rosy) Luo, Ph.D. 
Leslie Nehring 
Washington University School of Medicine             Washington University School of Medicine 
660 S. Euclid Ave., CB 8100  
             
Telephone:  314-362-9679 
St. Louis, MO 63110  
 
             
Pager:  314-253-1295 
Telephone:  314-362-3718 
Email:  lnehring@wustl.edu  
Email:  jingqinluo@wustl.edu 
Fax:  314-362-0206 


NCI Protocol #:  10287 
Version Date:  June 13, 2024 
 
2 
 
Co-investigators: 
Yiling Lu, M.D. 
 
 
Wei-Lien Wang, Ph.D. 
MD Anderson Cancer Center 
Clinical Immunohistochemistry Laboratory 
Email:  yilinglu@mdanderson.org 
MD Anderson Cancer Center 
 
 
Telephone:  713-792-4240 
 
 
Email:  wlwang@mdanderson.org 
Gerburg Wulf, M.D., Ph.D. 
Harvard Medical School 
Telephone:  617-667-1910 
Email:  gwulf@bidmc.harvard.edu 
 
Claire Dees, M.D. 
UNC Hospital 
Email:  Claire_dees@med.unc.edu 
 
NCI-Supplied Agent:  Copanlisib ([BAY 80-6946] NSC 784727) 
Other Agent(s):  Fulvestrant (NSC 719276, Commercial) 
Abemaciclib (NSC 783671, Commercial) 
 
IND #:   
IND Sponsor:  DCTD, NCI 
 
Protocol Type / Version # / Version Date: 
Original / December 6, 2018 
 
Revision 1 / March 5, 2019 
 
Revision 2 / April 3, 2019 
 
Revision 3a / June 20, 2019 
 
Revision 3b / July 18, 2019 
 
Revision 4 / August 20, 2019 
Amendment 1 / February 26, 2020 (Disapproved) 
Amendment 2 / March 17, 2020 
Amendment 3 / June 15, 2020 
Amendment 4 / August 25, 2020 
Amendment 5 / September 11, 2020 
Amendment 6 / February 4, 2021 (Disapproved) 
Amendment 6 / July 14, 2021 (Disapproved) 
Amendment 6a / August 13, 2021 
Amendment 6 / October 8, 2021 
Amendment 7 / April 26, 2023 
Amendment 8 / July 10, 2023 (Disapproved) 
Amendment 8a /September 7, 2023 (Disapproved) 
Amendment 8b / September 29, 2023 (Disapproved) 
Amendment 8c / November 28, 2023 (Disapproved) 
Amendment 8d / June 13, 2024 


NCI Protocol #:  10287 
Version Date:  June 13, 2024 
 
3 
SCHEMA 
 
Phase 1: 
 
Due to study closure, Amendment 8d dated 07Jun2024 removes the Phase 2 portion of the trial 
as it will not open. 
 
 
Note: Part A of Phase 1 tested abemaciclib at continuous dosing on Days 1-28 in combination with fulvestrant and 
copanlisib.  With Amendment 6, Part B was added to test abemaciclib at 5 days on and 2 days off each week in 
combination with fulvestrant and copanlisib.   
 
F:  Fulvestrant at 500 mg intramuscular (IM) Days 1 and 15 of Cycle 1, then on Day 1 of C2+ 
A: Abemaciclib as follows: 
Phase 1 Part A: at assigned dose BID orally (PO) Days 1-28 of each 28-day cycle. 
Phase 1 Part B: at assigned dose BID PO Days 1-5 of each week during each 28-day cycle (Days 1-5, 8-12, 15-
19, and 22-26). 
C: Copanlisib as follows: 
Phase 1: at assigned dose intravenously (IV) on an assigned schedule of Days 1, 8, 15 or Days 1 and 15 of each 
28-day cycle, depending on the dose level. 
 
Tumor biopsy:  Refer to Section 5.3 for details. 
Archival tumor specimens from prior diagnostic or therapeutic procedures are required. 
 


NCI Protocol #:  10287 
Version Date:  June 13, 2024 
 
4 
Phase 1 Regimen Part A: 
 
Potential Dose Level 
Possible 
Dose 
Level 
Copanlisib** 
Abemaciclib* 
Fulvestrant* 
Dose 
(mg) 
Administration 
and Schedule 
Dose 
(mg) 
Administration 
and Schedule 
Dose 
(mg) 
Administration 
and Schedule 
Level 4 
60 
IV on D1, D8, 
and D15 every 28 
days 
150 
PO BID 
500 
IM C1D2, 
C1D16, and D1 
of every cycle# 
thereafter 
Level 3 
45 
150 
500 
Level 2 
45 
100 
500 
Level 1 
(Starting 
dose) 
45 
IV on D1 and 
D15 every 28 
days 
100 
500 
Level -1 
30 
100 
500 
IV = intravenous, PO = by mouth, BID = twice a day, IM = intramuscular, C1D2 = Cycle 1 Day 2, 
C1D16 = Cycle 1 Day 16, and D = Day.  
Doses are stated as exact dose in units (e.g., mg/m2, mcg/kg, etc.) rather than as a percentage. 
*The first dose (C1D1) of abemaciclib and fulvestrant is delayed to CID2 following the 24 h blood 
draw for copanlisib pharmacokinetics (PK).  CID15 fulvestrant dose is delayed to C1D16 following the 
24 h blood draw for copanlisib PK. Note that C1D16 dose of fulvestrant could be omitted in patients on 
stable doses of fulvestrant prior to enrolling on this study. 
**Administered over 1 h (+/-10 minutes) 
#Cycle length = 28 days 
 
Phase 1 Regimen Part B: 
 
Potential Dose Level 
Possible Dose 
Level 
Copanlisib** 
Abemaciclib* 
Fulvestrant* 
Dose 
(mg) 
Route and 
Schedule 
Dose 
(mg) 
Route and Schedule 
Dose 
(mg) 
Route and 
Schedule 
Level 4b 
60 
IV on 
D1, D8, and 
D15 every 28 
days 
150 
 
 
PO BID 
5 days on and 2 days off 
each week 
 
 
 
500 
 
 
IM C1D2, 
C1D16, and D1 
of every cycle# 
thereafter 
Level 3b 
45 
150 
Level 2b 
45 
100 
Level 1b 
(Starting dose) 
45 
IV 
D1 and D15 
every 28 days  
100 
IV = intravenous, PO = by mouth, BID = twice a day, IM = intramuscular, C1D2 = Cycle 1 Day 2, C1D16 
= Cycle 1 Day 16, and D = Day.  
Doses are stated as exact dose in units (e.g., mg/m2, mcg/kg, etc.) rather than as a percentage. 
*The first dose (C1D1) of abemaciclib and fulvestrant is delayed to C1D2 following the 24 h blood draw 
for copanlisib pharmacokinetics (PK).  CID15 fulvestrant dose is delayed to C1D16 following the 24 h 
blood draw for copanlisib PK. Note that C1D16 dose of fulvestrant could be omitted in patients on stable 
doses of fulvestrant prior to enrolling on this study. 
**Administered over 1 h (+/-10 minutes) 
#Cycle length = 28 days 


NCI Protocol #:  10287 
Version Date:  June 13, 2024 
 
5 
 
TABLE OF CONTENTS 
SCHEMA 
......................................................................................................................3 
1. 
OBJECTIVES ......................................................................................................................8 
1.1 
Primary Objectives ...................................................................................................8 
1.2 
Secondary Objectives ...............................................................................................8 
1.3 
Exploratory Objectives ............................................................................................8 
2. 
BACKGROUND .................................................................................................................9 
2.1 
Study Disease ...........................................................................................................9 
2.2 
CTEP IND Agent ...................................................................................................13 
2.3 
Other Agents ..........................................................................................................24 
2.4 
Rationale ................................................................................................................28 
2.5 
Correlative Studies Background ............................................................................30 
2.6 
Rationale for Protocol Amendment #6 ..................................................................36 
2.7 
Rationale for Protocol Amendment #8d and Study Closure ....................................0 
3. 
PATIENT SELECTION ......................................................................................................0 
3.1 
Eligibility Criteria ....................................................................................................0 
3.2 
Exclusion Criteria ....................................................................................................2 
3.3 
Inclusion of Women and Minorities ........................................................................4 
4. 
REGISTRATION PROCEDURES .....................................................................................5 
4.1 
Investigator and Research Associate Registration with CTEP ................................5 
4.2 
Site Registration .......................................................................................................6 
4.3 
Patient Enrollment ...................................................................................................8 
4.4 
General Guidelines .................................................................................................10 
5. 
BIOMARKER, CORRELATIVE, AND SPECIAL STUDIES ........................................11 
5.1 
Summary Table for Specimen Collection ..............................................................11 
5.2 
Specimen Procurement Kits and Scheduling .........................................................13 
5.3 
Specimen Collection and Processing .....................................................................14 
5.4 
Specimen Tracking System Instructions ................................................................19 
5.5 
Shipping Specimens from Clinical Sites to the EET Biobank ...............................23 
5.6 
Shipping Specimens from Clinical Site to Other Laboratories ..............................26 
5.7 
Biomarker Plan ......................................................................................................28 
5.8 
Integrated Correlative Studies ................................................................................35 
5.9 
Exploratory/Ancillary Correlative Studies ............................................................37 
6. 
TREATMENT PLAN ........................................................................................................39 
6.1 
Agent Administration .............................................................................................39 
6.2 
Definition of Dose-Limiting Toxicity ....................................................................44 
6.3 
General Concomitant Medication and Supportive Care Guidelines ......................45 
6.4 
Duration of Therapy ...............................................................................................46 


NCI Protocol #:  10287 
Version Date:  June 13, 2024 
 
6 
6.5 
Duration of Follow-Up ..........................................................................................47 
7. 
DOSING DELAYS/DOSE MODIFICATIONS................................................................47 
7.1 
Copanlisib ..............................................................................................................47 
7.2 
Abemaciclib ...........................................................................................................50 
7.3 
Fulvestrant..............................................................................................................52 
8. 
PHARMACEUTICAL INFORMATION ..........................................................................52 
8.1 
CTEP IND Agent ...................................................................................................52 
8.2 
Commercial Agents ...............................................................................................56 
9. 
STATISTICAL CONSIDERATIONS...............................................................................57 
9.1 
Study Design/Endpoints.........................................................................................57 
9.2 
Continual reassessment method (CRM) for Phase 1 dose finding ........................58 
9.3 
Criteria for stopping of the phase 1 trial ................................................................61 
9.4 
Sample Size/Accrual Rate ......................................................................................62 
9.5 
Analysis of Primary Endpoints ..............................................................................63 
9.6 
Analysis of Secondary Endpoints ..........................................................................63 
9.7 
Populations for Analysis ........................................................................................63 
9.8 
Reporting and Exclusions ......................................................................................64 
9.9 
Data Safety Monitoring Board ...............................................................................65 
10. 
ADVERSE EVENTS:  LIST AND REPORTING REQUIREMENTS ............................65 
10.1 
Comprehensive Adverse Events and Potential Risks List (CAEPR) .....................66 
10.2 
Adverse Event Characteristics ...............................................................................70 
10.3 
Expedited Adverse Event Reporting ......................................................................71 
10.4 
Routine Adverse Event Reporting .........................................................................74 
10.5 
Pregnancy ...............................................................................................................74 
10.6 
Secondary Malignancy ...........................................................................................74 
10.7 
Second Malignancy ................................................................................................75 
11. 
STUDY CALENDAR .......................................................................................................75 
12. 
MEASUREMENT OF EFFECT........................................................................................78 
12.1 
Antitumor Effect – Solid Tumors ..........................................................................78 
13. 
STUDY OVERSIGHT AND DATA REPORTING / REGULATORY 
REQUIREMENTS .............................................................................................................84 
13.1 
Study Oversight .....................................................................................................84 
13.2 
Data Reporting .......................................................................................................85 
13.3 
Data Quality Portal ................................................................................................87 
13.4 
CTEP Multicenter Guidelines ................................................................................87 
13.5 
Collaborative Agreements Language .....................................................................88 
14. 
REFERENCES ..................................................................................................................90 
APPENDIX A 
PERFORMANCE STATUS CRITERIA ................................................102 


NCI Protocol #:  10287 
Version Date:  June 13, 2024 
 
7 
APPENDIX B 
LIST OF PROHIBITED MEDICATIONS WHILE ON 
COPANLISIB TREATMENT .........................................................................................103 
APPENDIX C 
PATIENT CLINICAL TRIAL WALLET CARD ...................................104 
APPENDIX D 
THE AVERAGE GLYCEMIC INDEX OF COMMON 
FOODS DERIVED FROM MULTIPLE STUDIES BY DIFFERENT 
LABORATORIES ...........................................................................................................105 
APPENDIX E 
MANAGEMENT OF TRANSIENT GLUCOSE 
INCREASE ON THE DAY OF COPANLISIB INFUSION ..........................................106 
APPENDIX F 
MANAGEMENT OF TRANSIENT GLUCOSE 
INCREASE ON SUBSEQUENT DAYS FOLLOWING COPANLISIB 
INFUSION 
107 
APPENDIX G 
DOSE MODIFICATION OF COPANLISIB FOR 
ARTERIAL HYPERTENSION.......................................................................................108 
APPENDIX H 
ABEMACICLIB MEDICATION DIARIES ...........................................109 
APPENDIX I 
 PK SAMPLING MANUAL ...................................................................111 
APPENDIX J 
TISSUE BIOPSY VERIFICATION .....................................................120 
 
 
 


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1. OBJECTIVES 
 
1.1 
Primary Objectives 
 
1.1.1 To evaluate the safety profile of fulvestrant + abemaciclib + copanlisib (FAC) and 
determine the recommended Phase 2 dose (RP2D). 
 
1.2 
Secondary Objectives 
 
1.2.1 To assess the objective response rate (ORR = partial response [PR] + complete response 
[CR]) and clinical benefit rate (CBR = PR + CR + stable disease [SD] ≥6 months) of 
FAC and median PFS with FAC  
 
1.3 
Exploratory Objectives 
 
1.3.1 To assess whether triplet therapy with FAC inhibits AKT phosphorylation, reduces cyclin 
D1, and inhibits Rb phosphorylation. 
 
1.3.2 To assess whether the combination of abemaciclib and fulvestrant affect the copanlisib 
pharmacokinetics (PK). 
 
1.3.3 To assess the ORR, CBR, and median PFS in the following molecularly defined 
subgroups treated with FAC, such as mutations in genes in the PI3K pathway (PIK3CA, 
AKT, PTEN etc), ESR1, TP53, or PTEN IHC loss vs not. 
 
1.3.4 To assess baseline and treatment induced changes in various cancer associated pathways, 
including but not limited to PI3K, MAPK, ER, cyclins, CDKs and CDK inhibitors; and to 
correlate with treatment response and progression. 
 
1.3.5 To correlate baseline and treatment induced changes in breast cancer intrinsic subtypes 
(PAM50), and PI3K mRNA signature and expression of candidate genes with treatment 
response and benefit from adding copanlisib. 
 
1.3.6 To evaluate ctDNA mutations at baseline and over time for response predictors at 
baseline, and clonal evolution associated with treatment.  
 
1.3.7 To correlate ctDNA mutation profiles with tumor sequencing, and correlate baseline 
ctDNA mutations, particularly in components of the PI3K pathway with treatment 
response, and correlate early changes in ctDNA VAFs with PFS, assess emergent 
resistant mutations at progression 
 
1.3.8 To assess resistance mechanisms to FAC at baseline and at disease progression. 
 
1.3.9 To examine the molecular effects of FAC on tumor and circulating markers. 
 
1.3.10 To analyze tumor infiltrating lymphocytes at baseline, during treatment, and at disease 


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progression. 
  
 
 
2. BACKGROUND 
 
2.1 
Study Disease 
 
2.1.1 Endocrine-resistant HR+ Breast Cancer and Efficacy of Cyclin Dependent Kinases 4 and 
6 (CDK4/6) inhibitors 
 
Hormone receptor positive (HR+) human epidermal growth factor receptor 2 (HER2) negative 
(HER2-) breast cancer represents over 70% of breast cancer diagnosis and is a leading cause of 
cancer death in women (Siegel et al., 2017).  Endocrine therapy includes the aromatase inhibitors 
(AI) and gonadotropin-releasing hormone (GnRH) agonists which reduce estrogen biosynthesis, 
the selective estrogen receptor modulator (SERM) - tamoxifen, and the selective estrogen 
receptor down regulator (SERD) - fulvestrant.  The clinical use of these agents has led to 
significant improvements in survival outcomes of patients with estrogen receptor positive (ER+) 
breast cancer (Early Breast Cancer Trialists’ Collaborative G, 2011).  However, systemic relapse 
occurs in approximately 20% of patients who were initially diagnosed with early stage breast 
cancer during or after completion of adjuvant endocrine agents due to de novo or acquired 
endocrine resistance mechanisms (Early Breast Cancer Trialists’ Collaborative G, 2011; Mauri et 
al., 2006). 
 
The cyclin D/CDK4/6 complex controls the G1 to S phase transition through phosphorylation of 
retinoblastoma susceptibility (RB1) gene product (Rb) and the subsequent release of E2F 
transcription factors to activate cell cycle progression genes (Sherr, 1996; Sherr and Roberts, 
1999; van den Heuvel and Harlow, 1993; Weinberg, 1995).  There is a significant association 
between CDK4/6 activation and ER signaling as cyclin D is a direct transcriptional target of ER 
and is the downstream effector of other mitogenic signals implicated in endocrine resistance 
(Thangavel et al., 2011; Musgrove et al., 2011; Finn et al., 2009; Knudsen and Witkiewicz, 
2017).  In addition, the poor prognosis luminal B ER+ breast cancer type is enriched for cyclin 
D1 amplification (58%), CDK4 gain (25%), and loss of p16, the negative regulator of CDK4/6, 
which could lead to constitutive activation of CDK4/6 (Network TCGA, 2012).  In preclinical 
studies, CDK4/6 inhibitors are particularly active in ER+ breast cancer and synergize with 
endocrine therapy in both endocrine sensitive and resistant cell lines (Finn et al., 2009).  Several 
CDK4/6 inhibitors, including palbociclib, ribociclib, and abemaciclib, are in clinical 
development and have shown efficacy in randomized Phase 3 trials with significantly improved 
PFS when added to standard endocrine therapy in the metastatic setting (Cristofanilli et al., 2016; 
O’Leary et al., 2016; Verma et al., 2016; Turner et al., 2015; Finn et al., 2015; Hortobagyi et al., 
2016; Finn et al., 2016a; George et al., 2017; Goetz et al., 2017; Slamon et al., 2018).  In the 
initial Phase 2 trial (PALOMA-1), palbociclib improved PFS when added to letrozole (20.2 
months vs. 10.2 months) as first-line therapy for patients with HR+/HER2- metastatic breast 
cancer, leading to the Food and Drug administration (FDA) approval of palbociclib (Beaver et 
al., 2015).  The benefit of palbociclib in the first line setting was confirmed in the Phase 3 
PALOMA-2 trial, in which the PFS was 24.8 (22.1-Normal Range [NR]) months in the 


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palbociclib/letrozole arm vs. 14.5 (12.9-17.1) months in the placebo/letrozole arm, HR 0.58; p< 
0.000001 (Finn et al., 2016b).  Subsequently, data from the randomized Phase 3 trial of 
ribociclib plus letrozole as first line therapy for HR+ advanced breast cancer (MONALEESA 2 
trial) again demonstrated a significantly improved PFS.  After 18 months, PFS was 63.0% (95% 
confidence interval [CI], 54.6 to 70.3) in the ribociclib group and 42.2% (95% CI, 34.8 to 49.5) 
in the placebo group (Hortobagyi et al., 2016).  Similarly, MONARCH 3, a double-blind, 
randomized Phase 3 trial of abemaciclib or placebo plus a nonsteroidal AI in postmenopausal 
women with HR-positive, HER2-negative advanced breast cancer who had no prior systemic 
therapy in the advanced setting, demonstrated that the median PFS was significantly prolonged 
in the abemaciclib arm (hazard ratio, 0.54; 95% CI, 0.41 to 0.72; p = 0.000021; median: not 
reached in the abemaciclib arm, 14.7 months in the placebo arm (Goetz et al., 2017).  
 
The benefit of CDK4/6 inhibition for treating endocrine-resistant HR+, HER2- breast cancer was 
demonstrated in PALOMA-3 trial (Cristofanilli et al., 2016) and more recently the MONARCH 
2 trial (George et al., 2017).  In PALOMA-3, 521 patients with HR+, HER2 negative metastatic 
breast cancer whose disease progressed after prior endocrine therapy were randomly assigned 2:1 
ratio to fulvestrant plus palbociclib (n = 347) and fulvestrant plus placebo (n = 174).  The median 
PFS was 9.5 months (95% CI 9.2–11.0) in the fulvestrant plus palbociclib group and 4.6 months 
(3.5–5.6) in the fulvestrant plus placebo group (hazard ratio 0.46, 95% CI, 0.36–0.59, p< 
0·0001).  The combination was well tolerated with the most common grade 3 or 4 adverse events 
(AEs) being uncomplicated neutropenia (65%), anemia (3%) and leucopenia (28%).  Results 
from the PALOMA-3 trial led to FDA approval for the combination of palbociclib and 
fulvestrant for the endocrine-resistant population, making this a new standard of care 
(Cristofanilli et al., 2016).  MONARCH 2 trial was a global, double-blind, Phase 3 study of 
women with HR+, HER2 negative advanced breast cancer who had progressed while receiving 
neoadjuvant or adjuvant endocrine therapy, ≤12 months from the end of adjuvant endocrine 
therapy, or while receiving first-line endocrine therapy for metastatic disease (George et al., 
2017).  Six hundred and sixty-nine (669) patients were randomly assigned to receive abemaciclib 
plus fulvestrant (n = 446) or placebo plus fulvestrant (n = 223).  Abemaciclib plus fulvestrant 
significantly extended PFS vs fulvestrant alone (median, 16.4 vs. 9.3 months; hazard ratio, 0.553; 
95% CI, 0.449 to 0.681; p< 0.001).  The most common adverse events in the abemaciclib vs. 
placebo arms were diarrhea (86.4% vs. 24.7%), neutropenia (46.0% vs. 4.0%), nausea (45.1% vs. 
22.9%), and fatigue (39.9% vs. 26.9%).  The longer PFS observed in the MONARCH 2 trial is 
explained by the requirement of no more than 1 prior endocrine therapy and no prior 
chemotherapy for advanced disease.   
 
As discussed above, CDK4/6 inhibitors prolong the PFS in patients with endocrine-resistant 
breast cancers.  However, metastatic HR+ HER2- breast cancer remains incurable due to 
inevitable disease progression (Cristofanilli et al., 2016).  Effective treatments that prevent or 
delay resistance to CDK4/6 inhibitors therefore remain an unmet clinical need. 
 
2.1.2 Phosphatidylinositol 3-kinase (PI3K) in mediating resistance to endocrine therapy. 
 
PI3K transmits signals from receptor tyrosine kinases (RTKs) to numerous cellular targets that 
are important for cell proliferation, survival, differentiation, and migration (Engelman, 2009; Lui 
et al., 2013).  PI3K/AKT signaling is commonly dysregulated in human cancers via various 


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mechanisms, e.g., gene amplification, rearrangement, or activating and/or loss-of-function 
mutations of the pathway’s molecular components (Engelman, 2009; Fruman and Rommel, 
2014).  Aberrant activation of class I PI3Ks has been associated with intrinsic and acquired 
resistance of tumors to targeted agents, chemotherapy, and radiotherapy (West et al., 2002; Clark 
et al., 2002). 
 
Four PI3K isoforms (PI3Kα, PI3Kβ, PI3Kγ, and PI3Kδ), all of which have a catalytic p110 
subunit (p110α, β, γ, or δ), comprise the class I PI3K subfamily (Vanhaesebroeck et al., 2010).  
Among the PI3K catalytic subunits, p110α and p110β are ubiquitously expressed and are 
implicated in promoting oncogenic growth, whereas the expression of p110δ and p110γ is mostly 
restricted to leukocytes (Engelman et al., 2006; Chang et al., 1997; Zhao et al., 2005; Zhao et al., 
2003).  Activating mutations have only been observed in PIK3CA and not in PIK3CB (Samuels 
et al., 2004; Yuan and Cantley, 2008).  p110α is required to mediate the signaling and 
tumorigenesis due to RTKs such as vascular endothelial growth factor receptor (VEGFR), 
epidermal growth factor receptor (EGFR), platelet-derived growth factor receptor (PDGFR), or 
HER2 (Graupera et al., 2008; Utermark et al., 2012; Zhao et al., 2006), as well as for Ras (Gupta 
et al., 2007; Ramjaun and Downward, 2007).  Tumor cells carrying PIK3CA mutations are 
highly dependent on p110α for survival (Crowder et al., 2009; Juric et al., 2012).  In contrast, 
p110β does not directly bind to Ras proteins (Fritsch et al., 2013).  There is evidence that the 
background signaling state in the absence of ligands for PI3K might be p110β dependent (Dbouk 
et al., 2010; Knight et al., 2006; Vogt, 2011), therefore phosphatase and tensin homolog 
(PTEN)-deficient tumors would have deregulated p110β signaling.  There is considerable 
evidence indicating that p110β is important in mediating PI3K signaling and AKT 
phosphorylation in PTEN-deficient cancers and p110β-selective inhibitors reduce pAKT and 
inhibit growth in both cell-based and in vivo studies of breast and other cancer cell lines (Jia et 
al., 2008; Ni et al., 2012; Torbett et al., 2008; Wee et al., 2008).  In addition, PI3Kβ is involved 
in signaling downstream of certain G-protein coupled receptors (GPCRs) and RTK in PTEN null 
and mutant Rac lines (Kawazu et al., 2013).  However, there are clearly tumor cell lines 
featuring PTEN loss that are not dependent on p110β (Ni et al., 2012; Wee et al., 2008; 
Berenjeno et al., 2012).  Additionally, recent work has indicated that loss of PTEN in certain 
tissues may lead to p110α-dependency (Berenjeno et al., 2012).  Other reports show that some 
tumors may be equally dependent on p110α and p110β (Jia et al., 2013; Wang et al., 2013; Oda 
et al., 2008).  PI3Kδ-specific inhibitors have shown remarkable therapeutic efficacy in some 
human leukemias and lymphomas (Yang et al., 2015).  A major component of the mechanism of 
action of PI3Kδ inhibition in the B-cell malignancies is to attenuate the responsiveness of the 
tumor cells to supportive stimuli from the microenvironment (Okkenhaug and Burger, 2016).  
Inhibition of PI3Kδ has been shown to protect mice against a broad range of cancers, including 
non-hematological solid tumors (Ali et al., 2014).  Inactivation of PI3Kδ breaks regulatory T-cell 
(Treg)-mediated immune tolerance that unleashes a cytotoxic T-cell response and resulting in 
tumor regression.  Copanlisib is a pan-class I PI3K small-molecule inhibitor exhibiting activity 
predominantly against the PI3Kα and PI3Kδ isoforms.   
 
Components of the PI3K pathway are frequently mutated in ER+ breast cancer (Network TCGA, 
2012; Ellis et al., 2012; Gellert et al., 2016; Ma et al., 2011).  PIK3CA, which encodes the alpha 
catalytic subunit of PI3K, is mutated in approximately 40% of ER+ breast cancer.  Mutations 
have also been identified in PIK3R1, the regulatory subunit of PI3K (0.4% - 2%), AKT1 (2% -


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4%), and PTEN (4%).  Although mutations in PTEN is at low frequency in ER+ breast cancer, 
loss of PTEN protein expression is more common.  The incidence of combined PTEN mut/loss 
was reported to be 13% in luminal A, and 24% in luminal B subtypes in the TCGA breast cancer 
study (Network TCGA, 2012).  Other studies reported loss of PTEN expression in 18% to 48% 
of ER+ breast cancers (Shoman et al., 2005; Depowski et al., 2001), and significant association 
between reduced PTEN expression in primary breast cancer and shorter relapse-free survival on 
adjuvant tamoxifen (Shoman et al., 2005). 
 
Up-regulation of the PI3K pathway signaling has also been observed in acquired endocrine-
resistant, long-term estradiol deprived (LTED), ER+ breast cancer cells compared to the parental 
cell lines (Miller et al., 2010).  Similarly, in clinical samples, higher PI3K activity determined by 
the levels of phosphorylated forms of AKT, mammalian target of rapamycin (mTOR), glycogen 
synthase kinase 3 (GSK3), ribosomal protein S6 kinase (S6K), and PTEN by reverse phase 
protein array (RPPA) analysis, was associated with lower ER levels and luminal B status 
(Creighton et al., 2010).  Importantly, dual targeting of ER and the PI3K pathway results in 
synergistic anti-tumor effect in preclinical studies (Bosch et al., 2015; Crowder et al., 2009; 
Sanchez et al., 2011), providing the rationale to combine endocrine therapy with PI3K pathway 
inhibitors in endocrine-resistant ER+ breast cancer.  The combination strategy is also supported 
by the preclinical finding that PI3K pathway inhibition alone induces ER transcriptional activity, 
potentially mediated by increased FOXO3A-mediated transcription, while ER inhibition 
activates PI3K pathway activity (Bosch et al., 2015; Miller et al., 2010; Miller et al., 2011).  
Figure 1 shows that treatment with the PI3K inhibitor copanlisib upregulates the mRNA 
expression of ESR1 and ER target genes including PgR, GREB1, and IGFBP4, in the ER positive 
breast cancer cell line MCF7 (Bosch et al., 2015).  Similar results were identified in tumors from 
patients treated with PI3K inhibitors (Bosch et al., 2015). 
 
Figure 1:  Copanlisib Stimulates ER-Dependent Gene Expression in ER+ MCF-7 Cells.  (Bosch et al., 2015).  
MCF7 cells were treated with vehicle (Ctrl) or BAY 80-6946 at 50 nM for 24 h. mRNA was isolated, and qPCR was 
performed to detect expression of β-ACTIN, ESR1, PGR, GREB1, and IGFBP4.  Two-tailed Student's unpaired t 
test was performed to compare control vs. treated groups.  Error bars represent the SEM of two independent 
experiments, each with three technical replicates. 
 
Initial success in targeting the PI3K/mTOR pathway in the clinic was demonstrated by using 
rapalogs which indirectly inhibit the activity of mTOR complex 1 (mTOC1), a downstream 
 


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component of the PI3K pathway, through its interaction with FKBP12 (Guertin and Sabatini, 
2009).  Everolimus has received FDA approval for AI-resistant metastatic breast cancer based on 
the BOLERO-2 trial, which demonstrated an improvement in PFS from 3.2 months to 7.8 
months with the addition of everolimus to exemestane (Hazard Ratio, 0.45; 95% CI, 0.38-0.54) 
(Piccart et al., 2014).  However, the median overall survival (OS) was not significantly different 
at 31 months (Hazard Ratio, 0.89; 95% CI, 0.73-1.10).  The lack of OS benefit could potentially 
be explained by the feedback upregulation of AKT activity upon inhibition of mTORC1 by 
everolimus (O’Reilly et al., 2006; Wan et al., 2007).  Direct kinase inhibitors against both 
mTORC1 and mTORC2, and inhibitors against AKT and PI3K are now in clinical trials with the 
hope for a more effective pathway inhibition (Ma, 2015). 
 
Pan-PI3K inhibitors including buparlisib and pictilisib in combination with the selective estrogen 
receptor downregulator - fulvestrant were evaluated in randomized trials for the treatment of AI 
resistant breast cancer, but efficacy was limited due to dose limiting toxicities that include rash, 
hyperglycemia, diarrhea, and elevated transaminases (Krop et al., 2014; Baselga et al., 2015).  In 
the Phase 3 BELLE-2 trial, 1,147 patients were randomly assigned in 1:1 ratio to receive either 
buparlisib 100 mg/day orally or placebo, in combination with fulvestrant (Baselga et al., 2015).  
The study met its primary endpoint, demonstrating a PFS of 6.9 months vs. 5.0 months (Hazard 
Ratio, 0.78; p< 0.001) with the addition of buparlisib vs. placebo.  However, up to 25% of 
patients in the combination arm experienced serious adverse events including hyperglycemia and 
increase in transaminases.  Nonetheless, the study provided the proof of concept that PI3K 
inhibition could overcome endocrine resistance. 
 
Alpha-specific PI3K inhibitors are likely with improved therapeutic window and are in Phase 3 
trials, including alpelisib (SOLAR-1 [NCT02437318]), or taselisib (SANDPIPER 
[NCT02340221]) (Rugo et al., 2016), but resistance mechanisms through acquiring mutations in 
PTEN, leading to growth dependence on PI3K beta, has been reported in clinical trials of alpha-
specific inhibitors (Juric et al., 2015).  Although tumor cells carrying PIK3CA mutations are 
highly dependent on p110α for survival (Crowder et al., 2009; Juric et al., 2012), there is 
considerable evidence indicating that p110β is important in mediating PI3K signaling and AKT 
phosphorylation in PTEN-deficient cancers and p110β-selective inhibitors reduce pAKT and 
inhibit growth in both cell-based and in vivo studies of breast and other cancer cell lines (Jia et 
al., 2008; Ni et al., 2012; Torbett et al, 2008; Wee et al., 2008).  Recent data also indicates that 
combined targeting of both p110α and p110β most effectively induces apoptosis and tumor 
regression of PTEN-deficient ER+ breast cancer cells both in vitro and in vivo (Hosford et al., 
2017).  Therefore, a pan-PI3K inhibitor may have therapeutic advantage if effective and safe 
administration could be achieved. 
 
Recent data demonstrated that short-term, complete PI3K inhibition blocks cell growth more 
effectively than chronic, incomplete inhibition in vitro (Yang et al., 2016; Toska et al., 2016).  
Copanlisib, which is a potent pan-PI3K inhibitor administered weekly (3 of 4 weeks), has 
demonstrated a favorable safety profile and preliminary activity in ER+ breast cancer, making it 
an attractive agent (discussed below). 
 
2.2 
CTEP IND Agent 
 


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2.2.1 Copanlisib 
 
Copanlisib (BAY 80-6946) was approved in the US on September 14, 2017 for the treatment of 
adult patients with relapsed follicular lymphoma who have received 2 prior systemic therapies.  
Copanlisib has an ongoing Phase 3 program in indolent non-Hodgkin’s lymphoma (NHL) and is 
being clinically evaluated in multiple investigator-initiated Phase 1 and Phase 2 studies of solid 
tumors. However, as of November 2023, Bayer has decided to voluntarily withdraw the NDA for 
copanlisib. The FDA required clinical benefit to be confirmed by further studies when the 
original approval for copanlisib was issued in 2017, and the CHRONOS-4 study failed to meet 
the primary endpoint of progression-free survival benefit in comparison with the control arm in 
patients with relapsed follicular lymphoma. 
 
Copanlisib is a novel small-molecule pan-class I PI3K inhibitor with exceptional inhibitory 
potency against δ and α PI3K isoforms (Investigator’s Brochure, 2018).  Copanlisib is an active 
ingredient (free base) of copanlisib dihydrochloride (BAY 84-1236), which is intended for an IV 
administration in humans.  The copanlisib hydrochloride product for clinical use is formulated as 
a lyophilized product for reconstitution in saline to be administered via IV.  Copanlisib 
dihydrochloride product is supplied in three formulation strengths:  20 mg, 60 mg, or 80 mg (free 
base) in a 6 mL injection vial for reconstitution with 2 mL, 4.4 mL, or 4 mL of saline, 
respectively, to produce copanlisib solution for injection at concentration of 10 mg/mL, 15 
mg/ml, or 20 mg/mL, respectively. 
 
2.2.1.1 
Nonclinical Studies 
 
A majority of the nonclinical data were produced using the copanlisib free-base.  
 
Mechanism of Action 
Copanlisib is a stronger inhibitor of PI3Kα and PI3Kδ than of PI3Kβ or PI3Kγ, as demonstrated 
by copanlisib half-maximal inhibitory concentrations (IC50) that confer 50% of the maximum 
inhibition of PI3Kα PI3Kδ, PI3Kβ and PI3Kγ (IC50 of 0.5, 0.7, 3.7, 6.4 nmol/L, respectively) 
(Liu et al., 2013).  Compared to the PI3K isoforms, copanlisib was a much weaker inhibitor of 
mTOR (IC50 = 45 nmol/L).  In a panel of ~220 kinases, copanlisib (1 mcmol/L) failed to achieve 
a 50% inhibition of any kinase other than PI3K isoforms and mTOR.  In tumor cell lines with 
hyperactive PI3K signaling, copanlisib antitumor activity was paralleled by a robust decrease in 
basal levels of phosphorylated AKT, both at serine 473 (AKTpS473) and threonine 308 
(AKTpT308), and by increases in caspase-9 levels, which is suggestive of induction of apoptosis.  
 
Nonclinical In vitro Antitumor Activity  
Copanlisib potently inhibited tumor cell proliferation (IC50 of 1-760 nmol/L) in human tumor 
cell lines of various histologies, including breast, ovary, endometrial, prostate, colon, lung, liver, 
brain, kidney, melanoma, pancreas, and hematological tumors (Figure 2), many of which exhibit 
constitutively activated PI3K signaling resulting from somatic mutations in PIK3CA and PTEN 
(Liu et al., 2013). 
 
To further analyze a relationship between molecular features and copanlisib activity, copanlisib 
was tested against 24 breast cancer cell lines with known PI3KCA gene mutation, PTEN gene 


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mutation or expression, and HER2 expression status (Liu et al., 2013).  Antiproliferation IC50s of 
copanlisib were ~40-fold lower in cells with activating mutations in PIK3CA (IC50 = 19 nmol/L; 
n = 9) or HER2-positive cells (IC50 = 17 nmol/L; n = 7) than for cells with PIK3CA wild-type 
(WT) and HER2-negative status (average IC50 = 774 nmol/L; n = 11).  However, no clear 
correlation has been found between sensitivity of cells to copanlisib and the loss of PTEN.  The 
IC50s for T47D (mutant PIK3CA), ZR-75-1 (PTEN null), or MCF7 (mutant PIK3CA) were 6, 24, 
and 27 nmol/L, respectively.  Of note, copanlisib efficiently inhibited cell proliferation of breast 
cancer cell lines that are resistant to HER2 inhibitors (trastuzumab or lapatinib) such as BT20, 
BT474, and ZR-75-1 HER2 positive cell lines (Liu et al., 2013). 
 
 
Figure 1:  Antiproliferative activity against a panel of human tumor cell lines.  (Liu et al., 2013). 
Panel A:  Cell lines of various tumor histologies; Panel B:  Breast cancer cell lines; Panel C:  Molecular and 
histological characterization of breast cancer cell lines shown in panel B. 
Legend:  B:  basal–like breast cancer cell lines; L:  luminal-type breast cancer cell lines; H:  HER2-positive breast 
cancer cell lines 
 


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Copanlisib was also tested against a panel of 32 human hematological cancer cell lines 
(Investigator’s Brochure, 2018).  Copanlisib was a more potent inhibitor than idelalisib, the 
PI3Kδ-selective inhibitor:  idelalisib IC50s were 1.4-fold to several thousand-fold higher than 
copanlisib IC50s against these cell lines.  Copanlisib IC50s were <100 nmol/L for 14 cell lines, 
including acute lymphoblastic leukemia (ALL), acute myelogenous leukemia (AML), NHL, and 
myeloma.  Some of the strongest responses to copanlisib (IC50 <10 nmol/L) occurred in AML 
(Kasumi-1, IC50 = 1.1 nmol/L), the Burkitt's lymphoma subtype of NHL (NAMALWA, IC50 = 
1.7 nmol/L), the DLBCL subtype of NHL (Pfeiffer, IC50 = 0.8 nmol/L), and myeloma (MM-1R, 
IC50 = 1.0 nmol/L; and NCI-H929, IC50 = 2.7 and 2.2 nmol/L in 2 different experiments).  
Copanlisib was also more potent inhibitor against an aggressive NHL type such as diffuse large 
B-cell lymphoma (DLBCL) than idelalisib or a Bruton’s tyrosine kinase (BTK) inhibitor - 
ibrutinib (Figure 3).   
 
 
Figure 2:  Antiproliferative effects of copanlisib (BAY 80-6946), idelalisib (CAL-101), and ibrutinib (PCI-32765) 
against DLBCL cell lines.  (Investigator’s Brochure, 2018).  Legend:  IC50:  a drug concentration causing 50% 
inhibition of cell proliferation  
 
Concurrent treatment with copanlisib and ibrutinib resulted in synergistic effects of the two 
inhibitors against ibrutinib-sensitive cell lines but antagonistic effects in ibrutinib-resistant cell 
lines. 
 


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In vivo Antitumor Activity  
Copanlisib demonstrated antitumor activity in vivo in a variety of xenograft models of tumors 
exhibiting an activated PI3K pathway (Liu et al., 2013).  The drug displayed robust antitumor 
activity in the nude rat xenograft model of the KPL4 breast tumor cell line, which is an estrogen-
independent HER2-positive breast carcinoma that carries a somatic PIK3CA mutation.  
Copanlisib was administered on Day 14 post-implant at doses ranging from 0.5-6 mg/kg IV 
every second day (Q2D) for a total of five doses.  On Day 25, 3 days after the last dose, tumor 
growth inhibition (TGI) rates of 77%-100% were achieved (Figure 4, Panel A).  Complete tumor 
regressions were observed in 100% of animals receiving dose of 3 or 6 mg/kg, and all rats 
remained tumor free at the termination of the study on Day 73.  Delays in tumor growth of >25 
days were observed in the 0.5- and 1- mg/kg groups.  Copanlisib at 3 and 6 mg/kg IV Q2D x 5 
doses resulted in the TGI of 75% and 88%, respectively, of the HCT-116 (colon tumor with 
mutant PIK3CA and mutant KRAS) xenograft rat model (Figure 4, Panel B).  Copanlisib was also 
effective in the nude mouse patient-tumor xenografts of Lu7860 (erlotinib-resistant non-small 
cell lung cancer [NSCLC]) and MAXF1398 (luminal breast tumor).  Copanlisib 14 mg/kg 
administered twice daily (BID) Q2D for 10 days led to an  88% TGI in the NSCLC model 
(Figure 4, Panel C) and a 71% TGI in the breast cancer model (Figure 4, Panel D).  
 
 
Figure 3:  Activity of copanlisib (BAY 80-6946) in xenograft models using Q2D treatment schedule.  (Liu et al., 
2013).  Panel A:  KPL4 breast cancer xenografts in nude rats (n=10/group).  Panel B:  HCT116 colon cancer 
xenografts in nude rats (n=10/group).  Panel C:  Lu7860 erlotinib-resistant, patient-derived NSCLC xenografts in 


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nude mice (n=5/group).  Panel D:  MAXF1398 patient-derived luminal breast cancer xenografts in nude mice 
(n=6/group).  Legend:  Q2D:  every 2 days; BID:  twice a day; IV:  intravenously; TGD:  tumor growth delay; PR:  
partial response; CR:  complete response 
 
Copanlisib was also evaluated on a weekly schedule.  Two doses of 9 mg/kg on day 1/week 
caused 64% TGI in the HCT-116 xenograft model, which was equivalent to the effect of 
copanlisib given at 6 mg/kg Q2D for 10 doses (Figure 5A).   
 
 
Figure 4:  Activity of copanlisib (BAY 80-6946) in xenograft models using a BID once-weekly schedule.  (Liu et 
al., 2013).  Copanlisib was formulated in 5% mannitol vehicle.  Panel A:  HCT-116 colon cancer xenografts in nude 
rats (8 rats/group).  Panel B:  Lu7343 patient-derived NSCLC xenografts in nude mice (10 mice/group).  Legend:  
BID:  twice a day; Q2D:  every 2 days. 
 
In vivo antitumor activity of copanlisib was also tested in combination with cytotoxic agent 
paclitaxel in the mutant PIK3CA squamous cell NSCLC patient-derived Lu7343 xenograft 
mouse model (Liu et al., 2013).  The drug combination was more potent in inhibiting tumor 
growth than either drug alone (Figure 5, Panel B).  Copanlisib was well tolerated at all doses and 


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schedules tested in these studies without producing any lethality.  The maximum tolerated dose 
(MTD) in rats was 6 mg/kg Q2D.  A maximum mean body weight loss of 6%-10% occurred 
during the first few days at this dose and then consistently returned to the normal range by the 
end of the dosing period.  The MTD in mice was more than 14 mg/kg Q2D. 
 
Nonclinical Pharmacokinetics and Pharmacodynamics 
Copanlisib plasma-free fraction across species was as follows:  35% in rats, 14% in mice, 33% in 
dogs, and 16% in humans (Liu et al., 2013).  The PK profile of copanlisib was evaluated 
following single and multiple IV doses in nude rats.  Single-dosed copanlisib exhibited a very 
large volume of distribution (Vd = 32 L/kg), high plasma clearance (3.95 L/kg/h) and a long half-
life (t1/2 = 6.0 h).  The copanlisib PK parameters at repeat dosing (Q2D x 5 doses), were similar 
those from single-dosing studies and suggested no drug accumulation in plasma.  Copanlisib had 
a higher clearance (16 L/kg/h), shorter t1/2 (0.7 h) and smaller Vd (12.9 L/kg) in mice than rats.  A 
single bolus IV dose of copanlisib (6 mg/kg) in the H460 NSCLC xenograft rat model produced 
100 times higher concentration of the drug in tumor tissue than in plasma at 48 h post-dosing; the 
drug clearance from the tumor was slower than from plasma.  The pharmacodynamics analysis 
showed 90% inhibition of AKT pS473 at 24 h post-dosing compared to the control animals, and 
the AKT pS473 level remained suppressed up to 72 h.  In addition, 65% and 75% reductions in 
Ki-67 and phospho-histone H3 levels, respectively, were observed at 24 h in the copanlisib group 
compared to the control group, suggesting copanlisib-induced G0 cell-cycle arrest.  Copanlisib 
also demonstrated sustained inhibition (over 24 - 48 h) of 18F-deoxyglucose (FDG) uptake in 
tumor.  These preclinical data suggested that high and prolonged copanlisib tumor exposures can 
be reached in vivo, and there was a correlation between copanlisib exposure and inhibition of the 
PI3K pathway in the tumor.  
 
In the rat tumor xenograft model studies, the efficacious exposure of copanlisib was estimated as 
the area under the concentration-time curve (AUC) for the unbound/free drug (AUCu) in plasma 
of 370 mcg•h/L based on weekly dosing (Investigator’s Brochure, 2018). 
 
Summary of Nonclinical Pharmacology and Metabolism  
Copanlisib is primarily metabolized by the cytochrome P450 (CYP)3A4 with a minor 
contribution of CYP1A1 (Investigator’s Brochure, 2018).  Copanlisib is a weak substrate of 
permeability glycoprotein (P gp) and of breast cancer resistance protein (BCRP).  There is a low 
risk for clinically relevant PK drug drug interactions (DDI) through inhibition or induction of 
CYP enzymes, inhibition of uridine diphosphate glucuronosyltransferase (UGT) enzymes and 
inhibition of dihydropyrimidine dehydrogenase (DPD) by copanlisib.  Copanlisib also inhibited 
P gp- and BCRP mediated transport in vitro.  Furthermore, copanlisib was a strong inhibitor of 
the drug transporter multidrug and toxin extrusion protein 2 (MATE2K).  
 
Summary of Nonclinical Safety 
IV infusion of copanlisib caused vasoconstriction, enhanced insulin and glucose levels, impaired 
glucose tolerance, reduced gastrointestinal (GI) motility, increased renal volume and electrolyte 
excretion, and central nervous system (CNS) depressant effects in nonclinical species 
(Investigator’s Brochure, 2018).  A majority of these effects could be explained by inhibition of 
PI3K-dependent signaling, and they occurred at or slightly above the plasma concentrations 
shown to be efficacious in tumor xenograft rat models (maximum concentration [Cmax]=30-80 


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mcg/L; Cmax of unbound fraction [Cmax,u] 11-28 mcg/L).  The CNS depressant effects occurred at 
high plasma concentrations and are considered secondary to hyperglycemia.  At 
pharmacodynamically relevant concentrations, copanlisib does not interfere with cardiac 
repolarization in vitro or in vivo. 
 
Based on the findings from repeat-dose toxicity studies in nonclinical species, copanlisib is 
expected to adversely affect male and female reproduction.  Developmental and reproductive 
toxicity of PI3K inhibitors is known.  Maternal toxicity of increasing severity, severe post-
implantation loss, and developmental toxicity, including teratogenicity, were seen in the rat 
starting at low doses.  Copanlisib was not genotoxic in vitro or in vivo.  There is no evidence that 
copanlisib has phototoxic potential.  Significant toxicities were observed in animals at doses 
achieving plasma concentrations observed in humans. 
 
2.2.1.2 
Effects in humans 
 
The First-in-Human Copanlisib Study 
In the first-in human (FIH) Phase 1b trial in patients with advanced and/or refractory 
malignancies, of 57 patients (51 non-diabetic) treated, 17 took part in the dose-escalation phase 
with copanlisib (0.1-1.2 mg/kg) administered IV weekly for 3 weeks of a 4-week cycle (Patnaik 
et al., 2016).  The copanlisib MTD was 0.8 mg/kg IV (1 h) weekly for 3 weeks on a 28-day 
cycle.  An additional 34 patients were treated in the MTD expansion cohorts:  the solid tumor 
cohort (n = 25), NHL cohort (n = 9; 6 patients with follicular lymphoma [FL] and 3 patients with 
DLBCL).  Finally, 6 patients with diabetes mellitus were treated with copanlisib at 0.4 mg/kg 
weekly x 3 weeks. 
 
Clinical Safety 
The most common (≥20%) copanlisib-related AEs (regardless of grade) included hyperglycemia 
(63%), nausea (37%), and hypertension (21%).  The most common drug-related grade 3 AEs 
were hyperglycemia (30%), hypertension (14%), and rash (7%) (Patnaik et al., 2016).  Grade 3+ 
diarrhea occurred in one patient.  Two patients (4%) experienced three drug-related grade 4 AEs:  
a dose-limiting hyperglycemia and increased aspartate aminotransferase (AST) in one patient 
and elevated serum amylase in another patient.  Overall, serious AEs (SAEs) with positive 
association to copanlisib were observed in six patients (11%):  grade 3 left ventricular systolic 
dysfunction (LVSD) which was a dose-limiting toxicity (DLT), chest pain, hypertension, and 
hyperglycemia (in one patient each), and pneumonitis (in two patients).  None of seven grade 5 
AEs (12%) were considered drug-related.  Dose modifications (delays, interruptions, and 
reductions) caused by drug-related AEs occurred in 14 patients (25%).  Four patients 
discontinued treatment due to toxicity.  One drug-related AE (dose-limiting LVSD) led to 
permanent discontinuation of treatment.  No patient discontinued the study because of 
hyperglycemia.  
 
Hyperglycemia was transient, with a glucose level peaking at 5 – 8 h after copanlisib infusion on 
Cycle 1 Day 1 and declining to baseline by the time of the next infusion.  Sixty-five percent of 
non-diabetic patients (33/51) received at least one dose of short-acting insulin to manage high 
blood glucose (>200 mg/dL).  There was no trend for increased pre-dose glucose values over 
time, and no patients developed diabetic ketoacidosis during the study.  Hemoglobin A1c 


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(HbA1c) levels changed only modestly over the course of copanlisib treatment.  Post-infusion 
increases in blood pressure peaked at 1–2 h and resolved within 24 h post-infusion. 
 
A similar transient pattern of elevated blood glucose post-infusion was seen for the cohort of six 
diabetic patients treated with 0.4 mg/kg copanlisib, all of whom received insulin following the 
first copanlisib infusion.  The AE profile in the diabetic cohort of patients was similar to that in 
non-diabetic patients, with a total of four drug-related grade 3 AEs observed in three patients:  
hypertension in two patients, and hyperglycemia and rash/desquamation in one patient each.  
 
Pharmacokinetics/Pharmacodynamics 
Copanlisib plasma Cmax was typically reached between 0.5 and 1 h (tmax) following the infusion 
[85].  Copanlisib exposure, expressed either as Cmax or AUC between 0-25 h (AUC0–25h), 
increased proportionally with dose between 0.1 and 1.2 mg/kg, and exhibited a moderate to high 
inter-patient variability.  The terminal t1/2 was 38.2 h and no accumulation was observed after 
once-weekly administration.  The trough levels of copanlisib on Cycle 1 Day 8 were 4.92 mcg/L 
(range, 2.74–23.0 mcg/L). 
 
A pharmacodynamic effect event was defined as an increase in plasma glucose level of ≥50 
mg/dL from baseline within 2 h after the completion of the copanlisib infusion, and / or an 
increase in plasma insulin level to greater than two times the baseline value (Investigator’s 
Brochure, 2018).  At the MTD (0.8 mg/kg), 100% of patients showed the pre-defined increases 
in glucose and insulin.  Overall, 53/57 (93%) patients experienced a predefined 
pharmacodynamics effect of an increased glucose plasma level following the first copanlisib 
infusion.  Increases in glucose levels strongly correlated with copanlisib exposure (AUC0-25h) 
(Patnaik et al., 2016).  A weak correlation between exposure and change in tumor FDG uptake 
(via FDG-PET) from baseline to Cycle 1 Day 3 or Day 4 was seen in 19/21 patients evaluated, 
with >25% reduction in the FDG uptake observed in the tumor of 7 patients (33%). 
 
Antitumor Activity/Response 
Among patients with solid tumors (n = 48), clinical responses were observed only in patients 
treated at the copanlisib MTD (Patnaik et al., 2016).  The responses were:  1 CR (2%) in a 
patient with endometrial cancer, 2 PRs (4%) in patients with breast cancer, 15 cases of SD 
(31%), and 15 cases of progressive disease (PD) (31%) according to the Response Evaluation 
Criteria in Solid Tumors (RECIST) version 1.1.  In comparison, by clinical assessment, 7 
patients (15%) had PD, and 8 patients (17%) were not assessed.  Overall CBR was 38%.   
 
The CR responder had endometrial cancer with PIK3CA and PTEN mutations and complete 
PTEN loss.  Of the two breast cancer patients who had PR, both had tumor positive for ER and 
progesterone receptor, one was negative and the other positive for HER2 and one had mutant and 
the other WT PIK3CA WT; PTEN status was unavailable in both.  No clear relationship was 
found between PI3KCA mutational status and disease control (p =1.0). 
 
2.2.1.3 
Copanlisib Reference Safety Information 
 
The recommended dose and administration of copanlisib 
Based on the FIH company-sponsored study, the MTD of copanlisib in non-diabetic patients 


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with solid malignancies was 0.8 mg/kg administered IV over 1 h once weekly for 3 weeks (Days 
1, 8, and 15) on a 28-day cycle (Investigator’s Brochure, 2018).   
 
A preliminary population PK analysis revealed no impact of either body weight, body surface 
area (BSA), or other body size-related factors on the clearance of copanlisib and thus a flat-dose 
regimen of copanlisib has been recommended.  In addition, age, gender and race were shown to 
have no effect on copanlisib exposure. 
 
Based on these data, the RP2D of copanlisib monotherapy is 60 mg given over a 1-h IV infusion 
once a week for 3 weeks (Days 1, 8, and 15) every 4 weeks.  A dose reduction to 45 mg for 
toxicities have been allowed. 
 
Drug-drug interactions 
In vitro studies in human hepatocytes indicate that CYP3A4 is a major metabolizer (>90%) while 
CYP1A1 contributes <10% to metabolism of copanlisib (Investigator’s Brochure, 2018).  
Therefore, the concomitant use of copanlisib with a strong CYP3A4 inhibitor (e.g., 
ketoconazole, itraconazole, clarithromycin, ritonavir, indinavir, nelfinavir, and saquinavir) may 
markedly increase copanlisib plasma concentration and concomitant administration of copanlisib 
with a strong CYP3A4 inducer (e.g., rifampin, phenytoin, carbamazepine, phenobarbital, and 
herbal preparations containing St. John’s Wort) may result in a marked decrease in copanlisib 
plasma concentration. 
 
Copanlisib metabolism is predominantly mediated by CYP3A4 (>90%) and to a minor extent by 
CYP1A1 (<10%).  Itraconazole, a strong CYP3A4 inhibitor and a P gp and BCRP transporter 
inhibitor, increased copanlisib (60 mg) AUC by 1.53-fold with no effect on Cmax (1.03–fold).  If 
concomitant use with strong CYP3A inhibitors cannot be avoided, a dosage reduction to 45 mg 
is recommended.  Rifampin, a strong CYP3A4 inhibitor and a P-gp transporter inhibitor, 
decreased the AUC of copanlisib (60 mg) by 63% with minimal effect on Cmax (15%) and should 
be avoided. 
 
Clinical pharmacology summary 
Copanlisib plasma exposure (Cmax and AUC) increased in a dose-proportional manner over an 
absolute dose range of 5 to 93 mg (0.08 to 1.55 times the approved recommended dose of 60 mg) 
(Investigator’s Brochure, 2018).  There is no time-dependency and no accumulation in the PK of 
copanlisib.  The geometric mean terminal elimination half-life (CV%) of copanlisib was 39.1 h 
(40.8%) based on the pooled analysis of 3 Phase 1 studies (12871, 15205 and 16270).  The 
geometric mean clearance (CV%) was 17.9 L/hr (45.6%).  Copanlisib is eliminated 
predominantly via feces (64% of the administrative radioactive dose mean recovery with 30% 
unchanged copanlisib) compared to urine (22% mean recovery with 15% unchanged copanlisib).  
Copanlisib is excreted as unchanged compound and metabolites (about 50:50).  Copanlisib 
metabolism is predominantly mediated by CYP3A4 (>90%) and to a minor extent by CYP1A1 
(<10%).  Itraconazole, a strong CYP3A4 inhibitor and a P gp and BCRP transporter inhibitor, 
increased copanlisib (60 mg) AUC by 1.53-fold with no effect on Cmax (1.03–fold).  If 
concomitant use with strong CYP3A inhibitors cannot be avoided, a dosage reduction to 45 mg 
is recommended.  Rifampin, a strong CYP3A4 inhibitor and a P-gp transporter inhibitor, 
decreased the AUC of copanlisib (60 mg) by 63% with minimal effect on Cmax (15%) and should 


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be avoided.  Copanlisib has low potential for DDI as a perpetrator to influence the PK of other 
drugs by inhibition or induction of metabolizing enzymes (CYPs, UGT) and transport proteins, 
except MATE2-K transporter at clinically relevant concentrations.  Copanlisib is a substrate of 
P-gp and BCRP and not a substrate for the efflux transporters MATE1 and MATE2K or the 
uptake transporters OCT, OAT and OATP.  Population PK analyses suggest that body weight, 
age (20 to 90 years), gender, race (White, Asian, Hispanic and Black), smoking status, body 
weight (41 to 130 kg), mild hepatic impairment and mild to moderate renal impairment had no 
clinically significant effect on the PK of copanlisib.  No dose adjustment is necessary based on 
these specific populations.  Preliminary analysis of central tendency and exposure-response 
analyses suggest that copanlisib does not prolong QT/QTc interval. 
 
Further details can be found in the latest available version of the investigator's brochure, which 
contains comprehensive information on the study drug and also the prescription drug labeling. 
 
Pregnancy and lactation 
Due to a mechanism of action as a PI3K inhibitor, adverse effects on development and 
reproduction are expected for copanlisib (Investigator’s Brochure, 2018).  Nonclinical repeat-
dose toxicity studies demonstrated adverse effects of copanlisib on male and female 
reproduction.  Maternal toxicity of increasing severity, severe post-implantation loss, and 
developmental toxicity, including teratogenicity were seen in a rat pilot developmental toxicity 
study beginning at a low dose.  In the rat study with 14C-labeled copanlisib, radioactivity was 
secreted into the milk of lactating animals although to a low extent (1.7% of dose).  No data are 
available on the distribution of copanlisib to human milk.  Therefore, unless potential benefits to 
patients outweigh unknown risks, women who are pregnant or nursing and children should be 
excluded from the clinical studies of copanlisib.  In addition, women of child-bearing potential or 
female partners of male patients will be required to use an adequately effective barrier method of 
birth control. 
 
Special safety warnings and precautions 
Nonclinical studies suggest, and clinical studies confirm, blood glucose increases that persist for 
approximately 1-3 days after copanlisib administration (Investigator’s Brochure, 2018).  Blood 
or serum glucose, serum and urine ketones, and electrolytes should be monitored while on 
copanlisib treatment.  
 
Standard cardiovascular parameters, including pulse and blood pressure (BP) should be 
monitored because of hypertension (during the first 3 h after start of infusion) that has been 
observed.  
 
Respiratory infections (including pneumonia, Pneumocystis jirovecii pneumonia, cryptococcosis 
and bronchopulmonary aspergillosis) have been observed in studies with monotherapy and 
combination therapies.  Some of these infections may have a life-threatening or a fatal outcome.  
Cases of pneumonitis observed in studies with monotherapy and in combination therapies were 
generally ≤grade 3 in severity and responded well to corticosteroid treatment; occasional events 
with life-threatening or fatal outcome have been observed.  Since the early symptoms of 
pneumonitis overlap with those of a respiratory infection, monitoring of patients for typical 
clinical symptoms like cough, dyspnea or fever and further evaluation for respiratory infections 


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is recommended.  Patients suspected of having a respiratory infection or noninfectious 
pneumonitis should be promptly treated with appropriate antimicrobial agents and/or 
corticosteroids as indicated. 
 
2.3 
Other Agents 
 
2.3.1 Abemaciclib 
 
2.3.1.1 
Mechanisms of action and approved indications for advanced hormone receptor 
positive breast cancer 
 
Abemaciclib is a highly selective small-molecule inhibitor of CDK4 and CDK6 activity and is 
14-fold more potent against CDK4/cyclin D1 than CDK6/cyclin D3 (Torres-Guzman et al., 
2017; Gelbert et al., 2014).  Abemaciclib is administered twice daily on a continuous schedule.  
In preclinical models, continuous in vitro exposure leads to senescence and apoptosis (Torres-
Guzman et al., 2017; Gelbert et al., 2014).  Abemaciclib is FDA approved in combination with 
fulvestrant for the treatment of women advanced or metastatic HR+ HER2- breast cancer.  It is 
also approved as a monotherapy for the treatment of adult patients with advanced or metastatic 
HR+ HER2- breast cancer with disease progression following endocrine therapy and prior 
chemotherapy in the metastatic setting (Abemaciclib package insert, 2018). 
 
2.3.1.2 
Pharmacokinetics of Abemaciclib  
 
The pharmacokinetics of abemaciclib were characterized in patients with solid tumors, including 
metastatic breast cancer, and in healthy subjects (Abemaciclib package insert, 2018).  Following 
single and repeated twice daily dosing of 50 mg (0.3 times the approved recommended 150 mg 
dosage) to 200 mg of abemaciclib, the increase in AUC and Cmax was approximately dose 
proportional.  Steady state was achieved within 5 days following repeated twice daily dosing, 
and the estimated geometric mean accumulation ratio was 2.3 (50% CV) and 3.2 (59% CV) 
based on Cmax and AUC, respectively. 
 
• Absorption 
 
The absolute bioavailability of abemaciclib after a single oral dose of 200 mg is 45% (19% CV).  
The median Tmax of abemaciclib is 8.0 h (range: 4.1-24.0 h). 
 
• Effect of Food 
 
A high-fat, high-calorie meal (approximately 800 to 1000 calories with 150 calories from 
protein, 250 calories from carbohydrate, and 500 to 600 calories from fat) administered to 
healthy subjects increased the AUC of abemaciclib plus its active metabolites by 9% and 
increased Cmax by 26%. 
 
• Distribution 
 
In vitro, abemaciclib was bound to human plasma proteins, serum albumin, and alpha-1-acid 


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25 
glycoprotein in a concentration independent manner from 152 ng/mL to 5066 ng/mL.  In a 
clinical study, the mean (standard deviation, SD) bound fraction was 96.3% (1.1) for 
abemaciclib, 93.4% (1.3) for M2, 96.8% (0.8) for M18, and 97.8% (0.6) for M20.  The geometric 
mean systemic volume of distribution is approximately 690.3 L (49% CV). 
 
In patients with advanced cancer, including breast cancer, concentrations of abemaciclib and its 
active metabolites N-desethylabemaciclib (M2) and hydroxyabemaciclib (M20) in cerebrospinal 
fluid are comparable to unbound plasma concentrations. 
 
• Elimination 
 
The geometric mean hepatic clearance (CL) of abemaciclib in patients was 26.0 L/h (51% CV), 
and the mean plasma elimination half-life for abemaciclib in patients was 18.3 h (72% CV). 
 
• Metabolism 
 
Hepatic metabolism is the main route of clearance for abemaciclib.  Abemaciclib is metabolized 
to several metabolites primarily by CYP3A4, with formation of M2, representing the major 
metabolism pathway.  Additional metabolites include M20, hydroxy-N-desethylabemaciclib 
(M18), and an oxidative metabolite (M1).  M2, M18, and M20 are equipotent to abemaciclib and 
their AUCs accounted for 25%, 13%, and 26% of the total circulating analytes in plasma, 
respectively. 
 
• Excretion 
 
After a single 150 mg oral dose of radiolabeled abemaciclib, approximately 81% of the dose was 
recovered in feces and approximately 3% recovered in urine.  The majority of the dose 
eliminated in feces was metabolites. 
 
• Specific Populations 
 
Age, Gender, and Body Weight 
Based on a population PK analysis in patients with cancer, age (range 24-91 years), gender (134 
males and 856 females), and body weight (range 36-175 kg) had no effect on the exposure of 
abemaciclib. 
 
Patients with Renal Impairment 
In a population PK analysis of 990 individuals, in which 381 individuals had mild renal 
impairment (60 mL/min ≤ Creatinine Clearance (CLcr) <90 mL/min) and 126 individuals had 
moderate renal impairment (30 mL/min ≤ CLcr <60 mL/min), mild and moderate renal 
impairment had no effect on the exposure of abemaciclib.  The effect of severe renal impairment 
(CLcr <30 mL/min) on pharmacokinetics of abemaciclib is unknown. 
 
Patients with Hepatic Impairment 
Following a single 200 mg oral dose of abemaciclib, the relative potency adjusted unbound 
AUC0-INF of abemaciclib plus its active metabolites (M2, M18, M20) in plasma increased 1.2-


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26 
fold in subjects with mild hepatic impairment (Child-Pugh A, n=9), 1.1-fold in subjects with 
moderate hepatic impairment (Child-Pugh B, n=10), and 2.4-fold in subjects with severe hepatic 
impairment (Child-Pugh C, n=6) relative to subjects with normal hepatic function (n=10).  In 
subjects with severe hepatic impairment, the mean plasma elimination half-life of abemaciclib 
increased to 55 h compared to 24 h in subjects with normal hepatic function. 
 
• Drug Interaction Studies 
 
Effects of Other Drugs on Abemaciclib 
 
Strong CYP3A Inhibitors   
Ketoconazole (a strong CYP3A inhibitor) is predicted to increase the AUC of abemaciclib by up 
to 16-fold.   
 
Itraconazole (a strong CYP3A inhibitor) is predicted to increase the relative potency adjusted 
unbound AUC of abemaciclib plus its active metabolites (M2, M18 and M20) by 2.2-fold.  
Coadministration of 500 mg twice daily doses of clarithromycin (a strong CYP3A inhibitor) with 
a single 50 mg dose of abemaciclib (0.3 times the approved recommended 150 mg dosage) 
increased the relative potency adjusted unbound AUC0-INF of abemaciclib plus its active 
metabolites (M2, M18, and M20) by 1.7-fold vs. abemaciclib alone in cancer patients. 
 
Moderate CYP3A Inhibitors 
Diltiazem and verapamil (moderate CYP3A inhibitors) are predicted to increase the relative 
potency adjusted unbound AUC of abemaciclib plus its active metabolites (M2, M18, and M20) 
by 1.7-fold and 1.3-fold, respectively. 
 
Strong CYP3A Inducers 
Coadministration of 600 mg daily doses of rifampin (a strong CYP3A inducer) with a single 200 
mg dose of VERZENIO decreased the relative potency adjusted unbound AUC0-INF of 
abemaciclib plus its active metabolites (M2, M18, and M20) by 67% in healthy subjects. 
 
Moderate CYP3A Inducers 
The effect of moderate CYP3A inducers on the PK of abemaciclib is unknown. 
 
Loperamide:  Co-administration of a single 8 mg dose of loperamide with a single 400 mg dose 
of abemaciclib in healthy subjects increased the relative potency adjusted unbound AUC0-INF of 
abemaciclib plus its active metabolites (M2 and M20) by 12%, which is not considered clinically 
relevant. 
 
Fulvestrant:  In clinical studies in patients with breast cancer, fulvestrant had no clinically 
relevant effect on the PK of abemaciclib or its active metabolites. 
 
Effects of Abemaciclib on Other Drugs 
 
Loperamide:  In a clinical drug interaction study in healthy subjects, coadministration of a single 
8 mg dose of loperamide with a single 400 mg abemaciclib (2.7 times the approved 


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27 
recommended 150 mg dosage) increased loperamide AUC0-INF by 9% and Cmax by 35% relative 
to loperamide alone.  These increases in loperamide exposure are not considered clinically 
relevant. 
 
Metformin:  In a clinical drug interaction study in healthy subjects, coadministration of a single 
1000 mg dose of metformin, a clinically relevant substrate of renal organic cation transporter 2 
(OCT2), multidrug and toxin extrusion 1 (MATE1), and MATE2-K transporters, with a single 
400 mg dose of abemaciclib (2.7 times the approved recommended 150 mg dosage) increased 
metformin AUC0-INF by 37% and Cmax by 22% relative to metformin alone.  Abemaciclib 
reduced the renal clearance and renal secretion of metformin by 45% and 62%, respectively, 
relative to metformin alone, without any effect on glomerular filtration rate (GFR) as measured 
by iohexol clearance and serum cystatin C. 
 
Fulvestrant:  In clinical studies in patients with breast cancer, abemaciclib had no clinically 
relevant effect on fulvestrant PK. 
 
• In Vitro Studies 
 
Transporter Systems:  Abemaciclib and its major active metabolites inhibit the renal transporters 
OCT 2, MATE1, and MATE2-K at concentrations achievable at the approved recommended 
dosage.  The observed serum creatinine increase in clinical studies with abemaciclib is likely due 
to inhibition of tubular secretion of creatinine via OCT2, MATE1, and MATE2-K.  Abemaciclib 
and its major metabolites at clinically relevant concentrations do not inhibit the hepatic uptake 
transporters OCT1, organic anion transporting polypeptide (OATP) 1B1, and OATP1B3 or the 
renal uptake transporters organic anion transporter (OAT) 1 and OAT3.  Abemaciclib is a 
substrate of P-gp and BCRP.  Abemaciclib and its major active metabolites, M2 and M20, are 
not substrates of hepatic uptake transporters OCT1, OATP1B1, or OATP1B3.  Abemaciclib 
inhibits P-gp and BCRP.  The clinical consequences of this finding on sensitive P-gp and BCRP 
substrates are unknown. 
 
• CYP Metabolic Pathways 
 
Abemaciclib and its major active metabolites, M2 and M20, do not induce CYP1A2, CYP2B6, 
or CYP3A at clinically relevant concentrations.  Abemaciclib and its major active metabolites, 
M2 and M20, down regulate mRNA of CYPs, including CYP1A2, CYP2B6, CYP2C8, 
CYP2C9, CYP2D6 and CYP3A4.  The mechanism of this down regulation and its clinical 
relevance are not understood.  However, abemaciclib is a substrate of CYP3A4, and time-
dependent changes in PK of abemaciclib as a result of autoinhibition of its metabolism was not 
observed. 
 
In vitro, abemaciclib is a substrate of P-gp and BCRP.  The effect of P-gp or BCRP inhibitors on 
the PK of abemaciclib has not been studied. 
 
2.3.2 Fulvestrant 
 


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2.3.2.1 
Background 
 
Fulvestrant (ICI-182,780) is a parenteral 7-alpha-alkylsulphinyl analog of estradiol.  Fulvestrant 
is a pure ER antagonist without any known estrogen agonist effects.  It is the first in a new class 
of antiestrogens that works by degrading the ER as opposed to blocking it as with tamoxifen.  
Fulvestrant has demonstrated potent inhibition of breast cancer cells in vitro and in vivo.  In 
clinical trials, fulvestrant was as effective as anastrozole, an aromatase inhibitor, in 
postmenopausal women who had received previous hormonal therapy.  The median time to 
progression (TTP) for fulvestrant (250 mg) and anastrozole was 5.4 and 3.4 months (North 
American trial) (Osborne et al., 2002), respectively, and 5.5 and 5.1 months (European trial) 
(Howell et al., 2002), respectively.  The FDA approved fulvestrant for the second-line treatment 
of advanced breast cancer in postmenopausal women on April 25, 2002.  In September 2010, the 
FDA changed the approved dosage regimen of fulvestrant to reflect data supporting increased 
efficacy with the administration of higher fulvestrant doses at 500 mg IM monthly.  Prior to 
September 2010, the FDA approved dose of fulvestrant was 250 mg IM once monthly.  In 
February 2016, it was approved in combination with palbociclib in women with HR-positive, 
HER2-negative advanced or metastatic breast cancer after disease progression following 
endocrine therapy.  In August 2017, fulvestrant received FDA approval for expanded use for 
advanced HR+ HER2 negative breast cancer patients not previously treated with endocrine 
therapy based on the FALCON trial demonstrating a statistically-significant increase in median 
PFS, 16.6 months in the fulvestrant arm compared to 13.8 months in the anastrozole arm (Hazard 
Ratio: 0.797; 95% CI: 0.637-0.999; p = 0.049), representing a 20% reduction in the risk of 
disease progression or death (Robertson et al., 2016). 
 
2.3.2.2 
Pharmacokinetics of Fulvestrant 
 
Fulvestrant is given by IM injection.  Fulvestrant undergoes rapid and extensive distribution.  
Fulvestrant is highly bound to plasma proteins, primarily very low-density lipoprotein (VLDL), 
low-density lipoprotein (LDL), and high-density lipoprotein (HDL) fractions.  The role of sex 
hormone-binding protein could not be determined.  Metabolism of fulvestrant is similar to other 
endogenous corticosteroids and includes oxidation, aromatic hydroxylation, conjugation with 
glucuronic acid and/or phosphate at the 2, 3, and 17 positions of the steroid nucleus, and 
oxidation of the sulphoxide side chain.  Identified metabolites are either less active or have 
similar activity as fulvestrant.  The hepatic CYP3A4 isoenzyme is involved in the oxidation of 
fulvestrant; however, the importance of the CYP3A4 mechanism in the metabolism of 
fulvestrant in vivo is unknown.  Fulvestrant is rapidly cleared by the hepatobiliary route with 
excretion primarily via the feces (approximately 90%).  Renal elimination is negligible (<1%). 
 
After an IM injection of fulvestrant, plasma concentrations are maximal at about 7 days and are 
maintained over a period of at least one month.  Trough concentrations were about one-third of 
the Cmax; steady state levels are reached within the first month of dosing. 
 
2.4 
Rationale 
 
2.4.1 Preclinical Rationale 
 


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Preclinical studies shown that CDK4/6 inhibition induces adaptive activation of mitogenic 
signals which is prevented by co-treatment with PI3K pathway inhibitors (Herrera-Abreu et al., 
2016; Zhang et al., 2016).  Several studies indicated that treatment with CDK4/6 inhibitors 
rapidly increases the levels of cyclin D1 (Herrera-Abreu et al., 2016; Dean et al., 2010, Paternot 
et al., 2014).  In breast cancer models, this was accompanied by increased AKT phosphorylation 
and activation of CDK2, which led to failure to fully inhibit retinoblastoma (Rb) 
phosphorylation.  However, concomitant treatment with PI3K pathway (PI3K, mTOR, AKT, 
PDK) inhibitors or insulin-like growth factor 1 receptor (IGF1R/InR) and CDK4/6 inhibitors 
reduced cyclin D1 accumulation, increased apoptosis and led to synergistic anti-tumor effects, 
therefore suggesting the role of receptor tyrosine kinase signaling/PI3K/AKT/mTOR signaling in 
the adaptive response (Herrera-Abreu et al., 2016).  Further studies suggested that upfront 
combination of PI3K inhibitors with CDK4/6 inhibitors could prevent resistance to CDK4/6 
inhibitors.  However, in the setting of acquired resistance to CDK4/6 inhibitors, although PI3K 
inhibition still modulates cyclin D1 expression, the combination was not able to restore the 
sensitivity to CDK4/6 inhibitors (Herrera-Abreu et al., 2016).  Zhang et al., also provided 
evidence that inhibition of CDK4/6 could lead to mTORC2-mediated phosphorylation and 
activation of AKT(S473) and inhibitors against AKT and CDK4/6 were synergistic in reducing 
cell proliferation (Zhang et al., 2016).  In another study, CDK4/6 inhibition stimulated glycolytic 
and oxidative metabolism and was associated with an increase in mTORC1 activity, which is 
suppressed by mTOR inhibition, leading to synergistic anti-tumor effect (Franco et al., 2016). 
 
On the other hand, studies also indicate that CDK4/6 inhibition could overcome resistance to 
PI3K inhibitors in ER+ breast cancer.  In a drug screen of 42 agents, the CDK4/6 inhibitor 
ribociclib was identified as a strong sensitizer to PI3K inhibition in 3 ER+ breast cancer cell lines 
with acquired resistance to PI3K inhibitors (Vora et al., 2014).  In this study, acquired resistance 
to PI3K inhibition was associated with maintained phosphorylation of S6 and Rb.  Addition of 
ribociclib reduced Rb phosphorylation and induced synergist anti-tumor effect of the PI3K 
inhibitor, particularly in those with PIK3CA mutation and intact Rb.  The synergism was also 
observed in the parental cell lines and those with de novo resistance to PI3K inhibitors.   
 
The mutually beneficial effect of preventing adaptive resistance mechanisms from combining 
inhibitors against PI3K and CDK4/6 is translated to impressive anti-tumor activity observed in 
preclinical studies by several groups and provided the strong rationale for clinical investigations 
of triplet combinations of endocrine therapy, PI3K, and CDK4/6 inhibitors for the treatment of 
ER+ breast cancer (Knudsen et al., 2017). 
 
The synergistic anti-tumor effect of copanlisib, fulvestrant, and palbociclib observed in the ER 
positive breast cancer xenografts MCF7 (PIK3CA-E545K) and ZR751 (PI3K WT) (O’Brien et 
al., 2016) (Figure 6).  In this study, single agent copanlisib induced significant tumor growth 
inhibition relative to vehicle control in each of the xenograft models.  Modest increases in anti-
tumor activity were achieved when copanlisib was combined with either tamoxifen or 
fulvestrant.  However, robust tumor regressions were observed with the triple combinations of 
copanlisib-palbociclib-tamoxifen and copanlisib-palbociclib-fulvestrant (Figure 6).  Each of the 
single agent and treatment combinations tested were well tolerated in animals.  These preclinical 
data provided the direct rational for investigating the triplet of fulvestrant, CDK4/6 inhibitor and 
copanlisib in HR+ breast cancer.  We have chosen abemaciclib to combine with copanlisib in 


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this trial since copanlisib could induce cytopenia and abemaciclib has the least myelosuppressive 
effect compared to palbociclib and ribociclib. 
 
 
Figure 5:  Robust Anti-tumor Activity of Copanlisib in Combination with Hormonal Blockade and Palbociclib in 
ER+ Breast Cancer (BC) Cell line Xenografts.  (O’Brien et al., 2016).  Tumor bearing mice were treated once 
weekly (BID) by intravenous injection with clinically achievable doses of copanlisib (10 mg/kg) as a single agent or 
in combination with tamoxifen or fulvestrant with or without 75 mg/kg daily palbociclib for 21 days.  Modest 
increases in anti-tumor activity were achieved when copanlisib was combined with hormonal blockade by either 
tamoxifen or fulvestrant.  However, robust tumor regressions were observed with the triple combinations of 
copanlisib-palbociclib-tamoxifen and copanlisib-palbociclib-fulvestrant. 
 
2.4.2 Potential Drug-Drug Interactions Between Copanlisib and Abemaciclib 
 
We do not anticipate significant interactions between abemaciclib and copanlisib.  Copanlisib is 
a CYP3A4 substrate, but not an inhibitor and inducer of CYP450s, uridine 5'-diphospho-
glucuronosyltransferase (UGT), or dihydropyrimidine dehydrogenase (DPD) at clinically 
relevant concentrations (O’Brien et al., 2016).  Abemaciclib is a CYP3A4 substrate.  
Abemaciclib and its major active metabolites, M2 and M20, do not induce CYP1A2, CYP2B6, 
or CYP3A at clinically relevant concentrations.  Since neither copanlisib or abemaciclib is an 
inhibitor and inducer of CYP450s, we do not expect any drug-drug interaction between these two 
drugs.  We have built in PK studies during the Phase 1 portion of the trial. 
 
In summary, CDK4/6 inhibitors in combination with endocrine therapy PFS compared to 
endocrine therapy alone in patients with HR+ HER2- metastatic breast cancer (MBC).  However, 
de novo or acquired resistance exists, leading to treatment failure and disease progression.  
Preclinical evidence supports the incorporation of PI3K inhibitor to prevent and delay resistance 
to CDK4/6 inhibitor therapy, providing the rationale to evaluate the triplet combination of 
fulvestrant, abemaciclib, and copanlisib (FAC) in CDK4/6 inhibitor naïve endocrine-resistant 
HR+ HER2- MBC. 
 
2.5 
Correlative Studies Background 
 
2.5.1 Integrated Studies 
 
2.5.1.1 
To assess tumor PIK3CA mutation, PTEN mutation/PTEN loss of expression 
 
Hypothesis:  Mutations in PIK3CA or PTEN or loss of PTEN protein expression activate PI3K 


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signaling, therefore are potential predictive markers for PI3K inhibitors.  We hypothesize that 
FAC has superior antitumor activity than FA in the subset with PIK3CA mutation or PTEN 
mutation/loss.  As a secondary objective of the study, we will compare the median PFS by 
PIK3CA/PTEN status.  
 
Rationale:  HR+ breast cancer is a heterogeneous group of disease.  There is a significant 
diversity in genomic mutation and proteomic profiles (Network TCGA, 2012; Ellis et al., 2012; 
Perou et al., 2000; Mertins et al., 2016).  The advent of genome wide next generation sequencing 
studies allowed the identification of recurrent or significantly mutated genes which are potential 
driver mutations.  As discussed in earlier sections, components of the PI3K pathway are 
frequently mutated in ER+ breast cancer (Network TCGA; Ellis et al., 2012; Gellert et al., 2016; 
Ma et al., 2011).  PIK3CA, which encodes the alpha catalytic subunit of PI3K, is mutated in 
approximately 40% of ER+ breast cancer.  Mutations have also been identified in PIK3R1, the 
regulatory subunit of PI3K (0.4% - 2%), AKT1 (2% -4%), and PTEN (4%).  Although mutations 
in PTEN is at low frequency in ER+ breast cancer, loss of PTEN protein expression is more 
common (18% to 48%) (Shoman et al., 2005; Depowski et al., 2001), and significantly 
associated with relapse risk (Shoman et al., 2005). 
 
Majority of the PIK3CA mutations, including the 3 hotspot mutations E542K, E545K, and 
H1047R, are missense mutations that cluster in the evolutionarily conserved accessary domain 
and the kinase domain (Saal et al., 2005).  The oncogenic property of the common PIK3CA 
mutations was demonstrated by their ability to induce cellular transformation and tumor 
formation when overexpressed in mammary epithelial cells (Zhang et al., 2008; Zhao et al., 
2005).  Cancer cells carrying PIK3CA mutations are highly dependent on PIK3CA for cell 
survival and are sensitive to PI3K inhibitors in preclinical studies (Crowder et al., 2009; Juric et 
al., 2012), while PTEN-deficient cancers are sensitive to p110β-selective PI3K inhibitor (Jia et 
al., 2008; Ni et al., 2012; Torbett et al., 2008; Wee et al., 2008) or by combined targeting of both 
p110α and p110β (Hosford et al., 2017). 
 
However, the role of PIK3CA mutation or PTEN in predicting response to PI3K inhibitors in 
clinical trials have been inconclusive.  The ctDNA sequencing analysis of the BELLE2 and 
BELLE3 trial indicated PIK3CA mutation in ctDNA was associated with buparlisib (pan PI3K 
inhibitor)-induced improvement in PFS (2-7).  In the BELLE2 study of fulvestrant plus 
buparlisib/placebo, PFS was not significantly different between the two treatment arms in 
patients with PI3K activation (PIK3CA mutation and/or PTEN loss) in tumor (6.8 vs. 4 months).  
However, in an exploratory analysis, the improvement in PFS by buparlisib vs. placebo was 
found to be restricted to those with PIK3CA mutation identified in ctDNA (Baselga et al., 2016).  
In the BELLE3 trial of 432 patients with AI and everolimus-resistant breast cancer (2:1 ratio to 
buparlisib vs. placebo plus fulvestrant), buparlisib significantly improved the PFS (3.9 vs. 1.8 
months) and was associated with PIK3CA mutation in ctDNA or in the tumor (Angelo et al., 
2016).  However, an improvement in PFS was also observed in the ctDNA PIK3CA WT cohort 
(Angelo et al., 2016).  The Phase 2 FERGI trial of the pan-PI3K inhibitor pictilisib (Krop et al., 
2016), however, show no difference in PFS with pictilisib in either PIK3CA mutant or WT 
patients (Krop et al., 2016).  
 
In a Phase 1b study of the PI3Kα inhibitor alpelisib, with letrozole, in patients with endocrine-


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resistant metastatic ER+ breast cancer, efficacy was observed independently of PIK3CA 
mutation status, although a higher proportion of patients with PIK3CA mutated tumors 
experienced clinical benefit (Mayer et al., 2017).  Similarly, in a Phase 2 trial of another PI3Kα 
inhibitor taselisib (also had delta inhibitory effect) plus fulvestrant in HR+ breast cancer, activity 
was observed in both PIK3CA mutant and WT tumors although a numerically higher response 
was observed in the mutant population (Dickler et al., 2016).  However, in a Phase 1study of 34 
patients with locally advanced or metastatic solid tumors treated with taselisib, responses were 
restricted to PIK3CA mutant tumors (ORR was 36% (5/14) for patients with PIK3CA mutant 
tumors compared to the 0% (0/15) in those without PIK3CA mutations).  
 
In the 25 patients treated in the MTD cohort in the Phase 1 study of copanlisib, 2 PR, both with 
breast cancers, were observed, including 1 HR+/HER2-/PIK3CA WT and 1 
HR+/HER2+/PIK3CA Mut (Patnaik et al., 2016).  One CR occurred in a patient with 
endometrial cancer with mutations in both PIK3CA and PTEN.  Fifteen (15) SDs, with 6 lasting 
≥6 cycles, including 1 with PIK3CA WT/KRAS Mut endometrial cancer, 1 PTEN loss 
endometrial cancer, 1 PIK3CA Mut breast cancer, were observed.  Interestingly, of the 10 
patients without complete PTEN loss, none had objective response or SD for ≥4 cycles.  Among 
the 7 with complete PTEN loss, 3 (43%) had CR/PR/SD ≥6 cycles.  Therefore, it appears that 
copanlisib may have enhanced activity among those with PTEN loss.  No clear relationship was 
observed with PIK3CA status. 
 
Therefore, it remains unclear whether PIK3CA mutation status and/or PTEN mutation status in 
the tumor is predictive of response to PI3K alpha selective or pan-PI3K inhibitors.  Furthermore, 
there are no studies available to date that investigated whether PIK3CA and/or PTEN mutation 
status is predictive of benefit of a PI3K inhibitor when combined with a CDK4/6 inhibitor and 
endocrine therapy combination regimen. 
 
Approach:  PIK3CA/PTEN mutations will be determined by whole exome sequencing at the 
Molecular Characterization (MoCha) Laboratory.  PTEN protein expression will be assessed by 
immunohistochemistry (IHC) under the CLIA CAP provision at Clinical IHC laboratory at the 
University of Texas MD Anderson Cancer Center. 
 
2.5.1.2 
To test whether baseline AKT phosphorylation level correlates with PFS benefit from 
the addition of copanlisib and whether triplet therapy with FAC inhibits AKT 
phosphorylation, reduces cyclin D1 expression, and is more effective than FA therapy 
in reducing Rb phosphorylation. 
 
Rationale:  Based on preclinical data (Folkes et al., 2008; Muranen et al., 2016; Kwei et al., 
2012), we hypothesize that tumors with increased PI3K pathway activity at baseline would 
benefit the most from adding copanlisib to the FA regimen.  In addition, in ER+ breast cancer 
cell lines, treatment with a CDK4/6 inhibitor has been shown to rapidly induce PI3K pathway 
signaling activation and upregulate cyclin D expression, leading to recovery of Rb 
phosphorylation, which is prevented with combined therapy with PI3K inhibitors (Herrera-Abreu 
et al., 2016).  Therefore, we expect that treatment with FA would lead to up-regulation of PI3K 
pathway signaling on C1D15, while the triplet FAC treatment inhibits PI3K pathway signaling, 
decreases cyclin D level, leading to a more profound decrease in Rb phosphorylation.   


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Approach:  Snap-frozen tumor biopsies will be analyzed by RPPA at MD Anderson. 
 
2.5.2 Exploratory Studies  
 
2.5.2.1 
To examine archival or pre-treatment tumor tissue for somatic mutations 
 
Rationale:  As part of the exploratory objectives, we will examine somatic mutation profiles that 
may correlate with treatment response.  Candidate genes include, but not limited to, other genes 
in the PI3K pathway such as AKT1, PIK3R1, as well as other recurrent mutations in HR+ breast 
cancer, including ESR1, TP53, Rb1, RAS, and others.  Several studies found that KRAS or BRAF 
mutation is associated with resistance to PI3K pathway inhibitors (Engelman et al., 2008; Ihle et 
al., 2009; Garnett et al., 2012; Di Nicolantonio et al., 2010; Janku et al., 2012).  There is little 
data in the literature that examined the impact of mutations in other genes on sensitivity to PI3K 
inhibitors (Weigelt et al., 2012).  Rb1 mutation has been implicated in resistance to CDK4/6 
inhibitor (Finn et al., 2009), but not all Rb1 mutations are the same and CDK4/6 inhibitors are 
broadly effective regardless of the presence of mutations in ESR1, TP53 and others (Cristofanilli 
et al., 2016; Ma et al., 2017a; Fribbens et al., 2016).  More data is needed. 
 
Approach:  Whole exome sequencing of tumor and germline DNA will be performed at the 
MoCha Laboratory. 
 
2.5.2.2 
To assess baseline and treatment-induced proteomic changes 
 
Rationale:  As an exploratory objective, we will examine fresh tumor biopsies collected at 
baseline (pre-treatment), C1D15, and at disease progression using reverse phase protein assay 
(RPPA) analysis to examine baseline and treatment-induced changes in various cancer associated 
pathways, including but not limited to PI3K, MAPK, ER, cyclins, CDKs and CDK inhibitors, to 
correlate with treatment response.  Based on preclinical data (Folkes et al., 2008; Muranen et al., 
2016; Kwei et al., 2012), we hypothesize that tumors with increased PI3K pathway activity at 
baseline would benefit the most from adding copanlisib to the FA regimen, while increased ERK 
pathway signaling predicts resistance to the addition of copanalisib.  In addition, in ER+ breast 
cancer cell lines, treatment with a CDK4/6 inhibitor has been shown to rapidly induce PI3K 
pathway signaling activation, upregulate cyclin D expression, leading to recovery of Rb 
phosphorylation, which is prevented with combined therapy with PI3K inhibitors (Herrera-Abreu 
et al., 2016).  Therefore, we expect that treatment with FA would lead to up-regulation of PI3K 
pathway signaling on C1D15, while the triplet FAC treatment inhibits PI3K pathway signaling, 
decreases cyclin D level, leading to a more profound decrease in Rb phosphorylation.  
Furthermore, baseline high levels of cyclin E and loss of Rb protein may be associated with 
resistance to FA combination (Herrera-Abreu et al., 2016).  We will also assess ER pathway 
signaling changes by examining ER phosphorylation, PgR levels, among others. 
 
Approach:  Snap-frozen tumor biopsies will be analyzed by RPPA at MD Anderson. 
 
2.5.2.3 
To assess baseline gene expression and treatment-induced gene expression changes 
 


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Rationale:  As an exploratory objective, we will examine fresh tumor biopsies collected at 
baseline (pre-treatment), C1D15, and at disease progression by gene expression microarray to 
determine breast cancer intrinsic subtypes (PAM50), gene signatures of PI3K and MAPK 
activation, ER regulated genes, as well as other genes and gene signatures to correlate with 
treatment response.  In NeoPalAna trial (neoadjuvant palbociclib and anastrozole), non-luminal 
subtype ER+ breast cancers were resistant to CDK4/6 inhibitors (Ma et al., 2017a) which is 
consistent with results from several preclinical studies (Finn et al., 2009).  In addition, copanlisib 
appears to be actively predominantly in HR+ and HER2 positive breast cancers (O’Brien et al., 
2016), justifying the assessment of molecular subtypes.  In preclinical studies, a gene expression 
signature of PI3K activation is associated with response, while MAPK or RAS signatures are 
associated with resistance to PI3K inhibitors (Folkes et al., 2008; Kwei et al., 2012).  Candidate 
genes implicated in PI3K and CDK4/6 inhibitor activities will also be assessed.  Examples 
include PIM1 (Le et al., 2016), cyclin B (Ihle et al., 2009), Myc and yes-associated protein 
(YAP) (Muranen et al., 2016), which have been associated with PI3K inhibitor resistance. 
 
Approach:  Total RNA from tumor biopsies will be extracted and subjected to RNASeq analysis 
at the MoCha Laboratory.   
 
2.5.2.4 
To examine ctDNA mutation profiles 
 
Rationale:  Plasma in cancer patients often carries small amounts of fragmented cell-free DNA of 
160-180 base pairs, which are originated from the necrosis or apoptotic process of cancer cells 
(Jahr et al., 2001; Snyder et al., 2016; Stroun et al., 2001).  Compared to a single tumor biopsy, 
ctDNA mutations may represent genomic alterations of different tumor clones or deposits and 
better reflect the inter- and intra-tumor heterogeneity (De Mattos-Arruda et al., 2016; Murtaza et 
al., 2015).  In addition, with a half-life ranging from 16 minutes to a few hours (Yu et al., 2013; 
Lo et al., 1999), ctDNA provides real-time status of the tumor genome.  Advances in the NGS 
technology and digital genomic techniques support the clinical validity of cell-free ctDNA 
sequencing analysis to non-invasively identify actionable genomic alterations, monitor treatment 
response, and investigate resistance mechanisms (De Mattos-Arruda et al., 2016). 
 
ctDNA sequencing is particularly helpful in cases that tumor DNA sequencing is not possible 
due to insufficient quality or quantity of the tumor tissue.  In addition, changes in the variant 
allele frequencies (VAFs) of ctDNA mutations occur rapidly, prior to the detection of changes in 
tumor size, upon treatment with cancer therapies including those that target the PI3K pathway 
(Ma et al., 2017b; Hyman et al., 2017) and serial monitoring of ctDNA mutation profile allows 
the identification of treatment emergent resistant mechanisms (Ma et al., 2017b; Hanker et al., 
2017; Ahronian et al., 2017; Diaz et al., 2012).  There have been a plethora of studies that 
demonstrated the ability of ctDNA analysis in the detection of PIK3CA mutation, PTEN 
mutations, ESR1, TP53, and others, which may be better than tumor DNA sequencing (De 
Mattos-Arruda et al., 2016; Juric et al., 2017; Ma et al., 2017c).  In this trial, as part of 
correlative studies, we will examine baseline ctDNA mutations, including PIK3CA, PTEN, 
ESR1, and others, with treatment response, examine the dynamics of ctDNA mutation profile 
over time for early tumor response and treatment-emergent resistant mechanisms. 
 
Approach:  NGS of ctDNA will be performed with the plasma collected from the streck tubes 


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using the TSO500 assay (Illumina, San Diego, CA).   
 
2.5.2.5 
To assess plasma and serum proteomics and metabolomics 
 
Rationale:  As part of the exploratory objectives, serum and plasma samples at baseline, on 
therapy and at disease progression are collected for circulating markers that reflect changes due 
to treatment.  In addition to regulating cell proliferation, PI3K pathway is important in regulating 
glucose and lipid metabolism (Engelman et al., 2006), and circulating markers of metabolism 
before and after PI3K inhibitor therapy may predict treatment response and resistance 
mechanisms.  Inhibition of PI3K pathway reduces glucose uptake in the cancer cells (Maynard et 
al., 2017; Maynard et al., 2016; Maynard et al., 2013).  PI3K inhibitors reduce glycolysis, affect 
the nonoxidative pentose phosphate pathway that delivers the Ribose-5-phosphate required for 
base ribosylation, therefore suppressing nucleotide synthesis and inducing replication stress and 
DNA damage (Juvekar et al., 2016).  In addition, there is evidence of reduction of enzymes 
involved in cholesterol biosynthesis upon PI3K inhibition, which leads to changes in levels of 
critical metabolites such as deoxyribonucleotide triphosphates (dNTPs), driving a cellular stress 
phenotype (Lynch et al., 2017).  Proteomic technology, such as mass spectrometry and 
SOMAscan technology, allows systematic profiling of cellular metabolites and metabolic 
enzymes in the serum or plasma in a parallel and multiplexed high-throughput manner (Gold et 
al., 2010; Mehan et al., 2014).  We are particularly interested in members of the glycolytic 
pathway, both the enzymes as well as the metabolic intermediates, as these are expected to be 
sensitive to PI3K-inhibition (Juvekar et al., 2016).  Some of these studies will be performed at 
the Beth Isreal Deaconess Medical Center Proteomics Core, in collaboration with Dr. Gerburg 
Wulf. 
 
Approach:  Unbiased proteomic scan will be performed either using Mass Spectrometry or the 
SOMAscan, aptamer-based technology.  In either case, a total of 1000-1500 proteins can be 
screened from a single plasma sample in an unbiased fashion.  Unbiased metabolomics will be 
performed using Mass Spectrometry of Plasma-samples after metabolite extraction with either 
methanol or methyl-ether butyrate (MBTE). 
 
2.5.2.6 
To assess tumor immune microenvironment 
 
Rationale:  As part of the exploratory objectives, we will examine tumor biopsies collected at 
baseline, on-treatment, and at disease progression for treatment induced changes in tumor 
infiltrating lymphocytes and to correlate response.  This is based on preclinical studies 
demonstrating that p110δ inhibition by copanlisib decreases both total Treg and CD4+ T cells, 
and increased IFNγ+ CD44 cells in tumors.   
 
Approach:  A multiplex IHC platform will be used to assess the immune cell populations in 
tumor biopsy FFPE sections before and after therapy.   
 
2.5.2.7 
Copanlisib and abemaciclib pharmacokinetics  
 
Rationale:  Copanlisib is predominantly metabolized by CYP3A4 (>90%) and to a minor extent 
by CYP1A1 (<10%).  Copanlisib has low potential for drug-drug interaction as a perpetrator to 


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influence the PK of other drugs by inhibition or induction of metabolizing enzymes (CYPs, 
UGT) and transport proteins, except MATE2-K transporter at clinically relevant concentrations. 
Abemaciclib is a CYP3A4 substrate.  Abemaciclib and its major active metabolites, M2 and 
M20, do not induce CYP1A2, CYP2B6, or CYP3A at clinically relevant concentrations.  Based 
on this information, we do not expect any drug-drug interaction between these two drugs.  
However, we have built in PK studies during the Phase 1 portion of the trial to make sure there is 
no drug-drug interactions. 
 
Approach:  Peripheral blood will be collected at different time points before and after drug 
administration in the presence or absence of the other drug (please refer to protocol Section 5 for 
details).  Serum/plasma will be analyzed by MS approach at Bayer with existing assays.  
 
2.6 
Rationale for Protocol Amendment #6 
 
Between June 2020 and Dec 2020, 7 patients were enrolled to Phase 1, Dose Level 1 (copanlisib 
45 mg IV D1 and D15; abemaciclib 100 mg PO Bid) in 2 sequential cohorts of 3 evaluable 
patients. One patient was not evaluable for DLT due to withdrawing consent during Cycle 1.  
The most common AE G3 or above experienced by the patients enrolled at Dose Level 1 was 
neutropenia.  Among the 6 DLT evaluable patients enrolled to Dose Level 1, 4 experienced a G3 
ANC during Cycle 1, leading to dose interruption of abemaciclib, although only one patient 
needed 2 weeks for ANC to recover sufficiently in order to resume abemaciclib (this is 
considered a DLT); the other 3 patients were able to resume abemaciclib after an interruption of 
1 week.  Since 1 of 6 patients experienced a DLT in Dose Level 1, dose escalation proceeded to 
Dose Level 2.   
 
Between 2/4/2021 and 2/9/2021, 3 patients were enrolled to Dose Level 2 (copanlisib 45 mg IV 
D1, D8, and D15; abemaciclib 100 mg PO Bid).  Two of these 3 patients experienced a DLT 
(one G3 rash, one G3 elevated bilirubin). Dose Level 2 therefore exceeded the maximum 
tolerated dose.   
 
After reviewing the AEs observed in Dose Levels 1 and 2 with the CTEP monitor, the dosing 
schedule of abemaciclib has been modified to 5 days on and 2 days off each week (5-on/2-off) to 
improve tolerability.  Therefore, the previous iteration of Phase 1 has been termed Phase 1 Part 
A, and the new Phase 1 dosing schedule has been termed Phase 1 Part B.  In Phase 1 Part B, a 
maximum of 4 dose levels with abemaciclib administered at 5-on/2-off schedule will be tested.  
This is based on our prior experience using an alternative dosing schedule of palbociclib (5-on/2-
off) in a phase II clinical trial in metastatic hormone receptor positive breast cancer 
(NCT03007979) (Krishnamurthy, J. et al 2020).  The alternative dosing schedule of palbociclib 
showed improved tolerability with reduced incidences of G3+ ANC and did not impact the 
efficacy of the treatment.  
 
The starting dose level to be tested in Phase 1 Part B (Dose Level 1b) is copanlisib 45mg IV D1 
and D15 and abemaciclib 100 mg BID on Days 1-5 each week (Days 1-5, 8-12, 15-19, and 22-26 
of each cycle).  
 
 


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2.7 
Rationale for Protocol Amendment #8d and Study Closure 
 
Bayer announced in November 2023 that they were voluntarily withdrawing their New Drug 
Application for copanlisib due to failure to meet their primary endpoint in ongoing clinical trials. 
This study is closing to any new patient enrollments. Patients currently on study who are 
incurring clinical and/or radiographic benefit may be allowed to continue on study treatment at 
the discretion of their treating physician, and if the patient consents. 
 
 
3. PATIENT SELECTION 
 
3.1 
Eligibility Criteria  
 
3.1.1 Men and women must have histologically or cytologically confirmed ER and/or PR 
positive, HER2 negative or non-amplified breast cancer that is stage IV, with measurable 
or non-measurable disease.  ER/PR positivity is defined as at least 1% positive or an 
Allred score of at least 3.  HER2 status is defined per the 2018 American Society of 
Clinical Oncology/College of American Pathologists (ASCO/CAP) guideline. 
 
3.1.2 All patients must agree to provide archival tumor material for research and must agree to 
undergo research tumor biopsy before treatment if presence of easily accessible lesions 
(judged by the treating physician).  For patients with bone only disease, or patients 
without easily accessible lesions for the baseline research biopsy, availability of archival 
tumor material (2 x 4-5 micron section unstained slides, plus 15-20 x 10 micron section 
unstained slides or a tumor rich block) from previous breast cancer diagnosis or treatment 
is required for central PTEN and PIK3CA analysis. 
 
3.1.3 No more than 1 prior chemotherapy in the metastatic setting.  There is no limit on prior 
lines of endocrine therapy.  (For patients enrolling to the Phase 1 portion of the study, 
prior fulvestrant, CDK4/6 inhibitor, and everolimus is allowed). 
 
3.1.4 For patients enrolling to the randomized Phase 2 portion of this study, demonstrated 
resistance to prior endocrine therapy in the metastatic setting is required; this is defined 
as: 
• Progressed on prior endocrine therapy in the metastatic setting or, 
• Relapsed on adjuvant endocrine therapy or, 
• Relapsed within 12 months of completing adjuvant endocrine therapy or, 
• If received adjuvant CDK4/6 inhibitor, relapsed at least 2 years after completion of 
adjuvant CDK4/6 inhibitor. 
 
3.1.5 Washout from prior systemic anti-cancer therapy of at least 3 weeks from chemotherapy 
or 5 half-lives from oral targeted drugs, and treatment related adverse events recovered to 
grade 1 (except for alopecia) before the start of study treatment.  Washout from prior 
radiation therapy of at least 2 weeks before the start of the study treatment.  Washout 
from prior endocrine therapy is not required. 
 


NCI Protocol #:  10287 
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1 
3.1.6 Age ≥18 years.  Because no dosing or AE data are currently available on the use of 
copanlisib in combination with abemaciclib and fulvestrant in patients <18 years of age, 
and because breast cancer is rare in children, children are excluded from this study. 
 
3.1.7 ECOG performance status ≤2 (Karnofsky ≥60%, see Appendix A). 
 
3.1.8 Patients must have adequate organ and marrow function collected no more than 7 days 
before starting study treatment as defined below: 
 
− 
leukocytes  
≥3,000/mcL 
− 
absolute neutrophil count 
≥1,500/mcL 
− 
platelets 
≥100,000/mcL 
− 
hemoglobin 
≥ 8.0 g/dL 
− 
total bilirubin 
≤1.5 × institutional upper limit of normal (≤3 × 
institutional upper limit of normal for patients with 
Gilbert syndrome)  
− 
AST(SGOT)/ALT(SGPT) 
≤3 × institutional upper limit of normal (≤5 × 
institutional upper limit of normal for patients with liver 
involvement) 
− 
Glomerular filtration rate 
≥30 mL/min according to the Modification of Diet in 
Renal Disease (MDRD) abbreviated formula  
− 
Lipase   
 
 
 
≤1.5 x ULN 
− 
INR and PTT   
 
≤1.5 x ULN (except those on anti-coagulation therapy) 
− 
HbA1c  
 
 
 
≤8.5% or fasting glucose ≤ 120 mg/dL on at least 2  
 
 
 
 
 
occasions within 14 days prior to registration if diabetic 
 
3.1.9 Left ventricular ejection fraction (LVEF) ≥50%. 
 
3.1.10 Patients may be postmenopausal or premenopausal women on or planned to receive 
GnRH agonist. 
 
3.1.11 The effects of copanlisib on the developing human fetus are unknown.  For this reason 
and because maternal toxicity, developmental toxicity and teratogenic effects have been 
observed in nonclinical studies and PI3K inhibitors as well as other therapeutic agents 
used in this trial are known to be teratogenic, women of child-bearing potential and men 
must agree to use adequate contraception (hormonal or barrier method of birth control; 
abstinence) prior to study entry, for the duration of study participation, and for 6 months 
after the last dose of copanlisib.  Should a woman become pregnant or suspect she is 
pregnant while she or her partner is participating in this study, she should inform her 
treating physician immediately.  Men treated or enrolled on this protocol must also agree 
to use adequate contraception prior to the study, for the duration of study participation, 
and 6 months after completion of copanlisib administration. 
 
3.1.12 Ability to understand and willing to sign a written informed consent document (or legally 
authorized representative, if applicable). Patient must agree to research team access to 
prior breast cancer diagnosis and treatment records, as well as reports of clinical tumor 


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2 
and blood sequencing results. 
 
3.1.13 Patients with a history of treated brain metastases are allowed in the Phase I portion of 
the trial provided there is no disease progression symptomatically and by imaging within 
28 days prior to registration AND if the patient is off steroids. 
 
3.1.14 Human immunodeficiency virus (HIV)-infected patients on effective anti-retroviral 
therapy with undetectable viral load within 6 months are eligible for this trial. 
 
3.1.15 For patients with evidence of chronic hepatitis B virus (HBV) infection, the HBV viral 
load must be undetectable on suppressive therapy, if indicated. 
 
3.1.16 Patients with a history of hepatitis C virus (HCV) infection must have been treated and 
cured.  For patients with HCV infection who are currently on treatment, they are eligible 
if they have an undetectable HCV viral load. 
 
3.1.17 Patients with a prior or concurrent malignancy whose natural history or treatment does 
not have the potential to interfere with the safety or efficacy assessment of the 
investigational regimen are eligible for this trial. 
 
3.2 
Exclusion Criteria 
 
3.2.1 For patients enrolling to the randomized Phase 2 portion of the study, prior treatment 
with a CDK4/6 inhibitor or fulvestrant, or a PI3K inhibitor in the metastatic setting is not 
allowed. 
 
3.2.2 Patients who have had chemotherapy within 3 weeks or radiotherapy within 2 weeks (6 
weeks for nitrosoureas or mitomycin C) prior to entering the study.  
 
3.2.3 Patients who are receiving any other investigational agents. 
 
3.2.4 Immunosuppressive therapy is not allowed while on study. 
 
3.2.5 Receiving anti-arrhythmic therapy (beta blockers or digoxin are permitted). 
 
3.2.6 History of allergic reactions attributed to compounds of similar chemical or biologic 
composition to copanlisib, PI3K inhibitors, or other agents used in study. 
 
3.2.7 For the randomized Phase 2 portion of the study, patients with brain metastasis or a 
history of brain metastasis are not eligible. 
 
For the Phase 1 portion of the study, patients with progressive brain metastases should be 
excluded because of their poor prognosis and because they often develop progressive 
neurologic dysfunction that would confound the evaluation of neurologic and other AEs. 
 
3.2.8 Copanlisib is primarily metabolized by CYP3A4.  Therefore, the concomitant use of 


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3 
strong inhibitors of CYP3A4 (e.g., ketoconazole, itraconazole, clarithromycin, ritonavir, 
indinavir, nelfinavir and saquinavir), and strong inducers of CYP3A4 (e.g., rifampin, 
phenytoin, carbamazepine, phenobarbital, St. John’s Wort) are not permitted from 14 
days prior to enrollment until the end of the study. 
 
For the list of specific medications prohibited while on copanlisib treatment refer to 
Appendix B.  Because the lists of these agents are constantly changing, it is important to 
regularly consult a frequently-updated medical reference for a list of drugs to avoid or 
minimize use of.  Appendix C (Patient Wallet Card) should be provided to patients.  As 
part of the enrollment/informed consent procedures, the patient will be counseled on the 
risk of interactions with other agents, and what to do if new medications need to be 
prescribed or if the patient is considering a new over-the-counter medicine or herbal 
product. 
 
3.2.9 Systemic corticosteroid therapy at a daily dose higher than 15 mg prednisone or 
equivalent is not permitted while on study.  Previous corticosteroid therapy must be 
stopped or reduced to the allowed dose at least 7 days prior to the CT/MRI screening.  If 
a patient is on chronic corticosteroid therapy, corticosteroids should be de-escalated to 
the maximum allowed dose before the screening.  Patients may be using topical or 
inhaled corticosteroids.  Short-term (up to 7 days) systemic corticosteroids above 15 mg 
prednisolone or equivalent will be allowed for the management of acute conditions (e.g., 
treatment non-infectious pneumonitis).   
 
3.2.10 Major surgical procedure or significant traumatic injury (as judged by the investigator) 
within 28 days before start of treatment, or have not recovered from major side effects, 
open biopsy within 7 days before start of treatment. 
 
3.2.11 Uncontrolled intercurrent illness, including but not limited to, symptomatic congestive 
heart failure (> NYHA class 2), unstable angina pectoris, new-onset angina, uncontrolled 
hypertension despite optimal medical management, seizure disorder requiring 
medication, or psychiatric illness/social situations that would limit compliance with study 
requirements. 
 
3.2.12 Myocardial infarction <6 months before start of treatment 
 
3.2.13 Arterial or venous thrombotic or embolic events such as cerebrovascular accident 
(including transient ischemic attacks), deep vein thrombosis or pulmonary embolism 
within 3 months before the start of study medication 
 
3.2.14 The patient has a personal history of any of the following conditions: syncope of 
cardiovascular etiology, ventricular arrhythmia of pathological origin (including, but not 
limited to, ventricular tachycardia and ventricular fibrillation), or sudden cardiac arrest. 
 
3.2.15 Proteinuria ≥grade 3 as assessed by a 24-h protein quantification or estimated by urine 
protein: creatinine ratio >3.5 on a random urine sample 
 


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4 
3.2.16 History of bleeding diathesis.  Any hemorrhage or bleeding event ≥grade 3 within 4 
weeks prior to the start of study medication. 
 
3.2.17 History or concurrent condition of interstitial lung disease of any severity and/or severely 
impaired lung function. 
 
3.2.18 History of having received an allogeneic bone marrow or organ transplant 
 
3.2.19 Patients with non-healing wound, ulcer, or bone fracture not due to breast cancer. 
 
3.2.20 Patients with active, clinically serious infections >grade 2 (CTCAEv5.0) 
 
3.2.21 Patients with HbA1c >8.5% at screening. 
 
3.2.22 Concurrent diagnosis of pheochromocytoma. 
 
3.2.23 Has undergone blood or platelet transfusion <7 days prior to start of treatment. 
 
3.2.24 Pregnant women are excluded from this study because copanlisib is a PI3K inhibitor 
agent with the potential for teratogenic or abortifacient effects.  Because there is an 
unknown but potential risk for adverse events in nursing infants secondary to treatment of 
the mother with copanlisib, breastfeeding should be discontinued if the mother is treated 
with copanlisib.  These potential risks may also apply to other agents used in this study. 
 
3.2.25 Hepatitis B (HBV) or hepatitis C (HCV).  All patients must be screened for HBV and 
HCV up to 28 days prior to study drug start using the routine hepatitis virus lab panel.  
Patients positive for HBsAg and/or HBcAb will be eligible if they are negative for HBV 
DNA, these patients should receive prophylactic antiviral therapy.  Patients positive for 
anti-HCV antibody will be eligible if they are negative for HCV RNA. 
 
3.2.26 HIV positive patients on combination antiretroviral agents that are strong CYP3A4 
inhibitors or inducers and who are unwilling or unable to change to antiretroviral 
therapies without such interactions are ineligible because of the potential for 
pharmacokinetic interactions with copanlisib, abemaciclib, and fulvestrant.  Appropriate 
studies will be undertaken in patients receiving combination antiretroviral therapy when 
indicated. 
 
3.2.27 Patients with history of, or current autoimmune disease are not eligible 
 
3.2.28 History of major surgical resection involving the stomach or small bowel, or preexisting 
Crohn’s disease or ulcerative colitis or a preexisting chronic condition resulting in 
baseline grade 2 or higher diarrhea 
 
3.3 
Inclusion of Women and Minorities 
 
National Institute of Health (NIH) policy requires that women and members of minority groups 


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5 
and their subpopulations be included in all NIH-supported biomedical and behavioral research 
projects involving NIH-defined clinical research unless a clear and compelling rationale and 
justification establishes to the satisfaction of the funding Institute & Center (IC) Director that 
inclusion is inappropriate with respect to the health of the subjects or the purpose of the research.  
Exclusion under other circumstances must be designated by the Director, NIH, upon the 
recommendation of an IC Director based on a compelling rationale and justification.  Cost is not 
an acceptable reason for exclusion except when the study would duplicate data from other 
sources.  Women of childbearing potential should not be routinely excluded from participation in 
clinical research.  Please see http://grants.nih.gov/grants/funding/phs398/phs398.pdf. 
 
 
4. REGISTRATION PROCEDURES 
 
4.1 
Investigator and Research Associate Registration with CTEP 
 
Food and Drug Administration (FDA) regulations require sponsors to select qualified 
investigators.  National Cancer Institute (NCI) policy requires all individuals contributing to 
NCI-sponsored trials to register with their qualifications and credentials and to renew their 
registration annually.  To register, all individuals must obtain a Cancer Therapy Evaluation 
Program (CTEP) ) credentials necessary to access secure NCI Clinical Oncology Research 
Enterprise (CORE) systems.  Investigators and clinical site staff who are significant contributors 
to research must register in the Registration and Credential Repository (RCR) at 
https://ctepcore.nci.nih.gov/rcr/. The RCR is a self-service online person registration application 
with electronic signature and document submission capability. 
 
RCR utilizes five person registration types. 
• Investigator (IVR):  MD, DO, or international equivalent, 
• Non Physician Investigator (NPIVR):  advanced practice providers (e.g., NP or PA) or 
graduate level researchers (e.g., PhD), 
• Associate Plus (AP):  clinical site staff (e.g., RN or CRA) with data entry access to CTSU 
applications such as the Roster Update Management System (RUMS), OPEN, Rave, 
acting as a primary site contact, or with consenting privileges, 
• Associate (A):  other clinical site staff involved in the conduct of NCI-sponsored trials, 
and 
• Associate Basic (AB):  individuals (e.g., pharmaceutical company employees) with 
limited access to NCI-supported systems. 
 
RCR requires the following registration documents: 
 
Documentation Required 
IVR NPIVR AP 
A 
AB 
FDA Form 1572 
✔ 
✔ 
Financial Disclosure Form 
✔ 
✔ 
✔ 
NCI Biosketch (education, training, employment, license, 
and certification) 
✔ 
✔ 
✔ 
GCP training 
✔ 
✔ 
✔ 


NCI Protocol #:  10287 
Version Date:  June 13, 2024 
 
6 
Documentation Required 
IVR NPIVR AP 
A 
AB 
Agent Shipment Form (if applicable) 
✔ 
CV (optional) 
✔ 
✔ 
✔ 
 
IVRs and NPIVRs must list all clinical practice sites and Institutional Review Boards (IRBs) 
covering their practice sites on the FDA Form 1572 in RCR to allow the following: 
 
• Addition to a site roster, 
• Selection as the treating, credit, or drug shipment  investigator or consenting person in 
OPEN, 
•  Ability to be named as the site-protocol Principal Investigator (PI) on the IRB approval, 
and 
• Assignment of the Clinical Investigator (CI) task on the Delegation of Tasks Log (DTL).  
 
In addition, all investigators acting as the Site-Protocol PI (Investigator listed on the IRB 
approval), consenting/treating/drug shipment investigator in OPEN, or as the Clinical 
Investigator (CI) on the DTL must be rostered at the enrolling site with a participating 
organization.  
 
Refer to the NCI RCR page on the CTEP website for additional information.  For questions, 
please contact the RCR Help Desk by email at RCRHelpDesk@nih.gov. 
 
4.2 
Site Registration 
 
This study is supported by the NCI Cancer Trials Support Unit (CTSU). 
 
IRB Approval   
 
Sites participating with the NCI Central Institutional Review Board (NCI CIRB) must submit the 
Study Specific Worksheet (SSW) for Local Context to the CIRB using IRBManager to indicate 
their intent to open the study locally.  The NCI CIRB’s approval of the SSW is automatically 
communicated to the CTSU Regulatory Office, but sites are required to contact the CTSU 
Regulatory Office at CTSURegPref@ctsu.coccg.org to establish site preferences for applying 
NCI CIRB approvals across their Signatory Network.  Site preferences can be set at the network 
or protocol level.  Questions about establishing site preferences can be addressed to the CTSU 
Regulatory Office by email or calling 1-888-651-CTSU (2878). 
 
In addition, the Site-Protocol PI (i.e., the investigator on the IRB/REB approval) must meet the 
following criteria for the site to be able to have an Approved status following processing of the 
IRB/REB approval record: 
• Have an active CTEP status, 
• Have an active status at the site(s) on the IRB/REB approval (applies to US and Canadian 
sites only) on at least one participating organization’s roster, 
• If using NCI CIRB, be active on the NCI CIRB roster under the applicable CIRB 
Signatory Institution(s) record, 


NCI Protocol #:  10287 
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7 
• Include the IRB number of the IRB providing approval in the Form FDA 1572 in the RCR 
profile, 
• List all sites on the IRB/REB approval as Practice Sites in the Form FDA 1572 in the 
RCR profile; and 
Have the appropriate CTEP registration type for the protocol.  
 
Additional Requirements 
 
Additional site requirements to obtain an approved site registration status include: 
• An active Federal Wide Assurance (FWA) number, 
• An active roster affiliation with the Lead Protocol Organization (LPO) or a Participating 
Organization (PO),  
• An active roster affiliation with the NCI CIRB roster under at least one CIRB Signatory 
Institution (US sites only); and 
• Compliance with all applicable protocol-specific requirements (PSRs). 
 
4.2.1 Downloading Site Registration Documents 
 
Download the site registration forms from the protocol-specific page located on the CTSU 
members’ website.  Permission to view and download this protocol and its supporting documents 
is restricted to institutions and their associated investigators and staff on a participating roster.  
To view/download site registration forms:   
 
• Log in to the CTSU members’ website (https://www.ctsu.org), 
• Click on Protocols in the upper left of the screen 
o Enter the protocol number in the search field at the top of the protocol tree, or 
o Click on the By Lead Organization folder to expand, then select LAO-CT018, and 
protocol number 10287, 
• Click on Documents, Protocol Related Documents, and use the Document Type filter and 
select Site Registration to download and complete the forms provided.  (Note:  For sites 
under the CIRB, IRB data will load automatically to the CTSU.) 
 
4.2.2 Requirements For 10287 Site Registration 
 
• Site Initiation Meeting (SIM) by the Study Chair/Lead Principal Investigator (Prior to the 
start of subject enrollment, participating sites must contact the Study Chair/Study 
Coordinator to schedule a SIM.) 
• Specimen Tracking System Training Requirement: 
o All data entry users (Clinical Research Associate role) at each participating site 
will need to complete the Theradex-led training. 
o Theradex will provide a certificate of completion, which will need to be submitted 
to the CTSU through the Regulatory Submission Portal. 
o The training is a one-time only requirement per individual. If an individual has 
previously completed the training for another ETCTN study, the training does not 
need to be completed again nor does the certificate of completion need to be 


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8 
resubmitted to the CTSU.  Users are strongly encouraged to take a refresher of the 
training if they have not entered specimen data for an extended period of time. 
o This training will need to be completed before first/further patient enrollment at a 
given site. 
o Please contact STS Support at Theradex for the training 
(STS.Support@theradex.com).   
 
4.2.3 Submitting Regulatory Documents 
 
Submit required forms and documents to the CTSU Regulatory Office via the Regulatory 
Submission Portal on the CTSU members’ website. 
 
To access the Regulatory Submission Portal, log on to the CTSU members’ website go to the 
Regulatory section, and select Regulatory Submission.  
 
Institutions with patients waiting that are unable to use the Regulatory Submission Portal should 
alert the CTSU Regulatory Office immediately by phone or email: 1-866-651-CTSU (2878), or 
CTSURegHelp@coccg.org in order to receive further instruction and support. 
 
4.2.4 Checking Site Registration Status 
 
Site’s registration status may be verified on the CTSU website.  
• Click on Regulatory at the top of the screen, 
• Click on Site Registration, and  
• Enter the site’s 5-character CTEP Institution Code and click on Go. 
o Additional filters are available to sort by Protocol, Registration Status, Protocol 
Status, and/or IRB Type. 
Note:  The status shown only reflects institutional compliance with site registration requirements 
as outlined within the protocol.  It does not reflect compliance with protocol requirements for 
individuals participating on the protocol or the enrolling investigator’s status with NCI or their 
affiliated networks. 
 
4.3 
Patient Enrollment 
 
In addition to systems provided through CTSU, Duke Cancer Institute LAO (corresponding 
organization) is utilizing an online ‘study portal’ for key study communication from participating 
sites to the Lead Principal Investigator and Study Coordinator.  Communications via the study 
portal include notifications of subject consent, subject status updates (e.g., screen failure, OPEN 
registered, withdrawal, etc.), lab shipments, serious adverse events, and protocol deviations.  The 
study portal operates through REDCap, a secure, web-based application, managed by the Duke 
Cancer Institute LAO.  Participating sites will not require REDCap user accounts or passwords 
to access the study portal for this study 
 
Information about 10287 Study Portal use is available in LPO Documents for the study on 
www.ctsu.org. 
 


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Version Date:  June 13, 2024 
 
9 
Within 24 business hour of patient signing consent for this study, site staff must access the 10287 
Study Portal to provide notification of consent.  With this study portal notification, the Lead 
Principal Investigator and Study Coordinator will be alerted of subjects consented and in 
screening. 
 
A stratified randomization will be conducted to assign patients at a 1:1 ratio to FA or FAC for 
the phase II portion of the study. The stratification factors are (1) the presence or absence of 
visceral metastasis, (2) menopausal status at study entry (postmenopausal vs. premenopausal or 
perimenopausal), and (3) primary vs secondary endocrine resistance. 
 
4.3.1 OPEN / IWRS 
 
The Oncology Patient Enrollment Network (OPEN) is a web-based registration system available 
on a 24/7 basis.  OPEN is integrated with CTSU regulatory and roster data and with the Lead 
Protocol Organization (LPOs) registration/randomization systems or Theradex Interactive Web 
Response System (IWRS) for retrieval of patient registration/randomization assignment.  OPEN 
will populate the patient enrollment data in NCI’s clinical data management system, Medidata 
Rave. 
 
Requirements for OPEN access:   
 
• Active CTEP registration with the credentials necessary to access secure NCI/CTSU IT 
systems. 
• To perform enrollments or request slot reservations:  Must be on an LPO roster, ETCTN 
Corresponding roster, or PO roster with the role of Registrar.  Registrars must hold a 
minimum of an Associate Plus (AP) registration type. 
• Have an approved site registration for a protocol prior to patient enrollment. 
 
To assign an Investigator (IVR) or Non-Physician Investigator (NPIVR) as the treating, 
crediting, consenting, drug shipment (IVR only), or receiving investigator for a patient transfer in 
OPEN, the IVR or NPIVR must list the IRB number used on the site’s IRB approval on their 
Form FDA 1572 in RCR.   
 
Prior to accessing OPEN, site staff should verify the following: 
 
• Patient has met all eligibility criteria within the protocol stated timeframes, and  
• All patients have signed an appropriate consent form and Health Insurance Portability 
and Accountability Act (HIPAA) authorization form (if applicable). 
 
Note:  The OPEN system will provide the site with a printable confirmation of registration and 
treatment information.  Please print this confirmation for your records.  
 
Access OPEN at https://open.ctsu.org or from the OPEN link on the CTSU members’ website.  
Further instructional information is in the OPEN section of the CTSU website at 
https://www.ctsu.org or https://open.ctsu.org.  For any additional questions, contact the CTSU 
Help Desk at 1-888-823-5923 or ctsucontact@westat.com. 


NCI Protocol #:  10287 
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10 
 
4.3.2 Special Instructions for Patient Enrollment 
 
This Study will use the ETCTN Specimen Tracking System (STS).  
• All biospecimens collected for this trial must be submitted using the ETCTN Specimen 
Tracking System (STS) unless otherwise noted.   
• The system is accessed through Rave user roles:  “Rave CRA” and “Rave CRA 
(Labadmin)” for data entry at the treating institutions and “Biorepository” for users 
receiving the specimens for processing and storage at reference labs and the 
Biorepository.   
 
• Please refer to the Medidata Account Activation and Study Invitation Acceptance link on 
the CTSU website in the Data Management section  under the Rave Home tab and then 
under Rave Resource Materials. 
 
• Important:  Failure to complete required fields in STS may result in a delay in 
sample processing.  Any case reimbursements associated with sample submissions will 
not be credited if samples requiring STS submission are not logged into STS. 
 
Detailed instructions can be found in Section 5.4. 
 
4.3.3 OPEN/IWRS Questions? 
 
Further instructional information on OPEN is provided on the OPEN tab of the CTSU 
website at https://www.ctsu.org or at https://open.ctsu.org.  For any additional questions 
contact the CTSU Help Desk at 1-888-823-5923 or ctsucontact@westat.com.  
 
4.3.4 Patient Registration/Randomization 
 
Prior to accessing OPEN/IWRS to register/randomize patient, site staff should verify the 
following: 
• All eligibility criteria have been met within the protocol stated timeframes.   
• If applicable, all patients have signed an appropriate consent form and HIPAA 
authorization form. 
 
A stratified randomization will be conducted to assign patients at a 1:1 ratio to FA or FAC. The 
stratification factors are endocrine resistance in metastatic or adjuvant setting, bone-only or 
visceral metastases, and prior chemotherapy or not in the metastatic setting. 
 
The OPEN system will provide the site with a printable confirmation of registration and 
treatment information.  Please print this confirmation for your records.  
 
4.4 
General Guidelines 
 
Following registration, patients should begin protocol treatment within 14 days.  Issues that 
would cause treatment delays should be discussed with the Principal Investigator.  If a patient 


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11 
does not receive protocol therapy following registration, the patient’s registration on the study 
may be canceled.  The Study Coordinator should be notified of cancellations as soon as possible. 
 
Within 24 business hours of patient enrollment in OPEN, withdrawal of consent, or 
determination ineligible for study, site staff must access the 10287 Study Portal to provide 
update of subject status. With this study portal notification, the Lead Principal Investigator and 
Study Coordinator will be alerted of patient’s status on study.   
 
 
5. BIOMARKER, CORRELATIVE, AND SPECIAL STUDIES 
 
5.1 
Summary Table for Specimen Collection 
 
Patients who have treatment delays or holds should delay the PK blood draws until treatment 
resumes.  If PK samples are collected on a day when treatment is held or delayed, these samples 
should be discarded and collected at the next scheduled dosing visit.  
 
Blood draws for the EDTA (purple top), red top, and Streck cfDNA tubes could still be 
submitted on a day when treatment is held or delayed - do not discard samples. 
 
Time Point 
Specimen 
Send Specimens To: 
Archival 
 
• Archival tumor sample1: 
− 1 tumor-rich (more than 50% tumor 
cellularity) FFPE block (preferred) 
 
If a block cannot be submitted, then submit: 
− 
1 H&E-stained slide at 3-5 microns 
− 
15-20 unstained, uncharged, air-dried slides 
cut at 10 microns* 
− 
2 unstained, charged slides cut at 4-5 
microns* 
EET Biobank 
Pre-treatment 
 
• Fresh tumor biopsy2: 
− 1st and 2nd tumor cores snap-frozen 
− 3rd and 4th tumor cores in formalin 
• 20 mL blood in Streck cfDNA tubes 
• 10 mL blood in EDTA (purple top) tube, 
processed for plasma and frozen3 
• 10 mL blood in red top tube, processed for 
serum and frozen4 
EET Biobank 
Cycle 1 Day 1 (C1D1)  


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12 
Time Point 
Specimen 
Send Specimens To: 
Baseline 
10 min 
1 h 
2 h 
3 h 
5 h 
24 h 
• 4 mL blood in Li-Heparin BD vacutainers 
(green top) for each PK time point before 
(baseline) and after copanlisib infusion at 
indicated time6. 
NorthEast 
Bioanalytical 
Laboratories 
Cycle 1 Day 8 (C1D8) 
 
• 10 mL blood in EDTA (purple top) tube, 
processed for plasma and frozen3 
• 10 ml blood in red top tube, processed for 
serum and frozen4 
• 20 mL blood in Streck cfDNA tubes 
EET Biobank 
 
Cycle 1 Day 15 (C1D15)  
 
• Fresh tumor biopsy2 (optional) 
− 1st and 2nd tumor cores snap-frozen 
− 3rd and 4th tumor cores in formalin 
• 20 mL blood in Streck cfDNA tubes  
• 10 mL blood in red top tube, processed for 
serum and frozen4 
• 10 mL blood in EDTA (purple top) tube, 
processed for plasma and frozen3 
 
Note that for patients on copanlisib, the tumor 
biopsy schedule should follow that of copanlisib, in 
case if C1D15 copanlisib is delayed. 
EET Biobank 
 
Baseline 
10 min 
1 h 
2 h 
3 h 
5 h 
24 h 
• 4 mL blood in Li-Heparin BD vacutainers 
(green top) for each PK time point before and 
after copanlisib infusion6. 
Note:  Abemaciclib should be taken right after 
the 1 h blood draw. 
 
Note that the PK sampling schedule should follow 
that of copanlisib, in case if C1D15 copanlisib is 
delayed. 
NorthEast 
Bioanalytical 
Laboratories 
Cycle 1 Day 22 (C1D22)  
Baseline 
1 h 
2 h 
4 h 
23 h 
• 4 mL blood in Li-Heparin BD vacutainers 
(green top) for each PK time point before 
(baseline) and after taking the morning dose of 
abemaciclib6. 
Note that the PK sampling schedule should follow 
that of copanlisib, in case if delays of copanlisib 
occurs in Cycle 1. 
NorthEast 
Bioanalytical 
Laboratories 
Cycle 2 Day 1 (C2D1) 


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Time Point 
Specimen 
Send Specimens To: 
 
• 20 mL blood in Streck cfDNA tubes  
• 10 mL blood in red top tube, processed for 
serum and frozen4 
• 10 mL blood in EDTA (purple top) tube, 
processed for plasma and frozen3 
EET Biobank 
Cycle 4 Day 1 (C4D1), Cycle 7 Day 1 (C7D1) and every 3 cycles after 
 
• 20 mL blood in Streck cfDNA tubes  
• 10 mL blood in red top tube, processed for 
serum and frozen4 
• 10 mL blood in EDTA (purple top) tube, 
processed for plasma and frozen3 
EET Biobank 
Progression5 
 
• Fresh tumor biopsy2 (optional) 
− 1st and 2nd tumor cores snap-frozen 
− 3rd and 4th tumor cores in formalin 
• 20 mL blood in Streck cfDNA tubes  
• 10 mL blood in red top tube, processed for 
serum and frozen4 
• 10 mL blood in EDTA (purple top) tube, 
processed for plasma and frozen3 
EET Biobank 
 
1For archival tissue, a copy of the corresponding anatomic pathology report must be sent with the 
tissue and uploaded to Rave.  If submitting slides, then slides must be processed in order, and 
numbered sequentially (e.g., H&E stained slide is created first and labeled 1, unstained slides are 
then created and numbered 2 – 23). 
2For new biopsies, the Tissue Biopsy Verification Form (Appendix J), a copy of the 
radiology and/or operative reports from the tissue removal procedure and the diagnostic 
anatomic pathology report must be sent with the tissue to the EET Biobank.  Kits are provided 
by the EET Biobank.  Please refer to Section 5.3.2, 5.3.3 and 5.3.4 for details. 
3Process samples at Site according to Section 5.3.5.2. 
4Process samples at Site according to Section 5.3.5.1. 
5Progression specimens should be collected prior to beginning any additional therapies.  
6PK samples are required for patients enrolled in the phase 1 portion.  Kits are provided by 
NorthEast Bioanalytical Laboratories.  
 
*Clearly label the section thickness on slides. 
 
5.2 
Specimen Procurement Kits and Scheduling  
 
5.2.1 Specimen Shipping Kits  
 
Kits for the collection and shipment of specimens to the EET Biobank can be ordered online via 
the Kit Management system: (https://kits.bpc-apps.nchri.org/).  
 


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Users at the clinical sites will need to set up an account in the Kit Management system and select 
a specific clinical trial protocol to request a kit.  Please note that protocol may include more than 
one type of kit.  Each user may order two kit types per protocol per day (daily max = 6 kits).  
Kits are shipped ground, so please allow 5-7 days for receipt.  A complete list of kit contents for 
each kit type is located on the Kit Management system website. 
 
Note:  Kits or supplies are only provided for specimens shipped to the Biorepository. NorthEast 
Bioanalytical Laboratories will provide kits for collection and shipping of PK samples. Refer to 
the PK Sample Manual for instructions on how to order kits for PK samples. 
 
5.2.2 Scheduling of Specimen Collections 
 
Please adhere to the following guidelines when scheduling procedures to collect tissue:  
• 
Tumor tissue specimens collected during biopsy procedures and fixed in formalin must 
be shipped on the same day of collection.  
• 
Tissue can be collected Monday through Wednesday and shipped overnight for arrival on 
Tuesday through Thursday at the EET Biobank at Nationwide Children’s Hospital.   
 
Frozen specimens, including processed serum, plasma, and frozen tissue, may be collected, 
processed, and shipped to the EET Biobank on Monday through Thursday, since the 
Biorepository does not need to perform additional processing.  In the event that frozen samples 
cannot be shipped immediately, they must be stored in a -80 °C freezer. 
 
Fresh blood specimens may be collected and shipped Monday through Friday. 
 
5.3 
Specimen Collection and Processing 
 
5.3.1 Archival tumor (Mandatory) 
 
Tissue from previous diagnostic or therapeutic procedures of the primary breast cancer or 
metastatic site is required for all patients.  (There is no time limit for this specimen; any 
previously collected specimen is accepted.)  A tumor rich (more than 50% tumor cellularity) 
block is preferred.  Alternatively, 1 H&E-stained slide (3-5 microns), 15-20 unstained slides (10 
microns thick) and 2 unstained slides (4-5 microns) may be submitted in place of the FFPE 
block.  If submitting slides, then slides must be processed in order and numbered sequentially. 
 
5.3.2 Biopsy Collection Procedure - Tumor Specimen Allocation and Prioritization 
 
Pre-treatment (mandatory) 
Tumor biopsy is required for all patients with accessible tumors that could be safely biopsied as 
determined by the site investigator. Bone biopsy is acceptable. This will serve as additional 
tumor material to analyze in cases of insufficient quantity, or quality, archival tumor material for 
sequencing studies. 
• Biopsy Core Collection:  Either skin punches (in cases of skin metastasis) or core 
biopsies (in the clinic or by radiology guidance) will be performed according to the 
sequence of priority listed below.  If feasible, up to 4 cores or punches (with a minimum 


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of at least 2 cores) will be taken at each time point.  Punches could be divided to smaller 
pieces to make up the 4 cores.   
o Core (punch) #1:  Snap-freeze according to instructions in Section 5.3.4 (for 
RPPA).  
o Core (punch) #2:  Snap-freeze according to instructions in Section 5.3.4 (for 
RPPA). 
o Core (punch) #3:  Formalin fix following instructions in Section 5.3.3 (for NGS 
and IHC). 
o Core (punch) #4:  Formalin fix following instructions in Section 5.3.3 (for NGS 
and IHC). 
 
For cores 1 and 2, if immediate bedside freezing is not possible, place samples on ice for a 
maximum of 2 h before freezing procedure to avoid protein and RNA degradation.  
 
C1D15 and Disease Progression (optional)  
 
For patients on the FAC regimen, collect biopsy within 2-8 h post the administration of 
copanlisib, for scheduling issues, up to 24 hours following the copanlisib is acceptable. Note that 
for patients on copanlisib, the tumor biopsy schedule should follow that of copanlisib in C1D15, 
in case copanlisib is delayed. For patients on FA regimen, collect biopsy on C1D15 at least 1h 
after the first dose of abemaciclib that day. 
 
Biopsy core collection:  It is recommended the biopsy site at C1D15 the same as that at pre-
treatment time point. Either skin punches (in cases of skin metastasis) or core biopsies (in the 
clinic or by radiology guidance) will be performed according to the sequence of priority listed 
below.  If feasible, up to 4 cores or punches (with a minimum of at least 2 cores) will be taken at 
each time point.  Punches could be divided to smaller pieces to make up the 4 cores. 
o Core (punch) #1:  Snap freeze following instructions in Section 5.3.4 (for RPPA). 
o Core (punch) #2:  Snap freeze following instructions in Section 5.3.4 (for RPPA). 
o Core (punch) #3:  Formalin fix following instructions in Section 5.3.3 (for NGS 
and IHC). 
o Core (punch) #4:  Formalin fix following instructions in Section 5.3.3 (for NGS 
and IHC). 
 
For cores 1 and 2, if immediate bedside freezing is not possible, place samples on ice for a 
maximum of 2 h before freezing procedure to avoid protein and RNA degradation.  
 
5.3.3 Collection of formalin tissue specimen using kits  
 
1. Label formalin-filled containers according to instructions in Section 5.4.1.  
2. Obtain two 16-gauge or 18-gauge core needle biopsy specimens, and place one core in 
each cassette.  
3. Snap the cassette lids closed and place cassettes into a formalin-filled pre-labeled 
container as soon as possible after collection to prevent air drying.  Up to two cassettes 
may be placed in one formalin jar. 


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4. Perform fixation at room temperature (20-25°C).  Record the time of fixation and enter 
into the Sample Tracking System (Rave) for all submitted specimens.  The optimal 
duration of fixation should be 16-24 h by the time it is received at the EET Biobank. 
5. Secure the container lids and package containers into the shipping kit according to 
instructions in Section 5.5.  Keep tissue in formalin jars at room temperature until 
shipment to the ETCTN Biorepository.  
 
5.3.4 Collection of Biopsy to Snap-Freeze 
 
1. Tissue should be frozen as soon as possible.  Optimally, freeze within 30 minutes from 
resection. 
2. Prior to tissue collection: 
a. Label cryovial(s) according to instructions in Section 5.4.1.  
b. Place cryovial(s) on dry ice to freeze. The vials should appear frosty when ready. 
3. Immediately place tissue in foil and allow to completely freeze (using either direct 
contact with dry ice, or liquid nitrogen vapor).  
4. Gently remove the frozen tissue from the foil. If the tissue is sticking to the foil, then 
gently run a finger over the back of the foil to loosen the tissue.  
5. Using clean forceps place each tissue core in a separate pre-chilled cryovial. Tissue 
should move freely in the vial. 
 Place the tissue in a -70 to -80°C freezer.  Keep frozen until shipment to the EET Biobank. 
  
5.3.5 Blood Samples 
 
Blood samples for serum, plasma, and Streck cfDNA tubes are collection at the following time 
points: 
• Pre-treatment 
• C1D8, if applicable for cohort 
• C1D15 
• C2D1 
• C4D1 
• C7D1 then every 3 cycles 
• Progression 
 
5.3.5.1 
Whole blood collection in red-top tubes for serum processing 
1) Label one 10 mL red-top tube according to the instructions in Section 5.4.1. 
2) Collect 10 mL of whole blood in the red-top tube.  
3) Allow blood to clot upright at room temperature for at least 30 minutes (maximum 60 
minutes) prior to processing.  If the blood is not immediately processed after the 
clotting period, then tubes should be stored (after the 30-60 minutes of clotting time) 
at 4°C for no longer than 4 hours.  Process serum from red top tubes by centrifuging 
at 1,200 x g at 4°C for 10 minutes. 
4) Using a clean transfer pipette, aliquot serum into pre-labeled cryovials (using the 
label printed from the ETCTN Specimen Tracking System or following instructions 


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in Section 5.4.1) at an aliquot volume of 1 mL per tube.  Do not disturb the red blood 
cells when aliquoting by keeping the pipet above the red blood cell layer and leaving 
a small amount of serum in the tube.  Tightly secure the cap of the vials before 
storage.  Aliquoting and freezing of serum specimens should be completed within 1 h 
of centrifugation.  
5) Store serum cryovials upright in a specimen box or rack in an -70°C to -90°C or 
colder freezer prior to shipping.  Do not allow specimens to thaw after freezing.  
 
See Section 5.5 for instructions for shipping to the EET Biobank at Nationwide Children’s 
Hospital. 
 
5.3.5.2 
Whole blood collection in purple-top (EDTA) tubes for plasma processing 
 
1) Label 10 mL purple-top (EDTA) tube(s) according to the instructions in Section 
5.4.1. 
2) Collect 10 mL of whole blood in purple-top (EDTA) tube(s). 
3) After collection, gently invert tube(s) 5-10 times to ensure adequate mixing of 
anticoagulant.  
4) Process plasma from EDTA tube at all time points by centrifuging at 1,200 x g at 
4°C for 10 minutes. 
5) Using a clean transfer pipette, aliquot plasma into pre-labeled cryovials (using the 
label printed from the ETCTN Specimen Tracking System or following the 
instructions in Section 5.4.1) at a volume of 1 mL per tube.  Do not disturb the buffy 
coat or red blood cells when aliquoting by keeping the pipet above these layers and 
leaving a small amount of plasma in the tube. 
6) Tightly secure the caps of the vials before storage.  Aliquoting and freezing of plasma 
specimens should be completed within 1 h of centrifugation.  
7) Store plasma cryovials upright in a specimen box or rack in an -70°C to -90°C or 
colder freezer prior to shipping.  Do not allow specimens to thaw after freezing.  
 
See Section 5.5 for instructions for shipping to the EET Biobank at Nationwide Children’s 
Hospital. 
 
5.3.5.3 
Whole blood collection in Streck cfDNA tubes 
 
1) Label two Streck cfDNA tubes according to the instructions in Section 5.4.1. 
2) Collect 18 mL of blood into the pre-labeled tube and invert to mix.  Note:  blood must 
be thoroughly mixed to ensure preservation of specimen. 
3) After collection, blood in Streck cfDNA tubes should never be refrigerated, as this 
may compromise the specimen.  Blood collected in Streck cfDNA tubes is stable at 
room temperature.  
 
Streck cfDNA tubes must be shipped within a week of collection. See Section 5.5 for 
instructions for shipping to the EET Biobank at Nationwide Children’s Hospital. 
 


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5.3.5.4 
Whole blood collection for PK 
 
(Kits are provided by NorthEast Bioanalytical Laboratories, See PK sampling Manual [Appendix 
I]).  Note that the PK sampling schedule should follow that of copanlisib, in cases of treatment 
delays.  
 
1) Blood will be collected in 1 x 4 ml pre-labeled Li-Heparin BD vacutainers provided in the kit 
at each of the following time points: 
• C1D1 
For Copanlisib PK Only: 
o Prior to copanlisib infusion 
o 10 minutes after copanlisib infusion 
o 1 h after copanlisib infusion 
o 2 h after copanlisib infusion 
o 3 h after copanlisib infusion 
o 5 h after copanlisib infusion 
o 24 h after copanlisib infusion (before C1D2’s abemaciclib and fulvestrant) 
• C1D15 
For Copanlisib and Abemaciclib PK: 
o Prior to copanlisib infusion 
o 10 minutes after copanlisib infusion 
o 1 h after copanlisib infusion (take abemaciclib right after this blood draw) 
o 2 h after copanlisib infusion 
o 3 h after copanlisib infusion 
o 5 h after copanlisib infusion 
o 24 h after copanlisib infusion (before C1D16’s abemaciclib and fulvestrant dose) 
 
Note:  Instruct patient to take abemaciclib right after the 1 h blood draw 
 
• C1D22 
For Abemaciclib PK 
o Prior to morning dose of abemaciclib 
o 1 h after taking abemaciciclib 
o 2 h after taking abemaciciclib  
o 4 h after taking abemaciciclib 
o 23 h (1h before C1D16’s abemaciclib and fulvestrant dose) 
 
Note: Instruct patient to take the evening dose of abemaciclib 12 hours post the 
morning dose of abemaciclib. 
 
2) Gently invert tube several times to ensure adequate anticoagulation and place on wet ice.  
Deliver tube to laboratory within 30 minutes of draw. 
3) Centrifuge blood at 1000 x g for 10 minutes at 4°C.   
4) Remove plasma using a pipette and distribute evenly between three screw-top tubes (e.g., 
Corning 2 mL externally-threaded cryo-vial, provided in the kit) – roughly 1 mL of plasma 
per tube.  Avoid disturbing the buffy coat layer.   


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5) Store plasma in a -80°C freezer within three hours of venipuncture. 
 
See PK sampling manual and Section 5.6 for instructions for shipping to NorthEast Bioanalytical 
laboratories.  
 
5.4 
Specimen Tracking System Instructions 
 
5.4.1 Specimen Tracking System Overview and Enrollment Instructions 
 
For the ETCTN STS, the following information will be requested: 
• Protocol Number 
• Investigator Identification  
o Institution and affiliate name 
o Investigator’s name 
• Eligibility Verification:  Patients must meet all the eligibility requirements listed in 
Section 3. 
• Additional Requirements: 
o Patients must provide a signed and dated, written informed consent form. 
 
Upon enrolling a patient, IWRS will communicate with OPEN, assigning two separate and 
unique identification numbers to the patient, a Universal patient ID (UPID) and a Treatment 
patient ID.  The UPID is associated with the patient and used each and every time the patient 
engages with the portion of this or any other protocol that uses the ETCTN Specimen Tracking 
System.  The UPID contains no information or link to the treatment protocol.  IWRS will 
maintain an association between the UPID for ETCTN biobanking and molecular 
characterization and any treatment protocols the patient participates in, thereby allowing analysis 
of the molecular characterization results with the clinical data.   
 
Immediately following enrollment, the institutional anatomical pathology report for the diagnosis 
under which the patient is being enrolled must be uploaded into Rave.  The report must include 
the surgical pathology ID (SPID), collection date, block number, and the IWRS-assigned UPID 
and patient study ID for this trial.  For newly acquired biopsies, the radiology and operative 
report(s) must also be uploaded into Rave.  Important:  Do not redact SPID, block number, 
diagnosis, or relevant dates (such as collection date), and include the UPID and patient 
study ID on each document (either by adding a label or hand writing). 
 
Additionally, please note that the STS software creates pop-up windows when reports are 
generated, so you will need to enable pop-ups within your web browser while using the software.   
 
For questions regarding the Specimen Tracking System, please contact STS Support at 
STS.Support@theradex.com. 
 
The Shipping List report must be included with all sample submissions. 
 
5.4.2 Specimen Labeling 
 


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5.4.2.1 
Tissue Specimen Labels 
 
Include the following on all tissue specimens or containers (e.g., formalin jar):  
• Patient Study ID 
• Universal Patient ID (UPID) 
• Specimen ID (automatically generated by Rave) 
• Time point 
• Specimen type (e.g., FFPE Block, Formalin Fixed Tissue, Fresh Tissue in Media, 
etc.) 
• Tissue type (P for primary, M for metastatic or N for normal) 
• Surgical pathology ID (SPID) number   
• Block number from the corresponding pathology report (archival only) 
• Collection date (to be added by hand) 
• Core number (for snap-frozen tissue and tissue cores in formalin) 
• Section number (archival slides only) 
 
5.4.2.2 
Blood Specimen Labels 
 
Include the following on blood specimens (including whole blood and frozen, processed blood 
products – like serum and plasma): 
• Patient Study ID 
• Universal Patient ID (UPID) 
• Specimen ID (automatically generated by Rave) 
• Time point 
• Specimen type (e.g., blood, serum) 
• Collection date (to be added by hand) 
 
5.4.2.3 
Example of Specimen Label Generated by STS 
 
STS includes a label printing facility, accessed via the Print Label CRF in the All Specimens 
folder. A generated PDF is emailed to the user as a result of saving that form.  
 
The following image is an example of a tissue specimen label printed on a label that is 0.5” high 
and 1.28” wide. 
  
The QR code in the above example is for the Specimen ID shown on the second line.  
  


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Labels may be printed on a special purpose label printer, one label at a time, or on a standard 
laser printer, multiple labels per page. Theradex recommends the use of these low temperature 
waterproof labels for standard laser printers: https://www.labtag.com/shop/product/cryo-laser-
labels-1-28-x-0-5-cl-23-colors-available/ 
 
The last line item on the label includes the following data points joined together: 
1. Tissue only: Primary (P), Metastatic (M), Normal (N) tissue indicated at the 
beginning of the specimen ID; this field is blank if not relevant (e.g., for blood) 
2. Block ID or blank if not relevant 
3. SPID (Surgical Pathology ID) or blank if none 
4. An optional alpha-numeric code that is protocol specific and is only included if the 
protocol requires an additional special code classification 
Space is provided at the bottom of the label for the handwritten date and optional time.   
The last line on the example label is for the handwritten date and optional time. 
 
5.4.3 Overview of Process at Treating Site 
 
5.4.3.1 
OPEN Registration 
 
All registrations will be performed using the OPEN system. OPEN communicates automatically 
with the IWRS which handles identifier assignments, any study randomization and any 
prescribed slot assignments. If specimen analysis is required to determine eligibility, the protocol 
will be setup with multi-step registration. 
 
Registration without eligibility specimen analysis:  
1. Site enters registration data into OPEN during one or more steps. 
2. IWRS receives data from OPEN, generates the Patient Study ID and the Universal 
Patient ID, both of which are sent back to OPEN. 
3. IWRS sends all applicable registration data directly to Rave at the end of the final 
registration step. 
 
Any data entry errors made during enrollment should be corrected in Rave. 
 
5.4.3.2 
Rave Specimen Tracking Process Steps 
 
Step 0: Log into Rave via your CTEP-IAM account, then navigate to the appropriate 
participant. 
 
Step 1:  Complete the Histology and Disease form (but do not upload reports until a 
specimen label can be applied to them) and the Baseline forms regarding Prior 
Therapies. Enter the initial clinical specimen data:  
• Specimen Tracking Enrollment CRF:  Enter Time Point, Specimen Category, 
Specimen Type, Block number, Tissue type, Surgical Path ID, number of labels 
needed (include extra labels to apply to reports to be uploaded). CRF generates 
unique Specimen ID.  
 


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Step 2:  Print labels using the Print Labels CRF located in the All Specimens folder, 
then collect specimen. 
• Label specimen containers and write collection date on each label. 
• After collection, store labeled specimens as described in Section 5.3  
• Apply an extra specimen label to each report before scanning. Return to the 
Histology and Disease form to upload any initial Pathology, Radiology, 
Molecular Reports (up to 4), Surgical (or Operative) reports. Return to Specimen 
Tracking Enrollment CRF to upload any molecular report (one per specimen) 
and/or specimen specific pathology or related report (one per specimen) and/or 
the Tissue Biopsy Verification Form (Appendix J).   Uploaded reports should 
have protected health information (PHI) data, like name, date of birth, mailing 
address, medical record number or social security number (SSN) redacted. Do not 
redact SPID, block number or relevant dates (such as collection date), and include 
the UPID and the patient study ID on each document.  
 
Step 3:  Complete specimen data entry. 
• Specimen Transmittal Form: Enter Collection date and time and other required 
specimen details. 
 
Step 4:  When ready to ship, enter shipment information. 
• Shipping Status CRF:  Enter tracking number, your contact information, 
recipient, number of sample containers and ship date once for the first specimen 
in a shipment. 
• Copy Shipping CRF:  In the specimen folders for additional specimens (if any) 
that will be shipped with the initial specimen, please use the Copy Shipping form 
to derive common data into additional Shipping Status forms. A few unique 
fields will still need to be entered in Shipping Status.   
 
Step 5:  Print shipping list report and prepare to ship.  
• Shipping List report is available at the site level. 
• Print two copies of the shipping list, one to provide in the box, the other for your 
own records. 
• Print pathology or other required reports to include in the box. Be sure the printed 
copy includes the specimen label. 
 
Step 6:  Send email notification.  
• For only one of the specimens in the shipment, click “Send Email Alert” 
checkbox on the Shipping Status CRF to email recipient. 
 
Step 7:  Ship the specimen(s). 
 
Step 8: Monitor the Receiving Status form located in each specimen folder for 
acknowledgment of receipt and adequacy. 
 


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5.5 
Shipping Specimens from Clinical Sites to the EET Biobank 
 
5.5.1 General Shipping Information 
 
When kits are provided, the shipping container sent with kit contents should be used to ship 
specimens to the EET Biobank.  In winter months, please include extra insulation, such as bubble 
wrap, inside the shipping container. 
 
5.5.1.1 
Required Forms for Specimen Submissions 
 
Each document submitted with the specimen must be labeled with a label printed from the 
STS, or the Universal ID and Patient Study ID. 
 
Specimen  
Required Forms 
Archival 
1. Shipping List 
2. Corresponding Pathology Report 
New Biopsy 
 
1. Shipping List 
2. Tissue Biopsy Verification Form 
3. Diagnostic Pathology Report  
4. Operative and/or Radiology Report 
Blood in Streck cfDNA tubes, plasma, 
and serum 
1. Shipping List 
 
5.5.2 Specimen Shipping Instructions 
 
Tissue in formalin must be shipped on the day of collection.  Collect and ship on Monday 
through Wednesday. 
 
Frozen specimens and archival (FFPE) tissue may be shipped on Monday through Thursday.  
 
Fresh blood may be shipped on Monday through Friday.  Please select “Saturday Delivery” 
when shipping fresh blood on a Friday. 
 
5.5.2.1 
Shipping of FFPE Blocks and Glass Slides 
 
1. Before packaging blocks or slides, verify that each specimen is labeled according to 
Section 5.4.1. 
2. Blocks should be placed in a hard-sided container, preferably a special block holder, to 
protect the specimens.  Glass slides are to be placed in plastic slide holders.  Place tissue 
paper on top of the separated slides prior to closing the slide holder to reduce slide 
movement during shipment. 
3. Place the blocks or slides in a reinforced cardboard shipping box with appropriate 
packaging filler to minimize movement of specimens within the shipping box. 
4. Include a copy of the forms listed above and a shipping manifest from the Specimen 
Tracking System with each shipment. 
5. Please include a cold pack when shipping on hot days and extra insulation on cold days. 


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6. Ship specimens to the address listed below.  FedEx Priority Overnight is strongly 
recommended to prevent delays in package receipt. 
 
5.5.2.2 
Shipping Blood in cfDNA Streck Tubes in an Ambient Shipper 
 
1. Before packaging specimens, verify that each specimen is labeled according to the 
instructions above and that the lids of all primary receptacles containing liquid are tightly 
sealed. 
2. Prepare the SAFT-TEMP Gel Pack for shipment.  Note: If contents of the Pak are 
crunchy, place Pak in a warm water bath until gel is smooth.  Do not refrigerate, freeze 
or microwave. 
3. Pace the SAF-T-TEMP Pak in bottom of insulated chest.  Note: The insulated chest must 
be shipped inside the provided cardboard box. 
4. Place the blood collection tubes in zip-lock bags.  
5. Next, place blood into a biohazard envelope with absorbent material.  Expel as much air 
as possible and seal the envelope securely.  
6. Place the biohazard envelope into a Tyvek envelope.  Expel as much air as possible and 
seal securely. 
7. Place packaged blood collection tube(s) and a copy of the shipping manifest from the 
Sample Tracking System on top of SAF-T-TEMP Pak.  
8.  Place the lid on the insulated chest.  
9. Close the outer flaps of the shipping box and tape shut. 
10. Attach a shipping label to the top of the shipping container.  
11. Attach an Exempt Human Specimen sticker to the side of the box. 
12. Ship specimens via overnight courier to the address below.  FedEx Priority Overnight is 
strongly recommended to prevent delays in package receipt.  
 
5.5.2.3 
Shipping Frozen Plasma and Serum Specimens in an Insulated Shipping Container 
 
Serum and plasma collected at time points that do not include the collection of frozen tissue must 
be submitted using institutional supplies. 
 
1. Before packaging specimens, verify that each specimen is labeled according to the 
instructions above and matches the data on the paperwork to be included in the shipment 
and that lids of all primary receptacles containing liquid are tightly sealed. 
2. Place the specimens in zip-lock bags.  Use a separate zip-lock bag for each specimen type 
and time point. 
3. Place the zip-lock bags in a biohazard envelope containing absorbent material.  Expel as 
much air as possible and seal securely.  
4. Put the secondary envelope into a Tyvek envelope.  Expel as much air as possible and 
seal securely. 
5. Place frozen specimens in an insulated container with dry ice.  Layer the bottom of the 
container with dry ice until it is approximately one-third full.  Place the frozen specimens 
on top of the dry ice.  Cover the specimens with the dry ice until the container is almost 
completely full.   
6. Insert a copy of the required forms into a plastic bag and place in the shipping container. 


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7. Close the shipping container and tape it shut with durable sealing tape.  Do not 
completely seal the container. 
8. Complete a FedEx air bill and attach to top of shipping container. 
9. Complete a dry ice label. 
10. Attach a dry ice label and an Exempt Human Specimen sticker to the side of the shipping 
container. 
11. Ship specimens via overnight courier to the address below.  FedEx Priority Overnight is 
strongly recommended to prevent delays in package receipt. 
 
5.5.2.4 
Shipping Frozen and Ambient Specimens in a Dual Chambered Specimen 
Procurement Kit 
 
The Dual Chambered Specimen Procurement Kit is constructed to allow the shipment of frozen (on 
dry ice) and ambient (room temperature) specimens in the same container.  Dry ice may be placed 
in either compartment of the kit, but should not be put in both.  The dual chambered kit is 
provided for time points when both ambient and frozen tissue are shipped (Pretreatment, C1D15, 
and Progression) and should only be used for shipments that contain both frozen and ambient 
specimens.  If formalin-fixed tissue is shipped separately (not in the same shipment as frozen 
specimens), then it must be shipped using institutional shipping supplies. 
 
• Frozen specimens may be shipped on Monday through Thursday.  Ensure that enough dry 
ice is included to completely encase the specimens to maintain specimen integrity during 
shipment.   
 
• Formalin-fixed tissue may only be shipped on Monday through Wednesday.  
 
1. Before packaging specimens, verify that each specimen is labeled according to the 
instructions above and that lids of all primary receptacles containing liquid are tightly 
sealed.  If included in the shipment, formalin jar lids should be wrapped in parafilm. 
2. Pre-fill one of the kit chambers about 1/3 with dry ice. 
3. Prepare the frozen specimens for shipment: 
a. Place the specimens into zip-lock bags.  
b. Place the zip-lock bags into a biohazard envelope containing absorbent material.  
Expel as much air as possible before sealing the biohazard envelope. 
c. Put each biohazard envelope into a Tyvek envelope.  Expel as much air as possible 
and then seal the Tyvek envelope. 
4. Quickly place the Tyvek envelope containing frozen specimens in the kit compartment that 
is pre-filled with dry ice.  Place the Tyvek envelope on top of the dry ice.  Cover the 
specimens with additional dry ice until the compartment is almost completely full.   
5. Place the Styrofoam lid on top to secure specimens during shipment.  Do not tape the inner 
chamber shut. 
6. Prepare the ambient specimens for shipment: 
a. Seal the lids of the formalin jars with parafilm.  Place absorbent material around 
the primary container of each liquid specimen.  Place the specimens into zip-lock 
bags. 
b. Place specimens inside the secondary pressure vessel with bubble wrap.  


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26 
c. Secure the lid on the secondary pressure vessel and set it inside the kit chamber. 
7. Insert a copy of the required forms into a plastic bag and place in the kit chamber with the 
ambient samples. 
8. Place the Styrofoam lid on top of the kit compartment to secure specimens during shipment.  
Do not tape the inner chamber shut. 
9. Close the outer lid of the Specimen Procurement Kit and tape it shut with filament or other 
durable sealing tape.  Do not completely seal the container. 
10. Complete a FedEx air bill and attach to top of shipping container. 
11. Complete a dry ice label. 
12. Attach the dry ice label and an Exempt Human Specimen sticker to the side of the shipping 
container. 
13. Ship specimens via overnight courier to the address below.  FedEx Priority Overnight is 
strongly recommended to prevent delays in package receipt  
 
5.5.2.5 
Shipping Address 
 
Ship to the address below.  Ship formalin-fixed and fresh blood specimens the same day of specimen 
collection.  Do not ship specimens the day before a holiday. 
 
EET Biobank 
The Research Institute at Nationwide Children's Hospital 
700 Children's Drive, WA1340 
Columbus, Ohio 43205 
PH: (614) 722-2865 
FAX: (614) 722-2897 
Email: BPCBank@nationwidechildrens.org 
 
FedEx Priority Overnight service is very strongly preferred.   
 
NOTE:  The EET Biobank FedEx Account will not be provided to submitting institutions.   
 
There is no central Courier account for this study.  Sites are responsible for all costs for overnight 
shipments to the EET Biobank, utilizing the site screening and base intervention payments.  
 
5.5.2.6 
Contact Information for Assistance 
 
For all queries, please use the contact information below: 
 
EET Biobank 
Toll-free Phone:  (800) 347-2486 
E-mail:  BPCBank@nationwidechildrens.org 
 
5.6 
Shipping Specimens from Clinical Site to Other Laboratories  
 
Please refer to the PK Sample Manual for shipment of PK samples to NorthEast Bioanalytical 
Laboratories.  Ship to the address below.   


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27 
 
Vipin Agarwal, PhD 
925 Sherman Avenue 
Hamden, CT 06514 
USA 
Tel: +1-203-361-3768 
Fax: +1-203-407-0703 
E-mail: vipin.agarwal@nebiolab.com or jonathan.quick@nebiolab.com  
 
 
 


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28 
5.7 
Biomarker Plan 
 
List of Biomarker Assays in Order of Priority 
Note for participating sites: Please see Section 5.1 for details on specimens to collect.  The specimens tested are not always the 
same specimens that are submitted by the site, as processing of blood and tissue will occur at the Biobank prior to testing. 
Priority 
Biomarker Name 
Assay and  
CLIA: 
Y/N 
Use in the Trial and Purpose 
Specimens 
Tested 
Collection 
Time Points 
Mandatory 
or 
Optional 
Assay Laboratory, Lab 
PI, and Lab PI Email 
Tissue-based 
1 
Whole exome 
sequencing 
(WES) 
 
NGS 
CLIA:  N 
 
Integrated 
Mutations in PIK3CA or PTEN 
as predictive markers for 
response to PI3K inhibitors 
Additional exploratory analyses:  
To assess mutations in in 
candidate genes including ESR1, 
Rb, TP53, AKT1, PIK3R1, RAS, 
and others at baseline and 
progression and to correlate with 
response in each treatment arm. 
DNA from 
FFPE Tumor 
Tissue 
Archival, 
Pre-treatment 
(Baseline) 
M 
M 
MoCha, Frederick 
National Laboratory for 
Cancer Research (FNLCR) 
Dr. Chris Karlovich 
chris.karlovich@nih.gov 
2 
PTEN expression 
IHC 
CLIA:  N 
 
Integrated 
Loss of PTEN as predictive 
markers for response to PI3K 
inhibitors 
Unstained 
slides from 
FFPE Tumor 
Tissue 
 
Archival, 
Pre-treatment 
(Baseline) 
M 
M 
Clinical 
Immunohistochemistry 
Laboratory, MD Anderson 
Cancer Center (MDACC) 
Dr. Wei-Lien Wang 
wlwana@mdanderson.org 
3 
Reverse Phase 
Protein array 
(RPPA) 
 
RPPA 
CLIA:  N 
Integrated 
Levels of phosphorylated Rb 
(pS807_S811), AKT (pS473), 
Cyclin D1:  To test whether 
baseline AKT phosphorylation 
Snap-frozen 
Tumor Tissue 
Pre-
treatment, 
C1D15, 
M 
 
O 
O 
Functional Proteomics 
RPPA Core Facility, MD 
Anderson Cancer Center 
(MDACC) 
Dr. Yiling Lu  


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29 
Priority 
Biomarker Name 
Assay and  
CLIA: 
Y/N 
Use in the Trial and Purpose 
Specimens 
Tested 
Collection 
Time Points 
Mandatory 
or 
Optional 
Assay Laboratory, Lab 
PI, and Lab PI Email 
 
correlates with PFS benefit from 
the addition of copanlisib and 
whether the triplet therapy with 
copanlisib/fulvestrant/abemacicli
b inhibits AKT phosphorylation, 
reduces cyclin D1 expression, 
and is more effective in reducing 
Rb phosphorylation than with 
the fulvestrant/abemaciclib 
doublet;  
Additional exploratory analyses: 
To assess baseline and treatment 
induced changes in in various 
cancer associated pathways, 
including but not limited to 
PI3K, MAPK, ER, cyclins, 
CDKs and CDK inhibitors,; to 
correlate with treatment response 
and progression 
Disease 
progression  
yilinglu@mdanderson.org 
 
 
4 
RNAseq 
 
NGS 
 
Exploratory 
Gene expression analysis:  To 
correlate baseline and treatment 
induced changes in breast cancer 
intrinsic subtypes (PAM50), and 
PI3K mRNA signature and 
expression of candidate genes 
with treatment response and 
benefit from adding copanlisib. 
RNA from 
snap-frozen 
tumor tissue 
Pre-
treatment, 
 
C1D15, 
 
Disease 
progression  
O 
 
 
O 
 
O 
MoCha, Frederick 
National Laboratory for 
Cancer Research (FNLCR) 
Dr. Chris Karlovich 
chris.karlovich@nih.gov 
5 
Tumor immune 
microenvironment 
(TIL) 
Multi-plex 
IHC 
(CD4+, 
CD8+, 
Exploratory 
To assess tumor immune 
microenvironment to correlate 
changes in infiltrating 
Unstained 
Slides from 
FFPE Tumor 
Tissue 
Pre-
treatment, 
 
C1D15, 
O 
 
 
O 
Washington University 
Center for Human 
Immunology and 


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30 
Priority 
Biomarker Name 
Assay and  
CLIA: 
Y/N 
Use in the Trial and Purpose 
Specimens 
Tested 
Collection 
Time Points 
Mandatory 
or 
Optional 
Assay Laboratory, Lab 
PI, and Lab PI Email 
CD3+ T 
cells) 
lymphocytes with treatment 
response 
 
Disease 
progression  
 
O 
Immunotherapy Programs 
(CHiiPs) Core 
Diane Bender, PhD and 
MT (ASCP) 
dianebender@wustl.edu  
Blood-based 
1 
Whole exome 
sequencing 
(WES) 
 
NGS 
CLIA:  N 
 
Integrated 
Germline control for WES 
Germline 
DNA from 
buffy coat in 
Streck 
cfDNA tubes 
Pre-treatment 
(Baseline) 
M 
MoCha, Frederick 
National Laboratory for 
Cancer Research 
(FNLCR) 
Dr. Chris Karlovich 
chris.karlovich@nih.gov 


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31 
Priority 
Biomarker Name 
Assay and  
CLIA: 
Y/N 
Use in the Trial and Purpose 
Specimens 
Tested 
Collection 
Time Points 
Mandatory 
or 
Optional 
Assay Laboratory, Lab 
PI, and Lab PI Email 
2 
ctDNA 
sequencing 
(PIK3CA, PTEN, 
ESR1 and others) 
NGS 
 
 
Exploratory 
To correlate ctDNA mutation 
profiles with tumor sequencing, 
and correlate baseline ctDNA 
mutations, particularly in 
components of the PI3K 
pathway with treatment 
response, and correlate early 
changes in ctDNA VAFs with 
PFS, assess emergent resistant 
mutations at progression 
Plasma from 
blood in 
Streck 
cfDNA tubes 
Pre-treatment 
 
C1D8,  
 
C1D15,  
 
C2D1,  
 
C4D1,  
 
C7D1 and 
then every 3 
cycles after),  
 
Disease 
progression 
M 
 
M 
 
M 
 
M 
 
M 
 
M 
 
 
 
M 
 
MoCha, Frederick 
National Laboratory for 
Cancer Research 
(FNLCR) 
Dr. Chris Karlovich 
chris.karlovich@nih.gov 


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32 
Priority 
Biomarker Name 
Assay and  
CLIA: 
Y/N 
Use in the Trial and Purpose 
Specimens 
Tested 
Collection 
Time Points 
Mandatory 
or 
Optional 
Assay Laboratory, Lab 
PI, and Lab PI Email 
3 
Plasma and serum 
proteomics and 
metabolomics 
Proteomic 
Analysis 
 
Exploratory 
To characterize circulating 
markers before and after PI3K 
inhibitor therapy to predict 
treatment response and 
resistance mechanisms 
Plasma from 
blood in 
EDTA tube  
& 
Serum from 
blood in red 
top tube 
Pre-treatment 
 
C1D8,  
 
C1D15,  
 
C2D1,  
 
C4D1,  
 
C7D1 and 
then every 3 
cycles after),  
 
Disease 
progression 
M 
 
M 
 
M 
 
M 
 
M 
 
M 
 
 
 
M 
 
Beth Israel Deaconess 
Medical Center Proteomics 
Core/ Broad Institute 
Dr. Gerburg Wulf  
gwulf@bidmc.harvard.edu 
 


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33 
Priority 
Biomarker Name 
Assay and  
CLIA: 
Y/N 
Use in the Trial and Purpose 
Specimens 
Tested 
Collection 
Time Points 
Mandatory 
or 
Optional 
Assay Laboratory, Lab 
PI, and Lab PI Email 
4 
Copanlisib 
Pharmacokinetics
** 
LC/MS/MS 
 
Exploratory 
To evaluate whether abemaciclib 
impacts the PK of copanlisib 
Plasma from 
blood in Li-
Heparin BD 
vacutainers 
(i) C1D1  
(a) Prior to 
copanlisib 
infusion and 
(b) After 
copanlisib 
infusion (10 
min, 1 hr, 2 
hr, 3 hr, 5 hr, 
24 hr [before 
C1D2’s 
abemaciclib 
and 
fulvestrant]) 
 
(ii) C1D15 
(a) Prior to 
copanlisib 
infusion and 
(b) After 
copanlisib 
infusion (10 
min, 1 hr, 2 
hr, 3 hr, 5 hr, 
24 hr [before 
C1D16’s 
abemaciclib 
and 
fulvestrant]) 
M 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
M 
 
 
NorthEast Bioanalytical 
Laboratories 
Dr. Vipin Agarwal 
vipin.agarwal@nebiolab.co
m 
 
5 
Abemaciclib 
Pharmacokinetics
** 
LC/ MS/ 
MS 
 
Exploratory 
 
To evaluate whether copanlisib 
impacts the PK of abemaciclib 
Plasma from 
blood in Li-
Heparin BD 
vacutainers 
(i) C1D15: 
Use the blood 
collected the 
same time 
points for the 
M 
 
 
 
 
NorthEast Bioanalytical 
Laboratories 
Dr. Vipin Agarwal 


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34 
Priority 
Biomarker Name 
Assay and  
CLIA: 
Y/N 
Use in the Trial and Purpose 
Specimens 
Tested 
Collection 
Time Points 
Mandatory 
or 
Optional 
Assay Laboratory, Lab 
PI, and Lab PI Email 
copanlisib 
PK. 
 
(ii) C1D22:  
Prior to, 1h, 
2h, 4h, 23h 
post the 
morning dose 
of 
abemaciclib 
 
 
 
M 
vipin.agarwal@nebiolab.co
m 
 
** PK samples are required for patients enrolled in the phase 1 portion.   
 


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35 
5.8 
Integrated Correlative Studies 
 
5.8.1 Whole Exome Sequencing (WES) 
 
Please refer to Section 2.5.1 for the testing of PIK3CA mutation, PTEN mutation as integrated 
biomarkers in this trial.  Mutation status of PIK3CA and PTEN will be based whole exome 
sequencing and mutations will be called based on established methodology by the MoCha 
Laboratory. Redacted reports of prior clinical tumor and blood sequencing results will also be 
collected. 
 
5.8.1.1 
Specimens Receipt and Processing at the EET Biobank 
 
Tumor tissue received in formalin will be paraffin-embedded.  All FFPE blocks will be 
sectioned to generate an initial hematoxylin and eosin (H&E)-stained slide, and for nucleic acid 
extractions, additional RNase-free slides. 
 
DNA and RNA will be co-extracted from tumor tissue. The nucleic acids will be analyzed to 
determine concentration and quality.  Aliquots of DNA will be shipped to the central 
sequencing laboratory for analysis. 
 
Germline DNA will be extracted from blood collected in Streck cfDNA tubes at pre-treatment 
(baseline) following plasma processing. DNA will be quantitated. An aliquot of germline DNA 
will be shipped to the central sequencing laboratory for analysis. 
 
5.8.1.2 
Sites Performing Correlative Study 
 
MoCha, Frederick National Laboratory for Cancer Research (FNLCR) under the direction of Dr. 
Chris Karlovich (chris.karlovich@nih.gov). 
 
5.8.1.3 
Shipment of Specimens from the EET Biobank to Site Performing Correlative Study  
 
Specimens will be shipped from the EET Biobank to: 
MoCha, Frederick National Laboratory for Cancer Research (FNLCR) 
Attn: Alyssa Chapman or Ruth Thornton 
1050 Boyles St. 
Bldg. 459, Rm. 125 
Frederick, MD 21702 
 
5.8.1.4 
Contact Information for Notification of Specimen Shipment 
 
Thomas Forbes, mochasamplereceiving@nih.gov. 
 
5.8.2 PTEN Immunohistochemistry 
 
5.8.2.1 
Specimens Receipt and Processing at the EET Biobank 
 


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36 
Upon receipt, archival FFPE tissue blocks and slides will be accessioned, barcoded, and stored at 
room temperature.  Tissue received in formalin will be processed and embedded in paraffin, and 
stored as an FFPE tissue block.  Prior to distribution, the EET Biobank will prepare unstained 
slides for this assay.  All FFPE blocks will be sectioned to generate an initial hematoxylin and 
eosin (H&E)-stained slide to be provided, either digitally or physically, with unstained slides.  
Unstained, charged, air-dried 4-micron slides will be labeled appropriately and shipped under 
ambient conditions to the MD Anderson Clinical Immunohistochemical Laboratory.  When 
possible, slides should be prepared on the planned day of shipping. 
 
5.8.2.2 
Sites Performing Correlative Study 
 
PTEN IHC will be performed under the CLIA CAP provision at MD Anderson Clinical 
Immunohistochemistry Laboratory. 
 
5.8.2.3 
Shipment of Specimens from the EET Biobank to Site Performing Correlative Study 
 
Specimens will be shipped from the EET Biobank to: 
Wei-Lien Wang, M.D. 
Department of Pathology 
The University of Texas MD Anderson Cancer Center 
1515 Holcombe Blvd Unit 085 
Room B3.4611 
Houston, TX 77030 
 
5.8.2.4 
Contact Information for Notification of Specimen Shipment 
 
Wei-Lien Wang, M.D., wlwang@mdanderson.org  
 
5.8.3 RPPA  
 
5.8.3.1 Specimens Receipt and Processing at the EET Biobank 
 
Upon receipt at the Biorepository, the snap-frozen tissue will be accessioned, barcoded, and 
banked in a liquid nitrogen vapor phase freezer until distribution for testing. 
 
Snap-frozen tissue will be shipped from the EET Biobank to the RPPA Core lab at MD 
Anderson. 
 
5.8.3.2 Site Performing Correlative Study 
 
This correlative study will be performed at MD Anderson RPPA Core. 
 
5.8.3.3 
Shipment of Specimens from the EET Biobank to Site Performing Correlative Study 
 
Specimens will be shipped from the EET Biobank to: 
MD Anderson Cancer Center 


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37 
6565 MD Anderson Blvd, Rm Z4.2040 
Houston, TX 77030 
 
5.8.3.4 
Contact Information for Notification of Specimen Shipment 
 
Doris Siwak, PhD, dsiwak@mdanderson.org  
 
5.9 
Exploratory/Ancillary Correlative Studies 
 
5.9.1 Gene expression by RNA Seq 
 
5.9.1.1 
Specimens Receipt and Processing at the EET Biobank 
 
Snap frozen tissue or fresh tumor in formalin (if insufficient material from snap frozen tissue) will 
be embedded and sectioned to generate an initial hematoxylin and eosin (H&E)-stained slide, 
and for nucleic acid extractions, additional RNase-free slides. 
 
RNA will be co-extracted from tumor tissue.  The nucleic acids will be analyzed to determine 
concentration and quality.  Aliquots of RNA will be shipped to the central sequencing 
laboratory for analysis. 
 
5.9.1.2 
Site Performing Correlative Study 
 
RNASeq will be performed at MoCha, Frederick National Laboratory for Cancer Research 
(FNLCR) under the direction of Dr. Chris Karlovich (chris.karlovich@nih.gov). 
 
5.9.1.3 
Shipment of Specimens from the EET Biobank to Site Performing Correlative Study  
 
Specimens will be shipped from the EET Biobank to: 
MoCha, Frederick National Laboratory for Cancer Research (FNLCR) 
Attn: Alyssa Chapman or Ruth Thornton 
1050 Boyles St. 
Bldg. 459, Rm. 125 
Frederick, MD 21702 
 
5.9.1.4 
Contact Information for Notification of Specimen Shipment 
 
Thomas Forbes, mochasamplereceiving@nih.gov. 
 
5.9.2 ctDNA sequencing 
 
5.9.2.1 
Specimens Receipt and Processing at the EET Biobank 
 
Whole blood collected in Streck cfDNA tubes will be centrifuged to process plasma and buffy 
coat.  Plasma aliquots will be stored in a -80°C freezer. 
 


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Note that buffy coat will be saved from the baseline Streck cfDNA tube for germline DNA.  
 
5.9.2.2 
Site Performing Correlative Study   
 
At the end of the study, plasma aliquots from cfDNA Streck tubes will be distributed for testing.  
ctDNA will be performed at MoCha, Frederick National Laboratory for Cancer Research 
(FNLCR) under the direction of Dr. Chris Karlovich (chris.karlovich@nih.gov). 
 
5.9.2.3 
Shipment of Specimens from the EET Biobank to Site Performing Correlative Study 
 
Specimens will be shipped from the EET Biobank to: 
MoCha, Frederick National Laboratory for Cancer Research (FNLCR) 
Attn: Alyssa Chapman or Ruth Thornton 
1050 Boyles St. 
Bldg. 459, Rm. 125 
Frederick, MD 21702 
 
5.9.2.4 
Contact Information for Notification of Specimen Shipment 
 
Thomas Forbes, mochasamplereceiving@nih.gov. 
 
5.9.3 Plasma and serum proteomics and metabolomics 
 
5.9.3.1 
Specimens Receipt and Processing at the EET Biobank 
 
Upon receipt at the Biorepository, serum and plasma will be accessioned, barcoded, and banked 
in a -80°C freezer. 
 
5.9.3.2 
Site Performing Correlative Study 
 
At the end of the study, the EET Biobank will distribute serum and plasma processed from 
EDTA.  This correlative study will be performed at the Broad Institute and other laboratories if 
needed. 
 
5.9.4 Copanlisib and abemaciclib pharmacokinetics 
 
5.9.4.1 
Specimens Receipt and Processing at Northeast Bioanalytical Laboratories 
 
Blood samples for PK analysis will be further processed and analyzed using MS using 
established protocol at the Northeast Bioanalytical Laboratories. 
 
5.9.4.2 
Site Performing Correlative Study   
 
This correlative study will be performed at Northeast Bioanalytical Laboratories. 
 


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39 
5.9.5 Tumor immune microenvironment (TILs) 
 
5.9.5.1 
Specimens Receipt and Processing at the EET Biobank 
 
Upon receipt, archival FFPE tissue blocks and slides will be accessioned, barcoded, and stored at 
room temperature.  Tissue received in formalin will be processed and embedded in paraffin, and 
stored as an FFPE tissue block.  Prior to distribution, the EET Biobank will prepare unstained 
slides for this assay.  All FFPE blocks will be sectioned to generate an initial H&E-stained slide 
to be provided, either digitally or physically, with unstained slides.  Unstained, charged, air-dried 
4-micron slides will be labeled appropriately and shipped under ambient conditions to the 
Washington University CHiiP Core or other performing laboratories  When possible, slides 
should be prepared on the planned day of shipping. 
 
5.9.5.2 
Site Performing Correlative Study   
 
IHC analysis will be performed to identify CD4+, CD8+, CD3+ T cells according to SOP 
established at the Washington University CHiiP Core.  This correlative study will be performed 
at Washington University CHiiP Core or other laboratories if needed. 
 
5.9.5.3 
Shipment of Specimens from the EET Biobank to Site Performing Correlative Study 
 
Specimens will be shipped from the EET Biobank to: 
Diane Bender, PhD and MT (ASCP) 
Washington University School of Medicine 
425 S. Euclid Ave, BJC-IH Room 7105 
St. Louis, MO 63110 
 
5.9.5.4 
Contact Information for Notification of Specimen Shipment 
 
Diane Bender, PhD and MT (ASCP), dianebender@wustl.edu  
 
 
6. TREATMENT PLAN 
 
This trial will start with the Phase 1 portion. At the start of study, this was intended to be 
followed by the randomized Phase 2 portion; however, due to Bayer’s withdrawal of the NDA 
for copanlisib, the study is closing with Amendment 8d and will not continue to Phase 2.  
 
Note that premenopausal women need to receive GnRH agonist goserelin 3.6 mg SC Q28 days 
on trial. Patients on Q3 month dosing of goserelin prior to study entry should switch to monthly 
dosing with their next scheduled dose.  
 
6.1 
Agent Administration 
 
Phase 1 
 


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40 
Treatment will be administered on an outpatient basis.  Reported AEs and potential risks are 
described in Section 10.  Appropriate dose modifications are described in Section 7.  No 
investigational or commercial agents or therapies other than those described below may be 
administered with the intent to treat the patient's malignancy.  
 
Potential dose levels for Part A: 
 
Dose Level 
Dose* 
Copanlisib 
Abemaciclib# 
Fulvestrant# 
Level 4 
60 mg IV on Days 1, 
8 and 15 
150 mg PO BID 
500 mg IM on 
C1D2, C1D16, and 
D1 of every cycle** 
thereafter 
Level 3 
45 mg IV on Days 1, 
8 and 15 
150 mg PO BID 
Level 2 
45 mg IV on Days 1, 
8 and 15 
100 mg PO BID 
Level 1 (Starting dose) 
45 mg IV on Days 1  
and 15 
100 mg PO BID 
Level -1 
30 mg IV on Days 1  
and 15 
100 mg PO BID 
IV = intravenous, PO = by mouth, BID = twice a day, IM = intramuscular 
 
*Doses are stated as exact dose in units (e.g., mg/m2, mcg/kg, etc.) rather than as a percentage. 
Additional dose levels may be tested after discussion with NCI and Bayer. 
**Cycle length is 28 days (4 weeks) 
 #The first dose (C1D1) of abemaciclib and fulvestrant is delayed to C1D2 following the 
24-h blood draw for copanlisib PK.  C1D15 fulvestrant dose is delayed to C1D16 
following the 24-h blood draw for copanlisib PK. 
 
Notes: 
• C1D16 dose of fulvestrant could be omitted in patients on stable doses of fulvestrant 
prior to enrolling on this study. 
• Copanlisib will be administered IV over 1 h (+/- 10 min).   
• Copanlisib infusion should be scheduled early in the morning since patients should take 
the morning dose of abemaciclib at least 1 h after completion of the copanlisib infusion.  
This will limit any potential pharmacokinetics interactions between the copanlisib and 
abemaciclib.  The evening dose of abemaciclib should be taken 12 h after the morning 
dose.  If it is not possible to schedule copanlisib early in the morning, it should be 
scheduled in such a way that the abemaciclib doses may be taken 12 h apart, and that at 
least 1 h elapses after the end of the copanlisib infusion before a dose of abemaciclib is 
taken (This is only applicable on days that PKs are drawn.  On non-PK days the patient 
may take their abemaciclib at home.). 
• Premenopausal women will receive GnRH agonist goserelin 3.6 mg SC Q28 days on 
trial. 
 


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41 
Potential dose levels for Part B: 
 
Dose Level 
Dose* 
Copanlisib 
Abemaciclib# 
Fulvestrant# 
Level 4b 
60 mg IV  
Days 1, 8 and 15 
150 mg PO BID 
5 days on and 2 days off 
each week 
500 mg IM on 
C1D2, C1D16, 
and D1 of 
every cycle** 
thereafter 
Level 3b 
45 mg IV  
Days 1, 8 and 15 
Level 2b 
45 mg IV  
Days 1, 8 and 15 
100 mg PO BID  
5 days on and 2 days off 
each week 
Level 1b (starting dose) 
45 mg IV  
Days 1 and 15 
IV = intravenous, PO = by mouth, BID = twice a day, IM = intramuscular 
 
*Doses are stated as exact dose in units (e.g., mg/m2, mcg/kg, etc.) rather than as a percentage. 
Cycle length is 28 days (4 weeks). 
 
 
#The first dose (C1D1) of abemaciclib and fulvestrant is delayed to C1D2 following the 
24-h blood draw for copanlisib PK.  C1D15 fulvestrant dose is delayed to C1D16 
following the 24-h blood draw for copanlisib PK.  
 
Notes: 
• C1D16 dose of fulvestrant could be omitted in patients on stable doses of fulvestrant 
prior to enrolling on this study.  
• Copanlisib will be administered IV over 1 h (+/- 10 min).   
• Copanlisib infusion should be scheduled early in the morning, since patients should take 
the morning dose of abemaciclib at least 1 h after completion of the copanlisib infusion.  
This will limit any potential pharmacokinetics interactions between the copanlisib and 
abemaciclib.  The evening dose of abemaciclib should be taken 12 h after the morning 
dose.  If it is not possible to schedule copanlisib early in the morning, it should be 
scheduled in such a way that the abemaciclib doses may be taken 12 h apart, and that at 
least 1 h elapses after the end of the copanlisib infusion before a dose of abemaciclib is 
taken. (This is only applicable on days that PKs are drawn.  On non-PK days the patient 
may take their abemaciclib at home.) 
• Premenopausal women will receive GnRH agonist goserelin 3.6 mg SC Q28 days on 
trial. 
 
Patients will be requested to maintain a medication diary (Appendix H) of each dose of 
abemaciclib.  The medication diary will be returned to clinic staff at the end of each course. 
 
 
6.1.1 Copanlisib 
 
Based on the company-sponsored studies with copanlisib in patients with oncologic 
malignancies, the RP2D of copanlisib monotherapy is 60 mg administered by 1 h (+/- 10 min) IV 
infusion weekly for 3 weeks (Days 1, 8, and 15) every 4 weeks.  The starting dose for copanlisib 


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42 
is 45 mg administered IV on Days 1 and 15 every 4 weeks. The use of corticosteroids as 
antiemetics prior to copanlisib administration is not allowed. 
 
Administer copanlisib as an IV infusion over one hour (+/- 10 min).  After administration, flush 
the line with 0.9 % sodium chloride to ensure complete dose is given.  No IV glucose 
preparations should be administered on the days of infusion.   
 
Patients who do not meet the pre-dose glucose level may be treated the same day or the next day 
with copanlisib if hyperglycemia is treated and the glucose level comes down to within the 
acceptable pre-dose level.  Patients whose glucose level does not come down to within the 
acceptable pre-dose level by the next day will not receive that dose of copanlisib.  Modification 
of doses of copanlisib due to hyperglycemia is listed in Section 7. 
 
Recommendations on meal timing on copanlisib infusion days 
 
Because of an inhibitory effect on PI3Kα-isoform, which is implicated in insulin metabolism, 
copanlisib infusions could be associated with temporarily increase in blood glucose.  Consuming 
meal in close proximity to copanlisib infusion may exacerbate a glucose level increase.  It is 
recommended that timing and content of caloric intake on infusion days is monitored by the 
investigators.  Consultation with diabetologist or endocrinologist is advised. 
 
The investigator may manage the timing of post-infusion meals based on the glucose profile 
during prior infusion days to minimize glucose increases.  This is in addition to glucose lowering 
medication.   On infusion days, a low carbohydrate diet is recommended.  The timing and 
content of meal intake, and additional glucose testing (if clinically indicated), should be managed 
and monitored by the investigators based on glucose response patterns during prior treatment 
days.  However, caloric restriction is not intended for the population under study.  Refer to 
Appendix D for glycemic indices of common foods.  
 
NOTE:  If patient needs to take a low glycemic meal, then glucose test should be taken prior to 
meal intake and at 1 and/or 2 h after the meal.  All glucose measurements, oral glucose lowering 
medication and/or insulin administration, if applicable, and meal timing will be collected as part 
of the clinical source documentation.  
 
NOTE:  Caloric intake and timing recommendations for diabetic patients who require insulin 
treatment prior to the infusion at any cycle visit should be managed by the investigator based on 
consultation with treating physician or diabetes/endocrinologist physician. 
 


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43 
Pre-dose glucose levels 
 
Period 
     Pre-dose glucose levels  
(first glucose measurement) 
 
  
Day 1 of 
cycle 1 
<160 mg/dL (fasting*) 
 < 200 mg/dL (non-fasting**)  
 
Subsequent 
infusions after 
Cycle 1 Day 1 
 
 <160 mg/dL (fasting*) 
 < 200 mg/dL (non-fasting**)  
 
*Fasting refers to a ≥ 8 h fast. 
**Non-fasting status includes any caloric intake such as meals and also juice, snacks, and 
other caloric intake not consistently called a meal. 
 
Cycle 1 Day 1:   
On infusion days a low carbohydrate diet is recommended, the timing and content of meal intake 
and additional glucose testing (if clinically indicated) is managed and monitored by the 
investigators based on glucose response patterns during prior treatment days. 
 
Day 1 of Cycle 2+: 
Fasting is not required before the start of the infusion. A low carbohydrate meal may be taken at 
least 4 h before the start of the study drug infusion for patients who have their infusions 
scheduled at a later hour, or due to their age or medical condition when fasting prior to infusion 
is not viable. 
 
Day 8 and Day 15 of each cycle: 
Fasting is not required before the start of infusion.  A low carbohydrate meal may be taken at 
least 4 h before the start of the study drug infusion for patients who have their infusions 
scheduled at a later hour or due to their age or medical condition when fasting prior to infusion is 
not viable. 
 
Glucose monitoring is required before and after each copanlisib infusion.  The glucose testing is 
scheduled as follows:   
• On Cycle 1 Day 1:  Glucose test is performed before starting copanlisib IV infusion at 
time 0 h, at the end of the infusion (1 h after starting infusion), 1 h after completing 
the infusion, and 2 h after completing the infusion.  For fasting requirements refer to 
the table above. 
• On Cycle 1 Days 8 and 15 and all subsequent cycles:  Glucose test is performed 
before starting copanlisib IV infusion at time 0 h.  Post-dose glucose monitoring after 
C1D1 is performed as clinically indicated at the investigator’s discretion. 
 
6.1.2 Abemaciclib 
 


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44 
Abemaciclib will be taken by mouth at approximately the same time twice a day continuously 
(Days 1-28 of each 28-day cycle) or on a 5 days on and 2 days off each week schedule (Days 1-
5, 8-12, 15-19, and 22-26 of each 28-day cycle).  Schedule will be dictated in Phase 1 by 
enrollment to Part A or Part B.   
Note that in Phase 1 Regimen, abemaciclib is delayed to Day 2 of Cycle 1. 
 
Abemaciclib will be taken at the assigned dose (for patients randomized to FAC) or at 150 mg 
BID (for patients randomized to FA). 
 
If a patient misses a day’s dose entirely, he/she must be instructed not to make it up at the next 
dose but just take her regular dose at the next assigned time.  If a patient vomits any time after 
taking a dose, she must be instructed not to retake the dose but resume subsequent dosing at the 
next assigned time.  If a patient inadvertently takes an extra dose during the day, she must be 
instructed to not take the next day’s dose.  Patients are to swallow tablets whole (do not chew, 
crush, or spit them prior to swallowing). 
 
Instruct patients at the first sign of loose stools to initiate antidiarrheal therapy such as 
loperamide (4mg PO x 1, then 2mg after each loose stool, maximum 16 mg/day; loperamide 
prophylaxis per physician discretion is allowed), increase oral fluids, and notify their healthcare 
provider. 
 
6.1.3 Fulvestrant 
 
Fulvestrant will be administered at a dose of 500 mg as two IM injections (250 mg each into 
each buttock) on Days 1 and 15 of Cycle 1, and then on Day 1 of every cycle thereafter.  
Note that in the Phase 1 Regimen and in the first 4 patients randomized to FAC in the Phase 2 
Regimen, fulvestrant administration is delayed to Days 2 and 16 of Cycle 1. Note that C1D16 
dose of fulvestrant could be omitted in patients on stable dose of fulvestrant prior to enrolling to 
the study.   
 
6.2 
Definition of Dose-Limiting Toxicity  
 
6.2.1 Dose Limiting Toxicities (DLTs) 
 
Dose-limiting toxicity is defined as adverse events occurring during the first 28 days of treatment 
that are determined to be at least possible related to treatment using NCI-CTCAE v5.0 and that 
meet the following criteria: 
• Any death not clearly due to the underlying disease or extraneous causes 
• Hematology: 
o Febrile neutropenia 
o Grade ≥4 thrombocytopenia (regardless of duration) 
o Grade ≥3 thrombocytopenia with bleeding  
o Grade 4 neutropenia lasting more than 7 days 
• Hyperglycemia: persistent occurrence of blood glucose >250 mg/dL (Grade ≥3) for 
72 hours despite optimal glucose lowering therapy. 
• Grade 3 or above non-hematologic toxicity with the following exceptions:   


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45 
o Transient infusion-related hyperglycemia lasting <7 days 
o Transient infusion-related hypertension responsive to intervention. 
o Alopecia of any grade 
o Grade ≥3 fatigue < 1 week  
o Grade ≥3 amylase or lipase elevation NOT associated with symptoms 
or clinical manifestations of pancreatitis 
• Grade ≥3 nausea/vomiting or diarrhea >72 hours with adequate antiemetics and other 
supportive care. 
• Hy’s law  
• Grade ≥3 electrolyte abnormality that lasts >72 hours, unless the patient has clinical 
symptoms, in which case all grade 3+ electrolyte abnormality regardless of duration 
should count as a DLT  
• For patients with hepatic metastases, AST or ALT >8x ULN or AST or ALT >5x 
ULN for ≥14 days. 
• Failure to receive 2 copanlisib infusions during the first 28 days 
• Failure to receive at least 3 of the 4 weeks of abemaciclib scheduled doses for the first 
28 days  
• All AEs of the specified grades should count as DLTs except those that are clearly 
and incontrovertibly due to disease progression or extraneous causes.  
 
Note that patients who have major protocol deviations (as determined by the study chair and the 
study statistician) in the dose and/or schedule of the study drugs during Cycle 1 are not evaluable 
for DLT. These patients may be evaluable for overall AE and efficacy endpoints per statistical 
section.  
 
6.2.2 Dose Escalation Criteria 
 
Dose escalations/de-escalations will proceed continuously based on the CRM estimated DLT 
rate at each dose level (see Section 9).   
 
Management and dose modifications associated with the above adverse events are outlined in 
Section 7. 
 
6.3 
General Concomitant Medication and Supportive Care Guidelines 
 
Because there is a potential for interaction of copanlisib with other concomitantly administered 
drugs, the case report form must capture the concurrent use of all other drugs, over-the-counter 
medications, or alternative therapies.  The Principal Investigator should be alerted if the patient is 
taking any agent known to affect or with the potential for drug interactions.  The known potential 
targets for drug interaction are CYP3A4 inducers or inhibitors, as well as drugs modulating 
MATE2K function.  Concomitant use of medications listed in Appendix B is prohibited while on 
copanlisib.  The study team should check a frequently-updated medical reference for a list of 
drugs to avoid or minimize use of.  Appendix C (Patient Wallet Card) should be provided to 
patients if available. 
 
• Antihistamine administration, such as daily oral cetirizine, is required during the 


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46 
entire course of treatment with copanlisib to decrease the incidence and severity of 
rash. 
 
• Sensitive substrates of the renal drug transporter MATE2K (e.g., metformin) need to be 
used with caution.  Metformin should be interrupted for 48 h after receiving iodinated 
contrast media.  Please see prescribing information for further information. 
 
• Patients taking medications with narrow therapeutic indices should be proactively 
monitored if these medications cannot be avoided.  These medications may include, but 
are not limited to quinidine, cyclosporine, and digoxin. 
 
• Systemic corticosteroid therapy at a daily dose higher than 15 mg prednisone or 
equivalent is not permitted while on study.  Previous corticosteroid therapy must be 
stopped or reduced to the allowed dose at least 7 days prior to the CT/MRI screening.  If 
a patient is on chronic corticosteroid therapy, corticosteroids should be de-escalated to 
the maximum allowed dose before the screening.  Patients may be using topical or 
inhaled corticosteroids.  Short-term (up to 7 days) systemic corticosteroids above 15 mg 
prednisolone or equivalent will be allowed for the management of acute conditions (e.g., 
treatment non-infectious pneumonitis).  The use of corticosteroids as antiemetics prior to 
copanlisib administration will not be allowed. 
 
• Patients should stop using herbal medications at least 7 days prior to the first dose of 
copanlisib.  Herbal medications include, but are not limited to St. John’s Wort, Kava, 
ephedra, gingko biloba, dehydroepiandrosterone (DHEA), yohimbe, saw palmetto, black 
cohosh, and ginseng.   
 
• Prophylactic antiemetics may be administered according to standard practice.  The 
routine use of standard antiemetics, including 5-HT3 blockers such as granisetron, 
ondansetron, or equivalent agents, is allowed as needed. 
 
• Palliative radiation or other measures to non-target lesions for pain control is allowed 
while on study after consult with study PI.  Patients should hold abemaciclib and 
copanlisib during radiation course. 
 
While taking abemaciclib, patients should be instructed to avoid food or drugs that are known 
strong CYP3A4 inhibitors or inducers, including grapefruit and grapefruit juice.  Please refer to 
Appendix B for a list of prohibited medications. 
 
Patients should also not take any medications with the potential to prolong the QT interval.   
 
6.4 
Duration of Therapy 
 
In the absence of treatment delays due to adverse event(s), treatment may continue indefinitely 
until one of the following criteria applies: 
 
• 
Disease progression 


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47 
• 
Intercurrent illness that prevents further administration of treatment 
• 
Unacceptable adverse event(s) 
• 
Patient decides to withdraw from the study 
• 
General or specific changes in the patient's condition render the patient unacceptable 
for further treatment in the judgment of the investigator 
• 
Clinical progression 
• 
Patient non-compliance 
• 
Pregnancy 
o All women of child bearing potential should be instructed to contact the 
investigator immediately if they suspect they might be pregnant (e.g., missed 
or late menstrual period) at any time during study participation. 
o The investigator must immediately notify CTEP in the event of a confirmed 
pregnancy in a patient participating in the study. 
• 
Termination of the study by sponsor 
• 
The drug manufacturer can no longer provide the study agent 
 
The reason(s) for protocol therapy discontinuation, the reason(s) for study removal, and the 
corresponding dates must be documented in the Case Report Form (CRF). 
 
6.5 
Duration of Follow-Up 
 
Patients will be followed every 3 months for 5 years after removal from study or until death, 
whichever occurs first.  Patients removed from study for unacceptable adverse event(s) will be 
followed until resolution or stabilization of the adverse event. 
 
 
7. DOSING DELAYS/DOSE MODIFICATIONS 
 
7.1 
Copanlisib  
 
Dose Levels for Dose Modification  
Copanlisib 
1 
60 mg IV days 1, 8, 15 
-1 
45 mg IV days 1, 8, 15 
-2 
45 mg IV days 1, 15 
-3 
30 mg IV days 1, 15 
 
If a dose reduction beyond 30 mg on D1 and 15 of each cycle is required, the patient will 
discontinue copanlisib. 
 
7.1.1 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 Appendix E and Appendix F.  
Continuing occurrence of post-infusion blood glucose >400 mg/dL, based on repeated laboratory 


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48 
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 was not met. 
• 
Dose re-escalation is allowed when a patient has achieved controlled glucose levels per 
investigator’s judgment. 
• 
Persistent occurrence of post-infusion blood glucose >400 mg/dL based on laboratory 
analysis which occurred at the lowest dose level despite optimal glucose lowering therapy 
(after at least one cycle of treatment) with consultation of a diabetes specialist requires 
permanent discontinuation of the study drug.  Grade 4 hyperglycemia for any duration 
requires discontinuation of copanlisib. 
 
7.1.2 Treatment of blood pressure increases associated with copanlisib 
 
It is important that patients with pre-existing arterial hypertension adhere to their regular 
medication schedule and take their usual doses on the days of study drug infusion.  
 
The management of acute blood pressure (BP) increases following copanlisib will need to be 
individualized for each patient, but experience from a Bayer-sponsored Phase 1 study with 
copanlisib has suggested the benefit of dihydropyridine calcium channel blockers (i.e., amlodipine, 
felodipine).  Topical nitrates should also be considered.  In general, it is advisable for sites to be 
prepared, so that anti-hypertensive medication is readily available in case of need.  
 
In the event of the occurrence of arterial hypertension ≥150/90 mmHg (either systolic or diastolic) 
during infusion of copanlisib at any cycle, antihypertensive treatment is suggested as indicated in 
Appendix G.  In the event of the occurrence of grade 3 arterial hypertension (≥160/100 mmHg) 
during infusion of copanlisib, the infusion should be interrupted, and anti-hypertensive treatment 
as suggested above is administered.  Infusion can be resumed when BP has returned to <150/90 
mmHg (both systolic and diastolic). 
 
Blood pressure measurement on treatment days 
 
Blood pressure will be measured every 5-10 min prior to each copanlisib dose (no more than 4 
measurements) until there are two consecutive results <150/90 mmHg (both systolic and diastolic).  
If blood pressure is ≥150/90 mmHg, the investigator can consider a medical intervention or 
delaying the infusion of study drug.  The patient should rest for 5-10 min before blood pressure is 
recorded. 
 
On infusion days, blood pressure will be measured at 0 h (pre-dose), 30 min (mid-infusion), 60 
min (end of infusion), and 1 h and 2 h after the end of infusion. In patients who have not had any 
episodes of post infusion blood pressures ≥150/90 mmHg for at least 2 consecutive cycles of 
treatment, the blood pressure monitoring at 1h and 2h could be omitted at the discretion of the 
treating physician.  
 
NOTE: A window of ±10 min is allowed for all BP measurements, except for pre-dose (0 h) 


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49 
measurement. 
 
7.1.3 Non-infectious pneumonitis  
 
The investigator is requested to differentiate between non-infectious pneumonitis, and infectious 
pneumonitis (viral, bacterial, or fungal), aspiration pneumonitis, or other pneumonitis clearly not 
due to a potential hypersensitivity reaction to the copanlisib infusion; and provide the basis for 
his/her assessment that it is infectious or other, as appropriate.  The investigator is requested to 
report with the most specific clinical terms to describe the condition, not simple “pneumonitis”. 
 
In the event of suspected non-infectious pneumonitis, modify copanlisib treatment as per table 
below. 
 
Dose adjustment for non-infectious pneumonitis  
Suspected or confirmed 
NIP per CTCAE 
Action Taken 
Re-treatment dose after 
recovery 
Grade 1 
No Change 
NA 
Grade 2 
Dose Interruption Until 
recovery to ≤grade 1 
Decrease dose to the next 
lowest dose levela 
Grade 2 second re-occurrence Permanent Discontinuation 
NA 
Grade 3 
Permanent Discontinuation 
NA 
Grade 4 
Permanent Discontinuation 
NA 
NA = Not applicable; NIP = Non-infectious pneumonitis; CTCAE = Common Terminology Criteria for Adverse 
Events.   
a: Not applicable for 45 mg dose level.  No re-escalation is allowed after the dose reduction.   
The lowest dose level is 45 mg; if a patient is already on the 45 mg dose level and cannot tolerate treatment study 
treatment will be discontinued permanently 
 
7.1.4 Hematologic Toxicities 
 
Toxicities 
Adverse Reaction Grade 
Management 
Neutropenia 
 
ANC Grade 3 
Maintain or hold copanlisib at 
physician discretion, monitor 
ANC weekly. 
ANC Grade 4 
Hold copanlisib, monitor 
ANC weekly until ANC 
recovers to grade 3 or lower. 
If ANC grade 4 recurs, 
reduce copanlisib by 1 dose 
level. 
Thrombocytopenia 
Less than 25k 
Hold copanlisib; resume 
when platelet levels return to 
75k or greater.  If recovery 
occurs within 21 days, reduce 
one dose level.  If recovery 
does not occur within 21 


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50 
days, discontinue copanlisib. 
 
7.1.5 Other severe and non-life-threatening toxicities 
 
Toxicities 
Adverse 
Reaction Grade 
Management 
Other severe and non-life-
threatening toxicities 
Grade 3 
Hold copanlisib until toxicity is resolved 
to at least grade 1, then reduce by 1 dose 
level.  
 
7.1.6 Retreatment Criteria for Copanlisib 
 
A new cycle of treatment with copanlisib may start only if: 
 
• 
ANC ≥500/mcL 
• 
Platelet count ≥75,000/mcL 
• 
Glucose less than 160 mg/dL fasting or 200 mg/dL non-fasting.  
• 
Arterial blood pressure <150/90 mmHg (both systolic and diastolic) 
• 
Copanlisib related non-hematologic toxicities have returned to baseline or grade ≤1 
severity (or, at the investigator’s discretion, grade ≤2 if not considered a safety risk for 
the patient) 
 
Criteria for dose interruption for copanlisib within cycle:  
 
• 
Glucose >160, may start if controlled on the day or the day after. 
• 
BP >150/90, may start if controlled with antihypertensives. 
• 
Copanlisib related non-hematologic toxicities have not returned to baseline or grade ≤1 
severity (or, at the investigator’s discretion, grade ≤2 if not considered a safety risk for 
the patient) 
 
Note: If dose interruption for copanlisib is necessary, it is preferred that the dose of copanlisib be 
delayed rather than missed to maximize copanlisib dosing.  However, copanlisib dosing schedule 
could be adjusted in subsequent cycles so to align with the fulvestrant administration, with the 
condition that no more than 2 consecutive weekly doses of copanlisib are administered. Cycle 
length is 28+/- 7 days. A maximum duration to hold copanlisib is 3 consecutive weeks including 
the scheduled weeks off despite dose reduction to the lowest dose level.  
 
7.2 
Abemaciclib  
 
Patients will be monitored for toxicity and the dose of abemaciclib may be adjusted as indicated 
in the dose modification table below. 
 
Dose Levels for Dose Modification 
Abemaciclib Dose 
2 
150 mg BID1 
1 
100 mg BID1 
-1 
50 mg BID continuously 


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51 
1 patients who start on a 5 days on and 2 days off schedule will continue the same intermittent 
schedule of abemaciclib at 100 mg or 150 mg dosing.   
 
Recommended dose reductions for abemaciclib are detailed in the table above.  Doses may be 
held as needed for toxicity resolution during a cycle.  Cycle length is dictated by that of 
copanlisib. 
 
7.2.1 Abemaciclib Dose Modifications – Hematologic Toxicities 
 
Adverse Reaction Grade 
Management 
Grade 1 or 2 
No dose modification 
Grade 3 
Hold dose until toxicity resolves to ≤grade 2.  
Dose reduction is not required. 
Grade 3 recurrent, or grade 4 
Hold dose until toxicity resolves to ≤grade 2.  
Resume at next lower dose. 
 
7.2.2 Abemaciclib Dose Modification - Diarrhea 
 
At the first sign of loose stools, start treatment with antidiarrheal agents and increase intake of 
oral fluids. 
Adverse Reaction Grade 
Management 
Grade 1 
No dose modification 
Grade 2 
If toxicity does not resolve within 24 h to 
≤grade 1, hold dose until resolution.  No dose 
reduction is required. 
Grade 2 that persists or recurs after resuming 
the same dose despite maximal supportive 
measures 
Hold dose until toxicity resolves ≤grade 1.  
Resume at next lower dose. 
Grade 3 or 4 or requires hospitalization 
Hold dose until toxicity resolves to ≤grade 1.  
Resume at next lower dose. 
 
7.2.3 Abemaciclib Dose Modification – Hepatoxicity 
 
Adverse Reaction Grade 
Management 
Grade 1 (>ULN-3.0 x ULN) or grade 2 (>3.0-
5.0 x ULN), WITHOUT increase in total 
bilirubin above 2 x ULN 
No dose modification 
Persistent or recurrent grade 2, or grade 3 (>5-
20 x ULN), WITHOUT increase in total 
bilirubin above 2 x ULN 
Hold dose until toxicity resolves to ≤grade 1.  
Resume at next lower dose. 
Elevation in AST and/or ALT >3 x ULN 
WITH total bilirubin >2 x ULN, in the absence 
of cholestasis 
Discontinue abemaciclib 
Grade 4 (>20.0 x ULN) 
Discontinue abemaciclib 
 


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52 
7.2.4 Abemaciclib Dose Modification – Other Toxicities 
 
Adverse Reaction Grade 
Management 
Grade 1 or 2  
No dose modification 
Persistent or recurrent grade 2 toxicity that 
does not resolve with maximal supportive 
measures within 7 days to baseline or grade 1 
Hold dose until toxicity resolves to ≤grade 1.  
Resume at next lower dose. 
Grade 3, or grade 4  
Hold dose until toxicity resolves to ≤grade 1.  
Resume at next lower dose. 
 
If these conditions are not met, fulvestrant and copanlisib may be continued but treatment with 
abemaciclib must be delayed by one week.  If, after a one-week delay, all toxicities have 
recovered within the limits described above, treatment with abemaciclib can be resumed. 
 
If the patient has not recovered after 3 weeks despite dose reduction to the lowest dose level, 
treatment with abemaciclib will be permanently discontinued. 
 
7.3 
Fulvestrant  
 
No dose adjustments are permitted for fulvestrant, but interruptions are allowed at the discretion 
of the treating physician.  
 
 
8. PHARMACEUTICAL INFORMATION 
 
A list of the AEs and potential risks associated with the investigational or commercial agents 
administered in this study can be found in Section 10.1. 
 
8.1 
CTEP IND Agent 
 
8.1.1 Material Safety Data Sheets 
 
The current versions of the material safety data sheets (MSDS or SDS) for PMB-distributed 
agents will be accessible to site investigators and research staff through the PMB AURORA 
application. Questions about MSDS access may be directed to the PMB at 
PMBAfterHours@mail.nih.gov or by using the dialog function in AURORA to communicate 
with PMB staff. 
 
8.1.2 Copanlisib (NSC 784727) 
 
Chemical Name or Amino Acid Sequence:  2-amino-N-[7-methoxy-8-(3-morpholin-4-
ylpropoxy)-2,3-dihydroimidazo[1,2-c]quinazolin-5-yl]pyrimidine-5-carboxamide 
dihydrochloride 
 
Other Names: BAY 80-6946 (free base); BAY 84-1236 (dihydrochloride salt) 
 


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53 
Classification:  Pan class I PI3K inhibitor  
 
Molecular Formula:  C23H28N8O4 2HCl  
M.W.:  553.45 g/mol 
 
Approximate Solubility:  Freely soluble in water and 0.1 M hydrochloric acid (HCl) 
 
Mode of Action:  Copanlisib is a pan class I PI3K inhibitor with potent activity against the delta 
and alpha isoforms.  Class I PI3K is downstream of most cancer associated tyrosine kinase 
growth factor receptors or mesenchymal epithelial transition factor.  PI3K delta has a critical role 
in regulating downstream events of the B-cell receptor. 
 
Description:  The powder is white to yellow solid substance. 
 
How Supplied:  Copanlisib is supplied by Bayer HealthCare AG and distributed by the 
Pharmaceutical Management Branch, CTEP, DCTD, NCI.  The agent is available as a lyophilized 
product containing 60 mg of copanlisib in a 6 mL injection vial.  The excipients are mannitol, 
sodium hydroxide, citric acid, and water for injection. 
 
Preparation:  Using appropriate aseptic technique, reconstitute the 60 mg vial of copanlisib with 
4.4 mL of 0.9% sodium chloride resulting in a concentration of 15 mg/ml.  Gently shake for 30 
seconds and allow the vial to stand for 1 minute to let bubbles rise to the surface.  Repeat if 
undissolved substance is still present.  The reconstituted solution may be slightly yellow and should 
be clear prior to being withdrawn from the vial.  Withdraw the appropriate volume of the 
reconstituted solution and further dilute by adding to a 50-200 mL sterile 0.9% sodium chloride bag.  
Mix well by inverting.  
 
Storage:  Store intact vials between 2°C and 8°C.  
 
If a storage temperature excursion is identified, promptly return copanlisib to between 
2°C and 8°C and quarantine the supplies.  Provide a detailed report of the excursion 
(including documentation of temperature monitoring and duration of the excursion) to 
PMBAfterHours@mail.nih.gov for determination of suitability. 
 
Stability:  Stability studies of the vials are ongoing.  The diluted solution should be used 
immediately (stored up to 4 hours at room temperature including preparation and administration).  If 
the diluted solution for infusion is not used immediately, it is stable for up to 24 hours refrigerated 
between 2 °C and 8 °C.  It takes approximately 60 minutes for the diluted solution to return to room 
temperature after refrigeration.  The infusion should be completed within 24 hours of preparation. 
 
CAUTION:  The single-use lyophilized dosage form contains no antibacterial preservatives.  
Therefore, it is advised that the reconstituted product be discarded 4 hours after initial entry.  
 
Route of Administration:  IV infusion  
 
Method of Administration:  The diluted solution for infusion is administered IV over 1 hour.  
After administration, flush the line to ensure complete dose is given.  No IV glucose preparations 


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should be administered on the days of infusion. 
 
Potential Drug Interactions:  In vitro, copanlisib is metabolized primarily via CYP3A4 and to a 
minor extent by CYP1A1.  It is also a substrate of P-gp and BCRP, but not a substrate of MATEs, 
OCTs, OATs, or OATPs.  Concomitant administration with strong inhibitors or inducers of 
CYP3A4 should be avoided.  Use caution when administered with strong inhibitors and inducers of 
CYP1A1, P-gp, and BCRP. 
 
In vitro, copanlisib is a strong inhibitor of MATE2K.  Copanlisib and its metabolite M-1 have a low 
risk for inhibition or induction of CYP isoforms, inhibition of UGT isoforms, and inhibition of 
dihydropyrimidine dehydrogenase.  Copanlisib does not inhibit P-gp, BCRP, OATP1B1, 
OATP1B3, OAT1, OAT3, OCT1, OCT2, bile salt export pump (BSEP), MRP2, or MATE1 at 
therapeutic 60 mg dose plasma concentrations.  Use caution when administered with sensitive drug 
substrates of MATE2K.   
 
Copanlisib is not an inducer of CYP1A2, 2B6, and 3A. 
 
Special Handling:  Copanlisib is not genotoxic in vitro or in vivo.  Copanlisib is expected to 
adversely affect male and female reproduction. 
 
Patient Care Implications:  Females of child-bearing potential and male patients must use 
adequate contraception while receiving copanlisib and for 1 month after last dose of copanlisib.  Do 
not breastfeed during treatment with copanlisib and for at least 1 month after the last dose of 
copanlisib. 
 
Hypertension is frequently observed within the first 3 h after start of infusion and hyperglycemia 
is frequently observed persisting for approximately 1-3 days after study drug administration.  
Refer to protocol document for treatment and monitoring guidelines. 
 
Availability 
 
Copanlisib is an investigational agent supplied to investigators by the Division of Cancer 
Treatment and Diagnosis (DCTD), NCI. 
 
Copanlisib is provided to the NCI under a Collaborative Agreement between the Pharmaceutical 
Collaborator and the DCTD, NCI (see Section 13.5). 
 
8.1.3 Agent Ordering and Agent Accountability 
 
8.1.3.1 
NCI supplied agents 
 
NCI-supplied agents may be requested by eligible participating Investigators (or their authorized 
designee) at each participating institution.  The CTEP-assigned protocol number must be used 
for ordering all CTEP-supplied investigational agents.  The eligible participating investigators at 
each participating institution must be registered with CTEP, DCTD through an annual 
submission of FDA Form 1572 (Statement of Investigator), NCI Biosketch, Agent Shipment 


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Form, and Financial Disclosure Form (FDF).  If there are several participating investigators at 
one institution, CTEP-supplied investigational agents for the study should be ordered under the 
name of one lead participating investigator at that institution. 
 
Subjects must be enrolled prior to submitting the agent request to PMB.   
 
Submit agent requests through the PMB AURORA application.  Access to AURORA requires 
the establishment of credentials necessary to access secure NCI Clinical Oncology Research 
Enterprise (CORE) systems and the maintenance of an “active” account status, a “current” 
password, and active person registration status.  For questions about drug orders, transfers, 
returns, or accountability, call or email PMB any time.  Refer to the PMB’s website for specific 
policies and guidelines related to agent management.   
 
8.1.3.2 
Agent Inventory Records  
 
The investigator, or a responsible party designated by the investigator, must maintain a careful 
record of the receipt, dispensing and final disposition of all agents received from the PMB using 
the appropriate NCI Investigational Agent (Drug) Accountability Record (DARF) available on 
the CTEP forms page.  Store and maintain separate NCI Investigational Agent Accountability 
Records for each agent, strength, formulation and ordering investigator on this protocol. 
 
Product Quality Complaint (PQC): A product quality complaint is defined as any suspicion of a 
product defect related to a potential quality issue during   manufacturing, packaging, release 
testing, stability monitoring, dose preparation, storage or distribution of the product, or delivery 
system.  Not all PQCs involve a study subject.  Lot or batch numbers are of high significance and 
need to be provided where and when possible. PQC must be reported to the PMB as soon as the 
PQC is identified. Report PQC to PMB at PMBAfterHours@mail.nih.gov or by using the dialog 
function in AURORA to communicate with PMB staff. 
 
8.1.4 Investigator Brochure Availability 
 
The current versions of the IBs for the agents will be accessible to site investigators and research 
staff through the PMB AURORA application.  Access to AURORA requires the establishment of 
credentials necessary to access secure NCI Clinical Oncology Research Enterprise (CORE) 
systems and the maintenance of an “active” account status, a “current” password and active 
person registration status.  Questions about IB access may be directed to the PMB IB 
Coordinator via email. 
 
8.1.5 Useful Links and Contacts 
• CTEP Forms, Templates, Documents:  http://ctep.cancer.gov/forms/ 
• NCI CTEP Investigator Registration:  RCRHelpDesk@nih.gov 
• PMB policies and guidelines: 
http://ctep.cancer.gov/branches/pmb/agent_management.htm  
• 
PMB AURORA application:  https://ctepcore.nci.nih.gov/aurora/login  
• CTEP Identity and Access Management (IAM) account: 


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https://ctepcore.nci.nih.gov/iam/  
• CTEP IAM account help:  ctepreghelp@ctep.nci.nih.gov  
• IB Coordinator:  IBCoordinator@mail.nih.gov  
• PMB email:  PMBAfterHours@mail.nih.gov 
• PMB phone and hours of service: (240) 276-6575 Monday through Friday 
between 8:30 am and 4:30 pm (ET) 
 
8.2 
Commercial Agents 
 
8.2.1 Abemaciclib (NSC 783671) 
 
Chemical Name:  2-Pyrimidinamine, N-[5-[(4-ethyl-1-piperazinyl)methyl]-2-pyridinyl]-5-
fluoro-4-[4-fluoro-2-methyl-1-(1-methylethyl)-1H-benzimidazol-6-yl] 
 
Other Names:  Verzenio™. 
 
Classification:  Cyclin-dependent kinase 4 and 6 (CDK4 and CDK6) inhibitor. 
 
Molecular Formula:  C27H32F2N8 
 
 
M.W.:  506.59 g/mol 
 
Mode of Action:  Abemaciclib inhibits CDK4 and CDK6 pending phosphorylation of 
retinoblastoma protein (Rb), cell cycle progression and cell proliferation in ER+ breast cancer.   
 
Product description:  Abemaciclib is available as immediate release tablets packaged in blister 
packs containing 14 tablets of the following strengths:   
• 150 mg tablets are oval yellow tablet with “Lilly” debossed on one side and “150” on the 
other side. 
• 100 mg tablets ate oval white to practically white tablet with “Lilly” debossed on one 
side and “100” on the other side. 
• 50 mg tablets are oval beige tablet with “Lilly” debossed on one side and “50” on the 
other. 
 
Storage requirements:  Store at 20°C to 25°C (68°F to 77°F); excursions permitted to 15°C to 
30°C (59°F to 86°F). 
 
Route of administration:  Abemaciclib is taken by mouth.  Patients should be instructed to 
swallow tablets whole and not to chew, crush, or split them prior to swallowing.  No tablets 
should be ingested if it is broken, cracked, or otherwise not intact.  Patients should take 
abemaciclib with or without food and should be encouraged to take their dose at approximately 
the same times each day. 
 
Agent Ordering:  Abemaciclib is commercially available and will be billed to the patient or her 
insurance. 
 
8.2.2 Fulvestrant (NSC 719276) 
 


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57 
Chemical Name:  7-alpha-[9-(4,4,5,5,5-penta fluoropentylsulphinyl) nonyl]estra-1,3,5-(10)- 
triene-3,17 beta-diol. 
 
Other Names:  Faslodex®. 
 
Classification:  Cyclin-dependent kinase 4 and 6 (CDK4 and CDK6) inhibitor. 
 
Molecular Formula:  C32H47F5O3S  
 
M.W.:  606.77 g/mol 
 
Mode of Action:  Fulvestrant is an ER antagonist that binds to the ER in a competitive manner 
with affinity comparable to that of estradiol and downregulates the ER protein in human breast 
cancer cells. 
 
Product description:  Fulvestrant is indicated for the treatment of hormone receptor positive 
metastatic breast cancer in postmenopausal women with disease progression following 
antiestrogen therapy, and the treatment of hormone receptor positive, HER2-negative advanced 
or metastatic breast cancer in combination with palbociclib in women with disease progression 
after endocrine therapy.  Fulvestrant is available as two 5 mL clear neutral glass (type 1) barrels, 
each containing 250 mg/5 mL of fulvestrant solution for IM injection and fitted with a tamper 
evident closure.  The solution for injection is a clear, colorless to yellow viscous liquid. 
 
Storage requirements:  Refrigerate, 2°-8°C (36°-46°F).  To protect from light, store in the 
original carton until time of use. 
 
Route of administration:  Fulvestrant will be given as two IM injections (one in each buttock). 
 
Agent Ordering:  Fulvestrant is commercially available and will be billed to the patient or her 
insurance. 
 
 
9. STATISTICAL CONSIDERATIONS 
 
9.1 
Study Design/Endpoints 
 
The study originally consisted of a Phase 1 portion consisting of two parts (Part A followed by 
Part B) and a randomized Phase 2 portion. Between June 2020 and February 2021, 10 patients 
were enrolled to 2 dose levels in Phase 1 (Dose Level 1 and Dose Level 2).  Review of the 
associated data led to Amendment 6, which designated the original dosing schema for Phase 1 as 
Phase 1 Part A and added a second dosing schema for Phase 1 (Part B) to test an alternative 
schedule of abemaciclib (5 days on and 2 days off, each week) in combination with fulvestrant 
and copanlisib.  
 
The phase 1 trial is designed to determine the RP2D for the randomized Phase 2 part.  The CRM 
(O’Quigley et al., 1990; Lee & Cheung, 2009; Lee & Cheung, 2011) will be used for the Phase 1 
part (both Parts A and B, each having a maximum of 4 dose levels to be tested, see Section 6.1).  
The Phase 1 portion started at Dose Level 1 in the Dose Level Table for Part A in Section 6.1, 


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58 
then escalated to Dose Level 2 prior to Amendment 6.  Part A was initially conducted with 7 
patients tested on Dose Level 1 and 3 patients on Dose Level 2. Based on the AE profile of the 
10 enrolled patients in Part A, Part A was stopped at Dose Level 2 and Part B was added to test a 
maximum of 4 dose levels with abemaciclib administered at an intermittent schedule of 5-days 
on and 2-days off each week after the activation of Amendment 6. The MTD or RP2D for the 
randomized phase is defined as the dose level identified by CRM to have the highest probability 
of corresponding to the target DLT, i.e., the estimated DLT at the selected dose level is closest to 
the target toxicity level (here we set at 30%, see Section 9.2).  CRM will continuously monitor 
DLT and assign the next cohort of patients to dose level with DLT closer to the desired toxicity 
level using the data accumulated thus far in the trial.   
 
During the process of the Phase 1 results being formally reviewed and approved by CTEP prior 
to activation of the randomized Phase 2 portion, Bayer withdrew the NDA for copanlisib and the 
study is closing prior to opening Phase 2 with Amendment 8d dated 07Jun2024. 
 
9.1.1 Primary Endpoints 
 
The primary endpoint for the Phase 1 trial is DLT.  DLT will be determined based on the 
incidence, intensity and duration of AEs that are related to the drug combinations and occur 
within 28 days of drug administration.  The severity of AEs will be graded according to NCI 
Common Terminology Criteria for Adverse Events (CTCAE) v5.0.  All patients enrolled in the 
Phase 1 part who receive any dose level of the drug combination from the time of their first 
treatment will be evaluated for DLT. 
 
9.1.2 Secondary Endpoints 
 
The secondary endpoints are objective response rate (ORR) defined as proportion of response-
evaluable patients who achieve complete response (CR) or partial response (PR); clinical benefit 
rate (CBR) defined as proportion of response-evaluable patients who achieve complete response 
(CR) or partial response (PR) or stable of disease (SD) for at least 6 months; Progression free 
survival (PFS) is defined as the time from start of therapy to the event of disease progression or 
death due to any cause. Overall survival defined from time of randomization to time of death due 
to any cause or latest follow-up, whichever earlier.  All response evaluation will be based on 
RECIST v1.1.   
 
9.2 
Continual reassessment method (CRM) for Phase 1 dose finding 
 
The adaptive Phase 1 dose finding method, the continual reassessment method (CRM) 
(O’Quigley, et al., 1990; Lee & Cheung, 2009; Lee & Cheung, 2011), will be similarly used for 
both the Part A and Part B of the Phase 1 portion of the study.  For both Part A and B, the 
acceptable DLT rate range is 25~35% with a target DLT rate of 30% and the DLT rate at the 4 
dose levels (from lowest to highest) are assumed as 0.15, 0.2, 0.3, 0.45, respectively.  The 
anticipated RP2D is dose level 3, with a DLT rate expected at 0.3.  We allow a maximum sample 
size of 24, with a cohort size of 3.  The number of patients who need to be tested at a dose level 
to stop is set at 10, and the confidence level for the safety stopping rule, at the lowest study dose 
level is 90%.  The prior distribution on the CRM model parameter is N (0, 0.2), and the skeleton 


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59 
working model is 0.2, 0.3, 0.4, 0.5.  Based on 1000 simulations using a Bayesian CRM online 
app (https://uvatrapps.shinyapps.io/crmb/) (Wages & Petroni, 2018), the operating characteristics 
of the design for this set of assumed true DLT rates are provided in the table below.  The MTD 
selection % will be 32.2% at dose level 3, and 25.6% at dose level 2.  
 
Table 9.2.1:  CRM operating characteristics at true DLT rate of as (0.15, 0.2, 0.3, 0.45) from 
dose level 1 to dose level 4. 
 
Dose level 
1 
2 
3 
4 
True DLT probability:       
0.15 
0.2 
0.3 
0.45 
MTD selection percentage:    
4.5 
36.3 
   49.1 
10.0 
Average number of DLTs:    
0.2 
1.5 
2.3 
0.9 
Average number of patients:   
1.3 
7.7 
7.69 
2.06 
Percentage stopped for 
safety 
0.1 
 
The boundaries for early stopping due to safety concern at the lowest level (Dose level -1) were 
computed based on Argesti-Coull binomial confidence interval (Agresti & Coull, 1998) are 
provided in the Table below. 
 
 


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Table 9.2.2: The boundary for early stopping due to safety concern at the lowest level (Dose 
level -1) based on Argesti-Coull binomial confidence interval.  
 
# of patents treated # of DLTs 
2 
2 
3 
3 
4 
3 
5 
4 
6 
4 
7 
5 
8 
5 
9 
5 
10 
6 
11 
6 
12 
7 
13 
7 
14 
8 
15 
8 
16 
8 
17 
9 
18 
9 
19 
9 
20 
10 
21 
10 
22 
11 
23 
11 
24 
11 
 
Under other scenarios of DLT rates at the four dose levels, the operating characteristics based on 
1000 simulations indicate that the Bayesian CRM selects the target DLT with the greatest 
probability. 
 
 


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61 
 
Table 9.2.3: CRM operating characteristics at other scenarios of true DLT rate of dose levels 1-4. 
 
Dose level 
1 
2 
3 
4 
Scenario (1) 
True DLT probability:       
0.3 
0.4 
0.5 
0.6 
MTD selection percentage:   
45.7 
37.8 
6.2 
0.1 
Average number of DLTs:    
2.1 
3.3 
1 
0.1 
Average number of patients:  
6.98 
8.25 
2.06 
0.18 
Percentage stopped for 
safety 
10.2 
Scenario (2) 
True DLT probability:       
0.15 
0.3 
0.4 
0.5 
MTD selection percentage:   
15.7 
60.2 
20.7 
3.2 
Average number of DLTs:    
0.5 
2.9 
1.7 
0.3 
Average number of patients:  
3.48 
9.62 
4.35 
0.71 
Percentage stopped for 
safety 
0.2 
Scenario (3) 
True DLT probability:       
0.04 
0.1 
0.2 
0.3 
MTD selection percentage:   
0.1 
8.6 
42.9 
48.4 
Average number of DLTs:    
0 
0.5 
1.6 
1.9 
Average number of patients:  
0.19 
5.15 
8.18 
6.37 
Percentage stopped for 
safety 
0 
 
9.3 
Criteria for stopping of the phase 1 trial 
 
CRM will continuously monitor DLT and assign the next cohort of patients to the dose level with 
DLT closer to the desired toxicity level using the data accumulated thus far in the trial.  After 
each cohort of patients complete the DLT evaluation, the CRM analysis will be performed to 
determine the dose level to the next cohort of patients.  The RP2D will be the dose with the 
highest probability of lying in the acceptable DLT range of 25~35% and being close to the target 
DLT rate of 30%. 
 
The criteria for stopping the phase 1 trial are: 
 
(1) Before 24 patients are enrolled to the phase 1 trial, if 10 consecutive patients are assigned 
to receive the same dose level, then it is at least 90% certain that the current dose is the 
MTD and the trial will stop early with the dose level identified as MTD.  
(2)  After 24 DLT evaluable patients have been enrolled to the phase 1 and have completed 


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the first cycle of treatment and the DLT observation window, an MTD will be estimated;  
(3) The trial will stop and the protocol will be amended if the estimated probability of all the 
four dose levels having a DLT rate above (or below) the target DLT level is at least 90%. 
 
9.4 
Sample Size/Accrual Rate 
 
9.4.1 Sample Size for the Phase 1 Trial 
 
The primary objective of the Phase 1 trial is to determine the RP2D.  A maximum of 34 DLT 
evaluable patients (as defined in Section 9.7) will be treated in the Phase 1 trial, including 10 
patients enrolled in Phase 1 Part A prior to Amendment 6, and a maximum of 24 patients 
expected to enroll in Phase 1 Part B. At time of Amendment 8, 24 patients have enrolled to Phase 
1. 
 
The RPTD for FAC will be defined by the Bayesian CRM method.  The maximum sample size 
for part 1 of the study will depend on the number of patients treated at each dose level and the 
observed DLTs at each level.  
 
ORIGINAL PLANNED ENROLLMENT REPORT* 
Racial Categories 
Ethnic Categories 
Total 
Not Hispanic or Latino 
Hispanic or Latino 
 
Female 
Male 
Female 
Male 
 
American Indian/ Alaska 
Native 
1 
0 
1 
0 
2 
Asian 
2 
0 
0 
0 
2 
Native Hawaiian or 
Other Pacific Islander 
0 
0 
1 
0 
1 
Black or African 
American 
38 
0 
0 
0 
38 
White 
141 
2 
18 
0 
161 
More Than One Race 
0 
0 
0 
0 
0 
Total 
182 
2 
20 
0 
204 
PHS 398 / PHS 2590 (Rev. 08/12 Approved Through 8/31/2015) 
 
OMB No. 0925-0001/0002 
*Includes Phase 2 portion, which did not open to accrual. 
 
 


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63 
 
9.5 
Analysis of Primary Endpoints 
 
For Phase 1, AEs will be summarized by counts and percentages, overall as well as by dose 
levels and by patient characteristics.   
 
9.6 
Analysis of Secondary Endpoints 
 
The secondary endpoints ORR and CBR will be estimated with a 95% exact CI and difference 
between patient groups will be compared by Fisher’s exact test.  Raw and adjusted odds ratio 
(OR) will be derived with 95% CI from logistic regression without and with adjustment for 
patient characteristics.  OS will be analyzed similarly as PFS. 
 
9.6.1 Demographics and Baseline Characteristics 
 
Frequency distributions of gender, race, ethnicity, target gene mutation and other categorical 
baseline characteristics will be tabulated.  Baseline body mass index (BMI) will be derived from 
measurements of baseline body weight and height.  Summary statistics for age, body weight, 
height, and BMI will be provided using mean, median, standard deviation, inter-quartile range 
and range.  Baseline disease characteristics will be summarized overall and by patient groups of 
interest, as appropriate. 
 
9.6.2 Correlative Biomarker Analysis 
 
Descriptive statistics will be provided for selected demographic, safety, PK, candidate gene 
mutations, PTEN loss, and pharmacodynamic data (RPPA) by dose and time as appropriate.  
Descriptive statistics on continuous data (e.g., gene expression, proteomics, metabolomics, TILs) 
will include means, medians, standard deviations, and ranges, while categorical data (e.g., 
mutations) will be summarized using frequency counts and percentages.  Graphical summaries of 
the data will be presented as appropriate.  Prognostic effect of biomarker for PFS will be 
examined by the KM method or/and Cox proportional hazard model and for ORR using logistic 
regression model. For markers measured along multiple time points, generalized linear mixed 
effects model will be used to model longitudinal trajectories along time, without and with 
adjustment for other covariates.  Two sample t-test or Wilcoxon rank sum test will be applied to 
compare time-matched biomarkers between two groups.  Paired sample t-test or Wilcoxon 
signed rank test will be applied to compare subject-specific biomarkers between two time points.  
Multiple comparisons will be adjusted to control false discovery rate.  Proposed subset analyses 
will be applicable to biomarkers 
 
All data will be evaluated as they are, and no missing value imputations will be conducted. 
 
9.7 
Populations for Analysis 
 
• All Enrolled Subjects Analysis Set:  this analysis set contains all subjects who signed an 
informed consent for the study 
• DLT-evaluable set:  This set will be used for the DLT assessment in the Phase 1 part.  


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This analysis set refers to all subjects who receive at least 80% of the drug combinations 
during  the first 28 days of therapy from the time of their first treatment, or those who 
experience DLT within the first 28 days.  The patients who have no observed DLTs but 
drop out of the study before the completion of the first 28 days due to reasons other than 
treatment-emergent toxicities, will be replaced.  
• Safety/toxicity evaluable analysis set:  this analysis set contains all subjects who receive 
any dose level of the drug combinations from the time of their first treatment. 
• Response-Evaluable Subjects:  this analysis set contains all subjects who receive any 
amount of the study drugs, and have a baseline tumor assessment and at least one post-
baseline tumor assessment, or who were discontinued due to toxicity (counted toward 
PD).  This analysis set will be used for RECIST response analysis.  
• Copanlisib PK Analysis Set:  This analysis set includes all subjects who receive 
Copanlisib and have at least one valid PK parameter to be included in statistical analysis 
of the PK data. 
 
9.8 
Reporting and Exclusions 
 
9.8.1 Evaluation of Toxicity 
 
All patients will be evaluable for toxicity from the time of their first treatment with fulvestrant, 
abemaciclib and copanlisib.  
 
9.8.2 Evaluation of Response 
 
All patients included in the study must be assessed for response to treatment, even if there are 
major protocol treatment deviations or if they are ineligible.  Each patient will be assigned one of 
the following categories:  1) complete response, 2) partial response, 3) stable disease, 4) 
progressive disease, 5) early death from malignant disease, 6) early death from toxicity, 7) early 
death because of other cause, or 9) unknown (not assessable, insufficient data).  [Note:  By 
arbitrary convention, category 9 usually designates the “unknown” status of any type of data in a 
clinical database.] 
 
All of the patients who met the eligibility criteria (with the possible exception of those who 
received no study medication) should be included in the main analysis of the response rate.  
Patients in response categories 4-9 should be considered to have a treatment failure (disease 
progression).  Thus, an incorrect treatment schedule or drug administration does not result in 
exclusion from the analysis of the response rate.  Precise definitions for categories 4-9 will be 
protocol specific.  
 
All conclusions should be based on all eligible patients.  Subanalyses may then be performed on 
the basis of a subset of patients, excluding those for whom major protocol deviations have been 
identified (e.g., early death due to other reasons, early discontinuation of treatment, major 
protocol violations, etc.).  However, these subanalyses may not serve as the basis for drawing 
conclusions concerning treatment efficacy, and the reasons for excluding patients from the 
analysis should be clearly reported.  The 95% confidence intervals should also be provided.  
 


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9.9 
Data Safety Monitoring Board 
 
The Siteman Cancer Center independent standing Data and Safety Monitoring Board (DSMB) will 
review toxicity data for phase I of this trial.  The SCC standing DSMB includes clinical 
investigators and biostatisticians who are subject to the Washington University School of Medicine 
policies regarding standards of conduct and who have disclosed any potential conflicts of interest 
in accordance with institution policies.  
 
The DSM report for the SCC standing DSMB will be prepared by the study team with assistance 
from the study statistician, will be reviewed by the DSMB, and will be submitted to institutional 
safety monitoring committees as required.  The DSMB must review phase I data at least every six 
months beginning six months after study activation.  This report will include: 
 
• Study demographics (protocol number, protocol title, Principal Investigator name, data 
coordinator name, regulatory coordinator name, and statistician) 
• Date of initial IRB approval, date of most recent consent, date of most recent QA audit, 
study status, and phase of study 
• History of study including summary of substantive amendments; summary of accrual 
suspensions including start/stop dates and reason; and summary of protocol exceptions, 
error, or breach of confidentiality including start/stop dates and reason 
• Study-wide target accrual and study-wide actual accrual including numbers from 
participating sites 
• Protocol activation date at each participating site 
• Average rate of accrual observed in year 1, year 2, and subsequent years at each 
participating site 
• Expected accrual end date, accrual by site, and accrual by cohort 
• Objectives of protocol with supporting data and list the number of participants who 
have met each objective 
• Measures of efficacy 
• Early stopping rules with supporting data and list the number of participants who have 
met the early stopping rules 
• Summary of toxicities at all participating sites and separated by cohorts with the 
number of dose-limiting toxicities indicated 
• Abstract submissions/publications 
• Summary of any recent literature that may affect the safety or ethics of the study 
 
Further DSMB responsibilities are described in the DSMB charter. 
 
The study principal investigator and coordinator will monitor for serious toxicities on an ongoing 
basis. Once the principal investigator or coordinator becomes aware of an adverse event, the AE 
will be reported as described in the reporting requirements Section 9.11. 
 
 
10. ADVERSE EVENTS:  LIST AND REPORTING REQUIREMENTS  
 


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AE monitoring and reporting is a routine part of every clinical trial.  The following list of AEs 
(Section 10.1) and the characteristics of an observed AE (Sections 10.2 and 10.3) will determine 
whether the event requires expedited reporting via the CTEP Adverse Event Reporting System 
(CTEP-AERS) in addition to routine reporting. 
 
10.1 
Comprehensive Adverse Events and Potential Risks List (CAEPR) 
 
The Comprehensive Adverse Events and Potential Risks list (CAEPR) provides a single list of 
reported and/or potential AEs associated with an agent using a uniform presentation of events by 
body system.  In addition to the comprehensive list, a subset, the Specific Protocol Exceptions to 
Expedited Reporting (SPEER), appears in a separate column and is identified with bold and 
italicized text.  This subset of AEs (SPEER) is a list of events that are protocol specific 
exceptions to expedited reporting to NCI (except as noted below).  Refer to the 'CTEP, NCI 
Guidelines:  Adverse Event Reporting Requirements' 
http://ctep.cancer.gov/protocolDevelopment/electronic_applications/docs/aeguidelines.pdf for 
further clarification. 
 
NOTE:  Report AEs on the SPEER ONLY IF they exceed the grade noted in parentheses next to 
the AE in the SPEER.  If this CAEPR is part of a combination protocol using multiple 
investigational agents and has an AE listed on different SPEERs, use the lower of the grades to 
determine if expedited reporting is required.  
 
10.1.1 CAEPRs for CTEP IND Agent 
 
10.1.1.1 
CAEPR for Copanlisib dihydrochloride (BAY 80-6946 dihydrochloride, NSC 
784727) 
 
The Comprehensive Adverse Events and Potential Risks list (CAEPR) provides a single list of 
reported and/or potential adverse events (AE) associated with an agent using a uniform 
presentation of events by body system. In addition to the comprehensive list, a subset, the 
Specific Protocol Exceptions to Expedited Reporting (SPEER), appears in a separate column and 
is identified with bold and italicized text. This subset of AEs (SPEER) is a list of events that are 
protocol specific exceptions to expedited reporting to NCI (except as noted below).  Refer to the 
'CTEP, NCI Guidelines: Adverse Event Reporting Requirements’ 
http://ctep.cancer.gov/protocolDevelopment/electronic_applications/docs/aeguidelines.pdf for 
further clarification. Frequency is provided based on 684 patients. Below is the CAEPR for 
Copanlisib dihydrochloride (BAY 80-6946 dihydrochloride). 
NOTE: Report AEs on the SPEER ONLY IF they exceed the grade noted in parentheses 
next to the AE in the SPEER.  If this CAEPR is part of a combination protocol using multiple 
investigational agents and has an AE listed on different SPEERs, use the lower of the grades 
to determine if expedited reporting is required. 
 
Version 2.3, April 2, 20231 
 


NCI Protocol #:  10287 
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67 
 
 Adverse Events with Possible  
 Relationship to Copanlisib dihydrochloride (BAY 80-6946 dihydrochloride) 
 (CTCAE 5.0 Term) 
[n= 684] 
 
 
 Specific Protocol Exceptions 
to Expedited Reporting 
(SPEER)  
 
Likely (>20%) 
Less Likely (<=20%) 
Rare but Serious (<3%) 
 
 
BLOOD AND LYMPHATIC SYSTEM DISORDERS 
  
 
Anemia 
 
 Anemia (Gr 2) 
 
 
Febrile neutropenia 
  
GASTROINTESTINAL DISORDERS 
  
Diarrhea 
 
 
 Diarrhea (Gr 2) 
 
Mucositis oral 
 
  
 
Nausea 
 
 Nausea (Gr 2) 
 
 
Pancreatitis 
  
 
Vomiting 
 
 Vomiting (Gr 2) 
GENERAL DISORDERS AND ADMINISTRATION SITE CONDITIONS 
  
Fatigue 
 
 
 Fatigue (Gr 2) 
 
Fever 
 
  
INFECTIONS AND INFESTATIONS 
  
Infection2 
 
 
 Infection2 (Gr 2) 
INVESTIGATIONS 
  
 
 
Electrocardiogram QT corrected 
interval prolonged 
  
 
Lymphocyte count decreased 
 
  
Neutrophil count decreased 
 
 
 Neutrophil count decreased (Gr 
2) 
 
Platelet count decreased 
 
 Platelet count decreased (Gr 2) 
 
White blood cell decreased 
 
 White blood cell decreased (Gr 2) 
METABOLISM AND NUTRITION DISORDERS 
  
 
Anorexia 
 
 Anorexia (Gr 2) 
Hyperglycemia 
 
 
 Hyperglycemia (Gr 2) 
MUSCULOSKELETAL AND CONNECTIVE TISSUE DISORDERS 
  
 
Muscle cramp 
 
 Muscle cramp (Gr 2) 
RESPIRATORY, THORACIC AND MEDIASTINAL DISORDERS 
  
 
Pneumonitis3 
 
  
SKIN AND SUBCUTANEOUS TISSUE DISORDERS 
  
 
 
Erythroderma 
  
 
 
Pruritus 
  
 
Rash maculo-papular 
 
 Rash maculo-papular (Gr 2) 
VASCULAR DISORDERS 
  
Hypertension 
 
 
 Hypertension (Gr 2) 
 
1This table will be updated as the toxicity profile of the agent is revised.  Updates will be distributed to all Principal 
Investigators at the time of revision.  The current version can be obtained by contacting 
PIO@CTEP.NCI.NIH.GOV.  Your name, the name of the investigator, the protocol and the agent should be 
included in the e-mail. 
 
2Infection includes all 75 sites of infection under the INFECTIONS AND INFESTATIONS SOC. 
 
3Pneumonitis is a group term that includes interstitial lung disease, dyspnea, dyspnea at rest, and dyspnea exertional. 


NCI Protocol #:  10287 
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68 
 
Adverse events reported on Copanlisib dihydrochloride (BAY 80-6946 dihydrochloride) trials, but for which 
there is insufficient evidence to suggest that there was a reasonable possibility that Copanlisib 
dihydrochloride (BAY 80-6946 dihydrochloride) caused the adverse event: 
 
BLOOD AND LYMPHATIC SYSTEM DISORDERS - Eosinophilia 
CARDIAC DISORDERS - Atrial fibrillation; Cardiac arrest; Left ventricular systolic dysfunction; Myocardial 
infarction; Palpitations; Sinus tachycardia 
GASTROINTESTINAL DISORDERS - Abdominal pain; Colitis; Constipation; Dry mouth; Dyspepsia; 
Dysphagia; Esophagitis; Flatulence; Gastritis; Gastroesophageal reflux disease; Oral dysesthesia; Oral pain; Upper 
gastrointestinal hemorrhage 
GENERAL DISORDERS AND ADMINISTRATION SITE CONDITIONS - Chills; Death NOS; General 
disorders and administration site conditions - Other (failure to thrive); Multi-organ failure; Non-cardiac chest pain 
HEPATOBILIARY DISORDERS - Hepatic failure 
IMMUNE SYSTEM DISORDERS - Allergic reaction; Autoimmune disorder 
INJURY, POISONING AND PROCEDURAL COMPLICATIONS - Fracture; Infusion related reaction; Injury, 
poisoning and procedural complications - Other (drug eruption) 
INVESTIGATIONS - Activated partial thromboplastin time prolonged; Alanine aminotransferase increased; 
Alkaline phosphatase increased; Aspartate aminotransferase increased; Blood bilirubin increased; CPK increased; 
Creatinine increased; Ejection fraction decreased; Electrocardiogram T wave abnormal; INR increased; 
Investigations - Other (electrocardiogram U wave abnormal); Investigations - Other (Hepatitis B DNA increased); 
Lipase increased; Serum amylase increased; Weight loss 
METABOLISM AND NUTRITION DISORDERS - Dehydration; Hypercalcemia; Hypertriglyceridemia; 
Hyperuricemia; Hypocalcemia; Hypokalemia; Hypomagnesemia; Hyponatremia; Hypophosphatemia; Metabolism 
and nutrition disorders - Other (diabetes mellitus) 
MUSCULOSKELETAL AND CONNECTIVE TISSUE DISORDERS - Arthralgia; Back pain; Generalized 
muscle weakness; Musculoskeletal and connective tissue disorder - Other (psoriatic arthropathy); Myalgia; Pain in 
extremity; Soft tissue necrosis upper limb 
NEOPLASMS BENIGN, MALIGNANT AND UNSPECIFIED (INCL CYSTS AND POLYPS) - Tumor 
hemorrhage 
NERVOUS SYSTEM DISORDERS - Amnesia; Dizziness; Dysesthesia; Dysgeusia; Headache; Paresthesia; 
Peripheral sensory neuropathy; Presyncope; Reversible posterior leukoencephalopathy syndrome; Syncope 
PSYCHIATRIC DISORDERS - Confusion 
RENAL AND URINARY DISORDERS - Acute kidney injury 
RESPIRATORY, THORACIC AND MEDIASTINAL DISORDERS - Aspiration; Cough; Dyspnea3; Hypoxia; 
Pleural effusion; Pulmonary hypertension; Respiratory failure; Respiratory, thoracic and mediastinal disorders - 
Other (pulmonary congestion); Sore throat 
SKIN AND SUBCUTANEOUS TISSUE DISORDERS - Alopecia; Dry skin; Eczema; Purpura; Rash acneiform; 
Stevens-Johnson syndrome 
VASCULAR DISORDERS - Hypotension; Thromboembolic event; Vascular disorders - Other (circulatory 
collapse) 
 
 
 
Note: Copanlisib dihydrochloride (BAY 80-6946 dihydrochloride) in combination with other agents could cause an 
exacerbation of any adverse event currently known to be caused by the other agent, or the combination may result in 
events never previously associated with either agent. 
 
 
10.1.2 CAEPR for Abemaciclib 
 
Below is the CAEPR for Abemaciclib (LY2835219).  Frequency is provided based on 950 
patients. 
 


NCI Protocol #:  10287 
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69 
Version 2.0, October 3, 20191 
 
 Adverse Events with Possible  
 Relationship to Abemaciclib (LY2835219) 
 (CTCAE 5.0 Term) 
[n= 950] 
 
 
 Specific Protocol Exceptions to 
Expedited Reporting (SPEER)  
 
Likely (>20%) 
Less Likely (<=20%) 
Rare but Serious (<3%)  
 
BLOOD AND LYMPHATIC SYSTEM DISORDERS 
  
Anemia 
 
 
 Anemia (Gr 2) 
GASTROINTESTINAL DISORDERS 
  
 
Abdominal pain 
 
  
Diarrhea 
 
 
 Diarrhea (Gr 2) 
 
Dry mouth 
 
  
 
Mucositis oral 
 
  
Nausea 
 
 
 Nausea (Gr 2) 
Vomiting 
 
 
 Vomiting (Gr 2) 
GENERAL DISORDERS AND ADMINISTRATION SITE CONDITIONS 
  
Fatigue 
 
 
 Fatigue (Gr 2) 
INVESTIGATIONS 
  
 
 
Alanine aminotransferase 
increased 
  
 
 
Aspartate aminotransferase 
increased 
  
 
Creatinine increased 
 
  
 
Lymphocyte count decreased 
 
  
Neutrophil count decreased 
 
 
 Neutrophil count decreased (Gr 2) 
Platelet count decreased 
 
 
 Platelet count decreased (Gr 2) 
 
White blood cell decreased 
 
  
METABOLISM AND NUTRITION DISORDERS 
  
Anorexia 
 
 
 Anorexia (Gr 2) 
NERVOUS SYSTEM DISORDERS 
  
 
Dysgeusia 
 
  
 
Headache 
 
  
RESPIRATORY, THORACIC AND MEDIASTINAL DISORDERS 
  
 
 
Pneumonitis 
  
SKIN AND SUBCUTANEOUS TISSUE DISORDERS 
  
 
Alopecia 
 
  
VASCULAR DISORDERS 
  
 
 
Thromboembolic event 
  
 
 
 
1This table will be updated as the toxicity profile of the agent is revised.  Updates will be distributed to all Principal 
Investigators at the time of revision.  The current version can be obtained by contacting 
PIO@CTEP.NCI.NIH.GOV.  Your name, the name of the investigator, the protocol and the agent should be 
included in the e-mail. 
 
 
Adverse events reported on abemaciclib (LY2835219) trials, but for which there is insufficient evidence to 
suggest that there was a reasonable possibility that abemaciclib (LY2835219) caused the adverse event: 
 
EYE DISORDERS - Watering eyes 
GASTROINTESTINAL DISORDERS - Constipation; Dyspepsia 


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70 
GENERAL DISORDERS AND ADMINISTRATION SITE CONDITIONS - Edema limbs; Fever; Pain 
INFECTIONS AND INFESTATIONS - Lung infection; Sepsis; Upper respiratory infection; Urinary tract 
infection 
INVESTIGATIONS - Blood bilirubin increased; GGT increased; Weight loss 
METABOLISM AND NUTRITION DISORDERS - Dehydration; Hypertriglyceridemia; Hypoalbuminemia; 
Hypokalemia; Hyponatremia 
MUSCULOSKELETAL AND CONNECTIVE TISSUE DISORDERS - Arthralgia; Back pain; Bone pain; 
Generalized muscle weakness; Myalgia 
NERVOUS SYSTEM DISORDERS - Somnolence 
RENAL AND URINARY DISORDERS - Acute kidney injury 
RESPIRATORY, THORACIC AND MEDIASTINAL DISORDERS - Cough; Dyspnea 
SKIN AND SUBCUTANEOUS TISSUE DISORDERS - Pruritus 
VASCULAR DISORDERS - Lymph leakage 
 
 
 
Note: Abemaciclib (LY2835219) in combination with other agents could cause an exacerbation of any adverse event 
currently known to be caused by the other agent, or the combination may result in events never previously 
associated with either agent. 
 
10.1.3 Adverse Event List for Fulvestrant 
 
The most common AEs reported in the fulvestrant study groups, regardless of causality, were GI 
symptoms including nausea and vomiting (26%/13%), constipation (12.5%), diarrhea (12.3%) 
and abdominal pain (11.8%); as well as headache (18.9%); back pain (15.4%); hot flashes 
(17.7%); and pharyngitis (16.1%).  Vaginal bleeding was reported in <1% of patients and 
occurred most commonly during the first 6 weeks after changing from existing hormonal 
treatment to fulvestrant.  If vaginal bleeding persists, further evaluation is required.  Injection site 
reaction with mild transient pain (9.1-11.6%) and inflammation were seen with fulvestrant.  
Seven percent of patients (1% of treatments) given a single 5 ml IM injection and 27% of 
patients (4.6% of treatments) given 2 x 2.5 ml IM injections experienced reactions.  Additional 
AEs occurring in >5% of patients treated with fulvestrant during clinical trials include asthenia 
(weakness) (68.3%), bone pain (15.8%), dyspnea (14.9%), increased cough (10.4%), pelvic pain 
(10%), anorexia (9%), peripheral edema (9%), rash (unspecified) (7.3%), chest pain 
(unspecified) (7.1%), dizziness (6.9%), insomnia (6.9%), fever (6.4%), paresthesias (6.4%), 
urinary tract infection (6.1%), depression (5.7%), anxiety (5%), diaphoresis (5%), and anemia 
(4.5%). 
 
Other AEs reported as fulvestrant-related and occurring infrequently (<1%) include 
thromboembolism, myalgia, vertigo, and leukopenia.  In addition, hypersensitivity reactions such 
as angioedema and urticaria have been infrequently reported 
 
10.2 
Adverse Event Characteristics  
 
▪ CTCAE term (AE description) and grade:  The descriptions and grading scales found 
in the revised NCI Common Terminology Criteria for Adverse Events (CTCAE) version 
5.0 will be utilized for AE reporting.  All appropriate treatment areas should have access 
to a copy of the CTCAE version 5.0.  A copy of the CTCAE version 5.0 can be 
downloaded from the CTEP website 


NCI Protocol #:  10287 
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71 
http://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm. 
 
▪ For expedited reporting purposes only:   
• 
AEs for the agent that are bold and italicized in the CAEPR (i.e., those listed in the 
SPEER column, Section 10.1) should be reported through CTEP-AERS only if the 
grade is above the grade provided in the SPEER. 
 
• Attribution of the AE: 
o Definite – The AE is clearly related to the study treatment. 
o Probable – The AE is likely related to the study treatment. 
o Possible – The AE may be related to the study treatment. 
o Unlikely – The AE is doubtfully related to the study treatment. 
o Unrelated – The AE is clearly NOT related to the study treatment. 
 
10.3 
Expedited Adverse Event Reporting 
 
10.3.1 Rave-CTEP-AERS Integration 
 
The Rave Cancer Therapy Evaluation Program Adverse Event Reporting System (CTEP-AERS) 
integration enables evaluation of Adverse Events (AEs) entered in Rave to determine whether 
they require expedited reporting and facilitates entry in CTEP-AERS for those AEs requiring 
expedited reporting.  Sites must initiate all AEs for this study in Medidata Rave. 
 
Treatment-emergent AEs:  All AEs that occur after start of treatment are collected in Medidata 
Rave using the Adverse Event form, which is available for entry at each treatment course or 
reporting period and is used to collect AEs that start during the period or persist from the 
previous reporting period.  AEs that occur 30 days after the last administration of the 
investigational agent/intervention are collected using the Late Adverse Event form. 
 
Prior to sending AEs through the rules evaluation process, site staff should verify the following 
on the Adverse Event form in Rave: 
 
• The reporting period (course/cycle) is correct, and 
• AEs are recorded and complete (no missing fields) and the form is query free.  
 
The CRA reports AEs in Rave at the time the Investigator learns of the event.  If the CRA 
modifies an AE, it must be re-submitted for rules evaluation. 
 
Upon completion of AE entry in Medidata Rave, the CRA submits the AE for rules evaluation 
by completing the Expedited Reporting Evaluation form (i.e., checking the box Send All AEs for 
Evaluation and save the form).  Both NCI and protocol-specific reporting rules evaluate the AEs 
submitted for expedited reporting.  A report is initiated in CTEP-AERS using information 
entered in Medidata Rave for AEs that meet reporting requirements.  The CRA completes the 
report by accessing CTEP-AERS via a direct link on the Medidata Rave Expedited Reporting 
Evaluation form.  Contact the CTSU Help Desk at 1-888-823-5923 or by email at 
ctsucontact@westat.com if you have any issues submitting an expedited report in CTEP-AERS. 


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72 
 
In the rare occurrence that internet connectivity is lost, a 24-hour notification is to be made to 
CTEP by telephone at 301-897-7497.  Once internet connectivity is restored, the 24-hour 
notification that was phoned in must be entered immediately into CTEP-AERS using the direct 
link from Medidata Rave. 
 
Additional information about the CTEP-AERS integration is available on the CTSU members’ 
website: 
 
• Study specific documents:   Protocols > Documents> Protocol Related Documents> 
Adverse Event Reporting, and   
• Additional resources: Resources > CTSU Operations Information> User Guides & Help 
Topics. 
 
NCI requirements for SAE reporting are available on the CTEP website:  
 
• NCI Guidelines for Investigators:  Adverse Event Reporting Requirements is available at 
https://ctep.cancer.gov/protocolDevelopment/electronic_applications/docs/aeguidelines.p
df. 
 
10.3.2 Distribution of Adverse Event Reports 
 
CTEP-AERS is programmed for automatic electronic distribution of reports to the following 
individuals:  Principal Investigator and Adverse Event Coordinator(s) (if applicable) of the 
Corresponding Organization or Lead Organization, the local treating physician, and the Reporter 
and Submitter.  CTEP-AERS provides a copy feature for other e-mail recipients.  
 
10.3.3 Expedited Reporting Guidelines 
 
Use the NCI protocol number and the protocol-specific patient ID assigned during trial 
registration on all reports. 
 
Note:  A death on study requires both routine and expedited reporting, regardless of 
causality as long as the death occurred within 30 days after the last administration of the 
investigational agent.  Attribution to treatment or other cause must be provided. 
 
Death due to progressive disease should be reported as grade 5 “Disease progression” in the 
system organ class (SOC) “General disorders and administration site conditions.”  Evidence that 
the death was a manifestation of underlying disease (e.g., radiological changes suggesting tumor 
growth or progression: clinical deterioration associated with a disease process) should be 
submitted.  
 
Phase 1 and Early Phase 2 Studies:  Expedited Reporting Requirements for Adverse 
Events that Occur on Studies under an IND/IDE within 30 Days of the Last Administration 
of the Investigational Agent/Intervention 1, 2 


NCI Protocol #:  10287 
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73 
FDA REPORTING REQUIREMENTS FOR SERIOUS ADVERSE EVENTS (21 CFR Part 312) 
NOTE:  Investigators MUST immediately report to the sponsor (NCI) ANY Serious Adverse Events, whether or not 
they are considered related to the investigational agent(s)/intervention (21 CFR 312.64) 
An adverse event is considered serious if it results in ANY of the following outcomes:   
1) 
Death 
2) 
A life-threatening adverse event  
3) 
An adverse event that results in inpatient hospitalization or prolongation of existing hospitalization for ≥ 24 
h  
4) 
A persistent or significant incapacity or substantial disruption of the ability to conduct normal life functions  
5) 
A congenital anomaly/birth defect.  
6) 
Important Medical Events (IME) that may not result in death, be life threatening, or require hospitalization 
may be considered serious when, based upon medical judgment, they may jeopardize the patient or 
subject and may require medical or surgical intervention to prevent one of the outcomes listed in this 
definition. (FDA, 21 CFR 312.32; ICH E2A and ICH E6). 
 
ALL SERIOUS adverse events that meet the above criteria MUST be immediately reported to the NCI via electronic 
submission within the timeframes detailed in the table below. 
Hospitalization 
Grade 1 and Grade 2 Timeframes 
Grade 3-5 
Timeframes 
Resulting in 
Hospitalization  
≥ 24 h 
10 Calendar Days 
24-H 5 Calendar Days 
Not resulting in 
Hospitalization  
≥ 24 h 
Not required 
NOTE:  Protocol specific exceptions to expedited reporting of serious adverse events are found in the Specific 
Protocol Exceptions to Expedited Reporting (SPEER) portion of the CAEPR. 
Expedited AE reporting timelines are defined as: 
o 
“24-H; 5 Calendar Days” - The AE must initially be submitted electronically within 24 h of learning of the 
AE, followed by a complete expedited report within 5 calendar days of the initial 24-h report. 
o 
“10 Calendar Days” - A complete expedited report on the AE must be submitted electronically within 10 
calendar days of learning of the AE. 
1Serious adverse events that occur more than 30 days after the last administration of investigational 
agent/intervention and have an attribution of possible, probable, or definite require reporting as follows:  
Expedited 24-h notification followed by complete report within 5 calendar days for: 
• 
All grade 3, 4, and grade 5 AEs 
Expedited 10 calendar day reports for: 
• 
Grade 2 AEs resulting in hospitalization or prolongation of hospitalization 
2For studies using PET or SPECT IND agents, the AE reporting period is limited to 10 radioactive half-lives, 
rounded UP to the nearest whole day, after the agent/intervention was last administered.  Footnote “1” above 
applies after this reporting period. 
Effective Date:  May 5, 2011 
 
10.3.4 Copanlisib Adverse Events of Special Safety Interest (AESI) 
 
AESI are events of scientific and medical interest specific to the further understanding of 
copanlisib’s safety profile and require close monitoring and rapid communication by the 
investigators to CTEP.  An AESI may be serious or non-serious.  The AESI for copanlisib are 
the following: 
 
o Non-infectious pneumonitis 


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74 
 
Non-infectious pneumonitis has been observed in studies with copanlisib.  As soon as there is a 
reasonable suspicion of a patient experiencing non-infectious pneumonitis, the investigator 
should report it within 24 h via CTEP-AERS regardless of whether the event is assessed as 
causally related/not related to the study therapy, or as serious/non-serious by an investigator. 
 
10.4 
Routine Adverse Event Reporting 
 
All Adverse Events must be reported in routine study data submissions.  AEs reported 
expeditiously through CTEP-AERS must also be reported in routine study data 
submissions. 
 
Adverse event data collection and reporting, which are required as part of every clinical trial, are 
done to ensure the safety of patients enrolled in the studies as well as those who will enroll in 
future studies using similar agents.  AEs are reported in a routine manner at scheduled times 
during the trial using Medidata Rave.  For this trial the Adverse Event CRF is used for routine 
AE reporting in Rave. 
 
10.5 
Pregnancy 
 
Although not an adverse event in and of itself, pregnancy as well as its outcome must be 
documented via CTEP-AERS.  In addition, the Pregnancy Information Form included within 
the NCI Guidelines for Adverse Event Reporting Requirements must be completed and 
submitted to CTEP.  Any pregnancy occurring in a patient or patient’s partner from the time of 
consent to 90 days after the last dose of study drug must be reported and then followed for 
outcome.  Newborn infants should be followed until 30 days old.  Please see the “NCI 
Guidelines for Investigators: Adverse Event Reporting Requirements for DCTD (CTEP and CIP) 
and DCP INDs and IDEs” (at http://ctep.cancer.gov/protocolDevelopment/adverse_effects.htm) 
for more details on how to report pregnancy and its outcome to CTEP.  
 
10.6 
Secondary Malignancy 
 
A secondary malignancy is a cancer caused by treatment for a previous malignancy (e.g., 
treatment with investigational agent/intervention, radiation or chemotherapy). A secondary 
malignancy is not considered a metastasis of the initial neoplasm. 
 
CTEP requires all secondary malignancies that occur following treatment with an agent under an 
NCI IND/IDE be reported expeditiously via CTEP-AERS.  Three options are available to 
describe the event:  
 
1. Leukemia secondary to oncology chemotherapy (e.g., acute myelocytic leukemia [AML])  
2. Myelodysplastic syndrome (MDS)  
3. Treatment-related secondary malignancy  
 
Any malignancy possibly related to cancer treatment (including AML/MDS) should also be 
reported via the routine reporting mechanisms outlined in each protocol.  


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75 
 
10.7 
Second Malignancy 
 
A second malignancy is one unrelated to the treatment of a prior malignancy (and is NOT a 
metastasis from the initial malignancy).  Second malignancies require ONLY routine AE 
reporting unless otherwise specified. 
 
 
11. STUDY CALENDAR 
 
Screening evaluations are to be conducted within 2 weeks prior to start of protocol therapy.  
Hepatitis panel, scans, ECHO/MUGA and x-rays must be done ≤ 4 weeks prior to the start of 
therapy (C1D1).  In the event that the patient’s condition is deteriorating, laboratory evaluations 
should be repeated within 48 h prior to initiation of the next cycle of therapy. 
 
After registration to the study, redacted clinical records will be collected. Records will include 
clinical tumor/blood sequencing result reports and prior breast cancer diagnosis and treatment 
history (a physician progress note is acceptable).   
 
 
 
 


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76 
 
 
Screening 
 
C1D1* 
C1D8* 
C1D15* 
C1D22* 
Subsequent cycles* 
EOT19 
Follow-
Up19 
D1 
D8 
D15 
Informed consent 
X 
 
 
 
 
 
 
 
 
 
Physical exam w/ECOG PS 
X 
X 
X16 
X16 
 
X 
 
 
 
 
Disease Assessment Imaging** 
X 
 
 
 
 
End of C3, then every 3 cycles thereafter 
X 
 
CBC 
X 
X 
X16 
X 
 
X 
 
X16 
 
 
Serum chemistry1 
X 
X 
X16 
X 
X21 
X 
X16 
X16 
 
 
Lipase 
X 
 
 
 
 
 
 
 
 
 
INR and PTT 
X 
 
 
 
 
 
 
 
 
 
HbA1c 
X 
 
 
 
 
 
 
 
 
 
Glucose2,4 
 
X12 
X13 
X13 
 
X13 
X13 
X13 
 
 
Echo/MUGA 
X 
 
 
 
 
 
 
 
 
 
ECG 
X 
As clinically indicated 
 
Serum β-hCG3 
X 
 
 
 
 
X3 
 
 
 
 
Hepatitis panel 
X 
 
 
 
 
 
 
 
 
 
Urinalysis14 
X 
 
 
 
 
 
 
 
 
 
Blood pressure2,4 
 
X 
X16 
X16 
 
X 
X16 
X16 
 
 
Fulvestrant15 
 
X 
 
X 
 
X 
 
 
 
 
Abemaciclib15 
 
Dosing per Section 6.1 
 
 
Copanlisib5 
 
X 
X5 
X 
 
X 
X 
X 
 
 
Archival tumor tissue6 
X 
 
 
 
 
 
 
 
 
 
Most Recent Tumor and/or 
blood genomic testing report if 
available22 
X 
 
 
 
 
 
 
 
 
 
Fresh tumor biopsy 
X7 
 
 
X17 
 
 
 
 
X8, 17 
 
Whole blood (cfDNA Streck 
tube), unprocessed6 
X20 
 
X 
X 
 
X9 
 
 
X8 
 
Blood (EDTA purple top tube) 
for plasma6 
X 
 
X 
X 
 
X9 
 
 
X8 
 
Blood (red top) for serum6 
X 
 
X 
X 
 
X9 
 
 
X8 
 
Blood (LiHep) for PKs10 
 
X11 
 
X11 
X18 
 
 
 
 
 
Concomitant medications5 
X ---------------------------------------------------------------------------------------------------------------------------------------- X 
 
AE assessment 
X ---------------------------------------------------------------------------------------------------------------------------------------- X 
 
Survival 
 
X 
1. 
Serum chemistry is albumin, alkaline phosphatase, total bilirubin, bicarbonate, BUN, calcium, chloride, creatinine, glucose, potassium, total protein, SGOT [AST], SGPT [ALT], sodium. 


NCI Protocol #:  10287 
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77 
 
2. 
Only if receiving copanlisib  
3. 
Women of childbearing potential only which is performed at screening and then every 3 cycles on study. 
4. 
Refer to Section 7.1 
5. 
All patients in the Phase 1 portion will receive copanlisib. Note copanlisib is not administered on day 8 in some dose levels (administered within 1 h (+/-10 minutes).  
6. 
Mandatory 
7. 
Mandatory if there is accessible tumor 
8. 
At time of progression 
9. 
C2D1, C4D1, and every 3 cycles after 
10. Patients enrolled in the Phase 1 portion.  
11. a) Prior to copanlisib infusion and (b) After copanlisib infusion (10 min, 1 hr, 2 hr, 3 hr, 5 hr, 24 hr [before C1D2’s abemaciclib and fulvestrant]) 
12. Before infusion, 60 minutes post-start of infusion (end of infusion), 1 hr post-end of infusion, and 2 hr post-end of infusion 
13. Before infusion and at end of infusion.  Post-dose glucose monitoring after C1D1 is performed as clinically indicated at the investigator’s discretion. 
14. If proteinuria is present, a 24h urine protein quantification or a random urine protein and creatinine test is needed to determine eligibility.  
15. Note that patients enrolled in the Phase 1 portion who have Copanlisib PK studies, the first two doses of abemaciclib on C1D1 are skipped and fulvestrant will be delayed to C1D2 following the 24 hr PK blood 
draw.  The C1D15 dose of fulvestrant will be administered on C1D16 following the 24 hr PK draw.  
16. If copanlisib is to be administered.  
17. Optional. For patients on the FAC regimen, collect biopsy within 2-8 hrs post the administration of copanlisib, for scheduling issues, up to 24 hrs following the copanlisib is acceptable. Note that for patients on 
copanlisib, the tumor biopsy schedule should follow that of copanlisib in C1D15, in case copanlisib is delayed. For patients on FA regimen, collect biopsy on C1D15 at least 1 hr after the first dose of abemaciclib 
that day. 
18. Prior to, 1 hr, 2 hr, 4 hr, 23 hr post the morning dose of abemaciclib on C1D22 
19. Follow up for survival status occurs every 3 months for 5 years after removal from the study or until death, whichever occurs first.  In addition, patients removed from study due to unacceptable adverse event(s) will 
be followed until resolution or stabilization of the adverse event. There is a +/- 7 day window for EOT and follow up for survival status visits. 
20. Whole blood (cfDNA streck tube) collected at baseline will be processed to buffy coat for germline DNA in addition to the cfDNA plasma at the EET Biobank.  
21. Phase 1 patients only 
22. Upload in RAVE. Tumor or blood genomic testing per SOC does not fall under 2 week window for baseline evaluations. 
*Visits can occur in ± 2 days window to allow for holidays, inclement weather, etc. 
** Tumor imaging for response assessment occurs at screening (within 28 days of C1D1), the completion of cycle 3 (+/- 7 days), then every 3 cycles. 


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12. MEASUREMENT OF EFFECT 
 
Although the clinical benefit of this drug combination has not yet been established, the intent of 
offering this treatment is to provide a possible therapeutic benefit, and thus the patient will be 
carefully monitored for tumor regression and symptom relief in addition to safety and 
tolerability.  Patients with measurable disease will be assessed by standard criteria.  For the 
purposes of this study, patients should be re-evaluated for response every 12 weeks.  In addition 
to a baseline scan, confirmatory scans should also be obtained not less than 4 weeks following 
initial documentation of objective response. 
 
12.1 
Antitumor Effect – Solid Tumors 
 
Response and progression will be evaluated in this study using the new international criteria 
proposed by the revised Response Evaluation Criteria in Solid Tumors (RECIST) guideline 
(version 1.1) [Eur J Ca 45:228-247, 2009].  Changes in the largest diameter (unidimensional 
measurement) of the tumor lesions and the shortest diameter in the case of malignant lymph 
nodes are used in the RECIST criteria. 
 
12.1.1 Definitions 
 
Evaluable for toxicity.  All patients will be evaluable for toxicity from the time of their first 
treatment with regimen. 
 
Evaluable for objective response.  Only those patients who have measurable disease present at 
baseline, have received at least one cycle of therapy, and have had their disease re-evaluated will 
be considered evaluable for response.  These patients will have their response classified 
according to the definitions stated below.  (Note:  Patients who exhibit objective disease 
progression prior to the end of cycle 1 will also be considered evaluable.) 
 
Evaluable Non-Target Disease Response.  Patients who have lesions present at baseline that are 
evaluable but do not meet the definitions of measurable disease, have received at least one cycle 
of therapy, and have had their disease re-evaluated will be considered evaluable for non-target 
disease.  The response assessment is based on the presence, absence, or unequivocal progression 
of the lesions.  
 
12.1.2 Disease Parameters 
 
Measurable disease.  Measurable lesions are defined as those that can be accurately measured in 
at least one dimension (longest diameter to be recorded) as ≥20 mm (≥2 cm) by chest x-ray or as 
≥10 mm (≥1 cm) with CT scan, MRI, or calipers by clinical exam.  All tumor measurements 
must be recorded in millimeters (or decimal fractions of centimeters). 
 
Note:  Tumor lesions that are situated in a previously irradiated area might or might not be 
considered measurable. 
 
Malignant lymph nodes.  To be considered pathologically enlarged and measurable, a lymph 


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


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80 
 
Clinical lesions.  Clinical lesions will only be considered measurable when they are superficial 
(e.g., skin nodules and palpable lymph nodes) and ≥10 mm (≥1 cm) diameter as assessed using 
calipers (e.g., skin nodules).  In the case of skin lesions, documentation by color photography, 
including a ruler to estimate the size of the lesion, is recommended.  
 
Chest x-ray.  Lesions on chest x-ray are acceptable as measurable lesions when they are clearly 
defined and surrounded by aerated lung.  However, CT is preferable.  
 
Conventional CT and MRI.  This guideline has defined measurability of lesions on CT scan 
based on the assumption that CT slice thickness is 5 mm (0.5 cm) or less.  If CT scans have slice 
thickness greater than 5 mm (0.5 cm), the minimum size for a measurable lesion should be twice 
the slice thickness.  MRI is also acceptable in certain situations (e.g., for body scans).   
 
Use of MRI remains a complex issue.  MRI has excellent contrast, spatial, and temporal 
resolution; however, there are many image acquisition variables involved in MRI, which greatly 
impact image quality, lesion conspicuity, and measurement.  Furthermore, the availability of 
MRI is variable globally.  As with CT, if an MRI is performed, the technical specifications of the 
scanning sequences used should be optimized for the evaluation of the type and site of disease.  
Furthermore, as with CT, the modality used at follow-up should be the same as was used at 
baseline and the lesions should be measured/assessed on the same pulse sequence.  It is beyond 
the scope of the RECIST guidelines to prescribe specific MRI pulse sequence parameters for all 
scanners, body parts, and diseases.  Ideally, the same type of scanner should be used and the 
image acquisition protocol should be followed as closely as possible to prior scans.  Body scans 
should be performed with breath-hold scanning techniques, if possible. 
 
PET-CT.  At present, the low dose or attenuation correction CT portion of a combined PET-CT 
is not always of optimal diagnostic CT quality for use with RECIST measurements.  However, if 
the site can document that the CT performed as part of a PET-CT is of identical diagnostic 
quality to a diagnostic CT (with IV and oral contrast), then the CT portion of the PET-CT can be 
used for RECIST measurements and can be used interchangeably with conventional CT in 
accurately measuring cancer lesions over time.  Note, however, that the PET portion of the CT 
introduces additional data which may bias an investigator if it is not routinely or serially 
performed. 
 
Ultrasound.  Ultrasound is not useful in assessment of lesion size and should not be used as a 
method of measurement.  Ultrasound examinations cannot be reproduced in their entirety for 
independent review at a later date and, because they are operator dependent, it cannot be 
guaranteed that the same technique and measurements will be taken from one assessment to the 
next.  If new lesions are identified by ultrasound in the course of the study, confirmation by CT 
or MRI is advised.  If there is concern about radiation exposure at CT, MRI may be used instead 
of CT in selected instances. 
 
Endoscopy, Laparoscopy.  The utilization of these techniques for objective tumor evaluation is 
not advised.  However, such techniques may be useful to confirm complete pathological 
response when biopsies are obtained or to determine relapse in trials where recurrence following 


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


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82 
12.1.4 Response Criteria 
 
12.1.4.1 
Evaluation of Target Lesions 
 
CR:  Disappearance of all target lesions.  Any pathological lymph nodes (whether target or non-
target) must have reduction in short axis to <10 mm (<1 cm). 
 
PR:  At least a 30% decrease in the sum of the diameters of target lesions, taking as reference the 
baseline sum diameters. 
 
PD:  At least a 20% increase in the sum of the diameters of target lesions, taking as reference the 
smallest sum on study (this includes the baseline sum if that is the smallest on study).  In 
addition to the relative increase of 20%, the sum must also demonstrate an absolute increase of at 
least 5 mm (0.5 cm).  (Note:  the appearance of one or more new lesions is also considered 
progressions). 
 
SD:  Neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD, 
taking as reference the smallest sum diameters while on study. 
 
12.1.4.2 
Evaluation of Non-Target Lesions 
 
CR:  Disappearance of all non-target lesions and normalization of tumor marker level.  All 
lymph nodes must be non-pathological in size (<10 mm [<1 cm] short axis). 
 
Note:  If tumor markers are initially above the upper normal limit, they must normalize for a 
patient to be considered in complete clinical response. 
 
Non-CR/Non-PD:  Persistence of one or more non-target lesion(s) and/or maintenance of tumor 
marker level above the normal limits. 
 
PD:  Appearance of one or more new lesions and/or unequivocal progression of existing non-
target lesions.  Unequivocal progression should not normally trump target lesion status.  It must 
be representative of overall disease status change, not a single lesion increase. 
 
Although a clear progression of “non-target” lesions only is exceptional, the opinion of the 
treating physician should prevail in such circumstances, and the progression status should be 
confirmed at a later time by the review panel (or Principal Investigator). 
 
12.1.4.3 
Evaluation of Best Overall Response 
 
The best overall response is the best response recorded from the start of the treatment until 
disease progression/recurrence (taking as reference for progressive disease the smallest 
measurements recorded since the treatment started).  The patient's best response assignment will 
depend on the achievement of both measurement and confirmation criteria. 
 


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83 
For Patients with Measurable Disease (i.e., Target Disease) 
 
Target 
Lesions 
Non-Target 
Lesions 
New 
Lesions 
Overall 
Response 
Best Overall Response when 
Confirmation is Required* 
CR 
CR 
No 
CR 
≥4 wks.  Confirmation** 
CR 
Non-CR/Non-
PD 
No 
PR 
≥4 wks.  Confirmation** 
CR 
Not evaluated 
No 
PR 
PR 
Non-CR/Non-
PD/not 
evaluated 
No 
PR 
SD 
Non-CR/Non-
PD/not 
evaluated 
No 
SD 
Documented at least once ≥4 
wks. from baseline** 
PD 
Any 
Yes or No 
PD 
no prior SD, PR or CR 
Any 
PD*** 
Yes or No 
PD 
Any 
Any 
Yes 
PD 
 
See RECIST 1.1 manuscript for further details on what is evidence of a new lesion. 
**    Confirmation of PR, CR is not required in this trial.  
***  In exceptional circumstances, unequivocal progression in non-target lesions may be 
accepted as disease progression. 
 
Note:  Patients with a global deterioration of health status requiring discontinuation of 
treatment without objective evidence of disease progression at that time should be 
reported as “symptomatic deterioration.”  Every effort should be made to document the 
objective progression even after discontinuation of treatment. 
 
For Patients with Non-Measurable Disease (i.e., Non-Target Disease) 
 
Non-Target Lesions 
New Lesions 
Overall Response 
CR 
No 
CR 
Non-CR/non-PD 
No 
Non-CR/non-PD* 
Not all evaluated 
No 
not evaluated 
Unequivocal PD 
Yes or No 
PD 
Any 
Yes 
PD 
 
‘Non-CR/non-PD’ is preferred over ‘stable disease’ for non-target disease since SD is 
increasingly used as an endpoint for assessment of efficacy in some trials so to assign this 
category when no lesions can be measured is not advised 
 
12.1.5 Duration of Response 
 
Duration of overall response:  The duration of overall response is measured from the time 
measurement criteria are met for CR or PR (whichever is first recorded) until the first date that 
recurrent or progressive disease is objectively documented (taking as reference for progressive 
disease the smallest measurements recorded since the treatment started). 


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84 
 
The duration of overall CR is measured from the time measurement criteria are first met for CR 
until the first date that progressive disease is objectively documented. 
 
Duration of stable disease:  Stable disease is measured from the start of the treatment until the 
criteria for progression are met, taking as reference the smallest measurements recorded since the 
treatment started, including the baseline measurements.  
 
12.1.6 Progression-Free Survival 
 
PFS is defined as the duration of time from start of treatment to time of progression or death, 
whichever occurs first. 
 
12.1.7 Response Review 
 
It is strongly recommended that all responses be reviewed by an expert(s) independent of the 
study at the study’s completion.  Simultaneous review of the patients’ files and radiological 
images is the best approach. 
 
 
13. STUDY OVERSIGHT AND DATA REPORTING / REGULATORY 
REQUIREMENTS 
 
Adverse event lists, guidelines, and instructions for AE reporting can be found in Section 10 
(Adverse Events: List and Reporting Requirements). 
 
13.1 
Study Oversight 
 
This protocol is monitored at several levels, as described in this section.  The Protocol Principal 
Investigator is responsible for monitoring the conduct and progress of the clinical trial, including 
the ongoing review of accrual, patient-specific clinical and laboratory data, and routine and 
serious adverse events; reporting of expedited adverse events; and accumulation of reported 
adverse events from other trials testing the same drug(s).  The Protocol Principal Investigator and 
statistician have access to the data at all times through the CTMS web-based reporting portal.   
 
For the Phase 1 portion of this study, all decisions regarding dose escalation/expansion/de-
escalation require sign-off by the Protocol Principal Investigator through the CTMS/IWRS.  In 
addition, for the Phase 1 portion, the Protocol Principal Investigator will have at least monthly, 
or more frequently, conference calls with the Study Investigators and the CTEP Medical 
Officer(s) to review accrual, progress, and adverse events and unanticipated problems.  
 
All Study Investigators at participating sites who register/enroll patients on a given protocol are 
responsible for timely submission of data via Medidata Rave and timely reporting of adverse 
events for that particular study.  This includes timely review of data collected on the electronic 
CRFs submitted via Medidata Rave. 
 


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All studies are also reviewed in accordance with the enrolling institution’s data safety monitoring 
plan. 
 
13.2 
Data Reporting 
 
Medidata Rave is the clinical data management system being used for data collection for this 
trial/study.  Access to the trial in Rave is controlled through the CTEP-IAM system and role 
assignments. 
 
Requirements to access Rave via iMedidata: 
 
• 
Active CTEP registration with the credentials necessary to access secure NCI/CTSU IT 
systems, and  
• 
Assigned a Rave role on the LPO or PO roster at the enrolling site of:  Rave CRA, Rave 
Read Only, Rave CRA (LabAdmin), Rave SLA, or Rave Investigator.   
Rave role requirements: 
 
o Rave CRA or Rave CRA (Lab Admin) role, must have a minimum of an 
Associate Plus (AP) registration type, 
o Rave Investigator role must be registered as a Non-Physician Investigator 
(NPIVR) or Investigator (IVR), and 
o Rave Read Only or Rave SLA role must have at a minimum an Associates (A) 
registration type. 
• 
Refer to https://ctep.cancer.gov/investigatorResources/default.htm for registration types 
and documentation required. 
 
If the study has a DTL, individuals requiring write access to Rave must also be assigned the 
appropriate Rave tasks on the DTL. 
 
Upon initial site registration approval for the study in the Regulatory application, all persons 
with Rave roles assigned on the appropriate roster will be sent a study invitation email from 
iMedidata.  To accept the invitation, site staff must either click on the link in the email or log in 
to iMedidata via the CTSU members’ website  under Data Management > Rave Home and click 
to accept the invitation in the Tasks pane located in the upper right-corner of the iMedidata 
screen.  Site staff will not be able to access the study in Rave until all required Medidata and 
study specific trainings are completed.  Trainings will be in the form of electronic learnings 
(eLearnings) and can be accessed by clicking on the eLearning link in the Tasks pane located in 
the upper right corner of the iMedidata screen.  If an eLearning is required for a study and has 
not yet been taken, the link to the eLearning will appear under the study name in the Studies pane 
located in the center of the iMedidata screen; once the successful completion of the eLearning 
has been recorded, access to the study in Rave will be granted, and a Rave EDC link will replace 
the eLearning link under the study name.  
 
Site staff who have not previously activated their iMedidata/Rave account at the time of initial 
site registration approval for the study in the Regulatory application will receive a separate 
invitation from iMedidata to activate their account.  Account activation instructions are located 


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on the CTSU website in the Data Management section under the Rave resource materials 
(Medidata Account Activation and Study Invitation Acceptance).  Additional information on 
iMedidata/Rave is available on the CTSU members’ website in the Data Management > Rave 
section or by contacting the CTSU Help Desk at 1-888-823-5923 or by email at 
ctsucontact@westat.com.  
 
13.2.1 Method 
 
This study will be monitored by the Clinical Trials Monitoring Service (CTMS).  Data will be 
submitted to CTMS at least once every two weeks via Medidata Rave (or other modality if 
approved by CTEP).  Information on CTMS reporting is available at:  
http://www.theradex.com/clinicalTechnologies/?National-Cancer-Institute-NCI-11.  On-site 
audits will be conducted on an 18 - 36 month basis as part of routine cancer center site visits. 
More frequent audits may be conducted if warranted by accrual or due to concerns regarding 
data quality or timely submission.  For CTMS monitored studies, after users have activated their 
accounts, please contact the Theradex Help Desk at (609) 619-7862 or by email at 
CTMSSupport@theradex.com for additional support with Rave and completion of CRFs. 
 
13.2.2 Responsibility for Data Submission 
 
For ETCTN trials, it is the responsibility of the PI(s) at the site to ensure that all investigators at 
the ETCTN Sites understand the procedures for data submission for each ETCTN protocol and 
that protocol specified data are submitted accurately and in a timely manner to the CTMS via the 
electronic data capture system, Medidata Rave.   
 
Data are to be submitted via Medidata Rave to CTMS on a real-time basis, but no less than once 
every 2 weeks.  The timeliness of data submissions and timeliness in resolving data queries will 
be tracked by CTMS.  Metrics for timeliness will be followed and assessed on a quarterly basis.  
For the purpose of Institutional Performance Monitoring, data will be considered delinquent if it 
is greater than 4 weeks past due. 
 
Data from Medidata Rave and CTEP-AERS is reviewed by the CTMS on an ongoing basis as 
data is received.  Queries will be issued by CTMS directly within Rave.  The queries will appear 
on the Task Summary Tab within Rave for the CRA at the ETCTN to resolve.  Monthly web-
based reports are posted for review by the Drug Monitors in the IDB, CTEP.  Onsite audits will 
be conducted by the CTMS to ensure compliance with regulatory requirements, GCP, and NCI 
policies and procedures with the overarching goal of ensuring the integrity of data generated 
from NCI-sponsored clinical trials, as described in the ETCTN Program Guidelines, which may 
be found on the CTEP 
(http://ctep.cancer.gov/protocolDevelopment/electronic_applications/adverse_events.htm)  and 
CTSU websites. 
 
CTMS will utilize a core set of eCRFs that are Cancer Data Standards Registry and Repository 
(caDSR) compliant (http://cbiit.nci.nih.gov/ncip/biomedical-informatics-
resources/interoperability-and-semantics/metadata-and-models).  Customized eCRFs will be 
included when appropriate to meet unique study requirements.  The PI is encouraged to review 


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87 
the eCRFs, working closely with CTMS to ensure prospectively that all required items are 
appropriately captured in the eCRFs prior to study activation.  CTMS will prepare the eCRFs 
with built-in edit checks to the extent possible to promote data integrity. 
 
CDUS data submissions for ETCTN trials activated after March 1, 2014, will be carried out by 
the CTMS contractor, Theradex.  CDUS submissions are performed by Theradex on a monthly 
basis.  The trial’s lead institution is responsible for timely submission to CTMS via Rave, as 
above. 
 
Further information on data submission procedures can be found in the ETCTN Program 
Guidelines 
(http://ctep.cancer.gov/protocolDevelopment/electronic_applications/adverse_events.htm). 
 
13.3 
Data Quality Portal 
 
 The Data Quality Portal (DQP) provides a central location for site staff to manage unanswered 
queries and form delinquencies, monitor data quality and timeliness, generate reports, and review 
metrics.  
 
The DQP is located on the CTSU members’ website under Data Management.  The Rave Home 
section displays a table providing summary counts of Total Delinquencies and Total Queries.  
DQP Queries, DQP Delinquent Forms, DQP Form Status and the DQP Reports modules are 
available to access details and reports of unanswered queries, delinquent forms, forms with 
current status, and timeliness reports.  Site staff should review the DQP modules on a regular 
basis to manage specified queries and delinquent forms. 
 
The DQP is accessible by site staff who are rostered to a site and have access to the CTSU 
website.  Staff who have Rave study access can access the Rave study data via direct links 
available on the DQP modules. 
 
CTSU Delinquency Notification emails are sent to primary contacts at sites twice a month. These 
notifications serve as alerts that queries and/or delinquent forms require site review, providing a 
summary count of queries and delinquent forms for each Rave study that a site is participating in. 
Additional site staff can subscribe and unsubscribe to these notifications using the CTSU Report 
and Information Subscription Portal on the CTSU members’ website. 
 
To learn more about DQP use and access, click on the Help Topics button displayed on the Rave 
Home, DQP Queries, DQP Delinquent Forms, DQP Form Status, and DQP Reports modules.  
 
This study does not use the Rave Calendaring functionality and therefore the DQP Delinquent 
Forms module will not include details for this study, and the DQP Summary table on the Rave 
Home page will display N/A for the Total Delinquencies summary count. 
 
13.4 
CTEP Multicenter Guidelines 
 
N/A 


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88 
 
13.5 
Collaborative Agreements Language 
 
The agent(s) supplied by CTEP, DCTD, NCI used in this protocol is/are provided to the NCI 
under a Collaborative Agreement (CRADA, CTA, CSA) between the Pharmaceutical 
Company(ies) (hereinafter referred to as “Collaborator(s)”) and the NCI Division of Cancer 
Treatment and Diagnosis.  Therefore, the following obligations/guidelines, in addition to the 
provisions in the “Intellectual Property Option to Collaborator”  
(http://ctep.cancer.gov/industryCollaborations2/intellectual_property.htm) contained within the 
terms of award, apply to the use of the Agent(s) in this study: 
 
1. Agent(s) may not be used for any purpose outside the scope of this protocol, nor can 
Agent(s) be transferred or licensed to any party not participating in the clinical study.  
Collaborator(s) data for Agent(s) are confidential and proprietary to Collaborator(s) and shall 
be maintained as such by the investigators.  The protocol documents for studies utilizing 
Agents contain confidential information and should not be shared or distributed without the 
permission of the NCI.  If a copy of this protocol is requested by a patient or patient’s family 
member participating on the study, the individual should sign a confidentiality agreement.  A 
suitable model agreement can be downloaded from: http://ctep.cancer.gov. 
 
2. For a clinical protocol where there is an investigational Agent used in combination with 
(an)other Agent(s), each the subject of different Collaborative Agreements, the access to and 
use of data by each Collaborator shall be as follows (data pertaining to such combination use 
shall hereinafter be referred to as "Multi-Party Data”): 
 
a. NCI will provide all Collaborators with prior written notice regarding the existence and 
nature of any agreements governing their collaboration with NCI, the design of the 
proposed combination protocol, and the existence of any obligations that would tend to 
restrict NCI's participation in the proposed combination protocol. 
 
b. Each Collaborator shall agree to permit use of the Multi-Party Data from the clinical trial 
by any other Collaborator solely to the extent necessary to allow said other Collaborator 
to develop, obtain regulatory approval or commercialize its own Agent. 
 
c. Any Collaborator having the right to use the Multi-Party Data from these trials must 
agree in writing prior to the commencement of the trials that it will use the Multi-Party 
Data solely for development, regulatory approval, and commercialization of its own 
Agent. 
 
3. Clinical Trial Data and Results and Raw Data developed under a Collaborative Agreement 
will be made available to Collaborator(s), the NCI, and the FDA, as appropriate and unless 
additional disclosure is required by law or court order as described in the IP Option to 
Collaborator (http://ctep.cancer.gov/industryCollaborations2/intellectual_property.htm).  
Additionally, all Clinical Data and Results and Raw Data will be collected, used and 
disclosed consistent with all applicable federal statutes and regulations for the protection of 
human subjects, including, if applicable, the Standards for Privacy of Individually 


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89 
Identifiable Health Information set forth in 45 C.F.R. Part 164. 
 
4. When a Collaborator wishes to initiate a data request, the request should first be sent to the 
NCI, who will then notify the appropriate investigators (Group Chair for Cooperative Group 
studies, or PI for other studies) of Collaborator's wish to contact them. 
 
5. Any data provided to Collaborator(s) for Phase 3 studies must be in accordance with the 
guidelines and policies of the responsible Data Monitoring Committee (DMC), if there is a 
DMC for this clinical trial. 
 
6. Any manuscripts reporting the results of this clinical trial must be provided to CTEP by the 
Group office for Cooperative Group studies or by the principal investigator for non-
Cooperative Group studies for immediate delivery to Collaborator(s) for advisory review and 
comment prior to submission for publication.  Collaborator(s) will have 30 days from the 
date of receipt for review.  Collaborator shall have the right to request that publication be 
delayed for up to an additional 30 days in order to ensure that Collaborator’s confidential and 
proprietary data, in addition to Collaborator(s)’s intellectual property rights, are protected.  
Copies of abstracts must be provided to CTEP for forwarding to Collaborator(s) for courtesy 
review as soon as possible and preferably at least three (3) days prior to submission, but in 
any case, prior to presentation at the meeting or publication in the proceedings.  Press 
releases and other media presentations must also be forwarded to CTEP prior to release.  
Copies of any manuscript, abstract and/or press release/ media presentation should be sent to: 
 
Email:  ncicteppubs@mail.nih.gov 
 
The Regulatory Affairs Branch will then distribute them to Collaborator(s).  No publication, 
manuscript or other form of public disclosure shall contain any of Collaborator’s confidential/ 
proprietary information. 
 
 
 
 
 


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Ni, J., Q. Liu, S. Xie, et al.  (2012).  Functional Characterization of an Isoform-Selective 
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Phosphatidylinositol 3′-Kinase Pathway Mutations to Effect Oncogenic Transformation. 
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Okkenhaug, K., and J.A. Burger.  (2016).  PI3K Signaling in Normal B Cells and Chronic 
Lymphocytic Leukemia (CLL).  Curr Top Microbiol Immunol.  393:123-142. 
 
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p110beta phosphatidylinositol 3-kinases in human mammary epithelial cells.  Proc Natl Acad Sci 
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growth factor signaling and oncogenic transformation. Proc Natl Acad Sci U S A 2006, 
103(44):16296-16300. 
 
 
 


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


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


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APPENDIX C 
PATIENT CLINICAL TRIAL WALLET CARD 
 
 
 
 
 
 
 
CLINCIAL TRIAL WALLET 
CARD 
Show this card to all of 
your healthcare 
providers and keep it 
with you in case you go 
to the emergency room. 
Patient Name:   
 
Diagnosis:        
Study Doctor:       
Study Doctor Phone #:       
NCI Trial #:  10287 
Study Drug(S)/regimen:        
 
 
 
 
For more information: 1-800-4-CANCER 
cancer.gov | clinicaltrials.gov 


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APPENDIX D 
THE AVERAGE GLYCEMIC INDEX OF COMMON FOODS DERIVED FROM MULTIPLE 
STUDIES BY DIFFERENT LABORATORIES 
 
Foods are categorized as having a low-glycemic index if the glucose reference index is ≤55.  High-Glycemic Index foods have a 
glucose reference index >55.  The summary table below contains glucose reference for common foods. 


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APPENDIX E 
MANAGEMENT OF TRANSIENT GLUCOSE INCREASE ON THE 
DAY OF COPANLISIB INFUSION 
 
Criteria 
Recommendation 
Suggested Treatment 
Asymptomatic 
glucose 
increases 
≤250mg/dL 
Does not generally require 
treatment with glucose lowering 
medication. 
None 
Asymptomatic 
glucose increase  
> 250 mg/dl 
• Should have repeated laboratory 
glucose determination. 
• If the repeated glucose value is 
decreasing, the glucose may be 
followed without glucose 
lowering medication treatment if 
hydration status is normal as 
clinically assessed. 
• Consultation with 
endocrinologist is recommended 
• Hydration if appropriate  
• When planning next 
infusion consider 
prophylaxis with oral 
glucose lowering medication 
Symptomatic or 
persisting 
glucose 
increases               
>250mg/dL 
• Hydration status should be 
clinically assessed.  
• If clinical assessment is 
consistent with dehydration, 
fluids should be given as 
clinically appropriate (orally or 
IV). 
• Laboratory test confirming 
increase should be repeated. If 
the repeated glucose value is 
persistent and/or patient is 
symptomatic and/or the hydration 
status indicates the need for 
hydration, glucose lowering 
medication should be 
administered. 
• Prompt input from a diabetes 
specialist should be obtained.  
• Hydration if appropriate  
• Rapid/ short acting insulin 
may be given for glucose 
persisting at >250 mg/dL, or 
if the patient is symptomatic 
during the infusion day. 
• 
According to the institution 
sliding scale coverage of 
glucose persisting at >250 
mg/dL is recommended, 
with oral or IV hydration as 
clinically appropriate When 
planning next infusion 
consider prophylaxis with 
oral glucose lowering 
medication 
 
 


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APPENDIX F 
MANAGEMENT OF TRANSIENT GLUCOSE INCREASE ON 
SUBSEQUENT DAYS FOLLOWING COPANLISIB INFUSION 
 
Criteria 
Recommendation 
Suggested Treatment 
Max post 
infusion 
glucose             
>200 mg/dL 
noted on  
subsequent 
days 
• Oral Glucose Lowering 
Medication Recommended 
on subsequent days.  
• Consultation with 
endocrinologist is 
recommended. 
• The use of 
sulphonylurea/metaglinides, insulin 
secretagogues medications to manage 
increased glucose levels post drug 
infusions is not recommended. 
• Treatment with glucose lowering 
medication suggested according the 
local standards of practice.  
• Based on mechanisms of action 
and decreased risk of 
hypoglycemia, metformin, SGLT- 
2-inhibitor or DPP4-inhibitor might 
be useful treatment options 
 
 


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APPENDIX G 
DOSE MODIFICATION OF COPANLISIB FOR ARTERIAL 
HYPERTENSION 
 
Toxicity (CTCAE) 
Study drug action 
Recommendation 
Pre-dose measurements 
BP ≥150/90 mmHg 
No dose should be given 
until recovery to 
<150/90 mmHg. 
Consider BP lowering medication. 
Dosing can proceed on the 
scheduled day if after at least 
2 consecutive measurements BP 
returns to <150/90 mmHg. If BP 
doesn’t return to <150/90 mmHg, 
delay dosing until next visit. 
During infusion: 
CTCAE hypertension of 
grade 3  
or ≥160/100 mmHg 
Infusion can be 
interrupted or slowed 
down and administration 
of BP lowering therapy 
should be initiated. 
Infusion may be resumed when BP 
has returned to <150/90 mmHg at 
the investigator’s discretion or 
skipped. 
Subsequent study drug 
administrations may be reduced by 
1 dose level at the investigator’s 
discretion.b 
Post-dose: 
Drug-related 
CTCAE hypertension of 
grade 3 
or ≥160/100 mmHg a  
– 
Administration of BP lowering 
therapy should be initiated 
according to local standard of 
care.   
Additional measurements to be 
performed as clinically indicated 
until recovery to <150/90 mmHg. 
Subsequent study drug 
administrations may be reduced by 
1 dose level at the investigator’s 
discretion.b 
CTCAE hypertension of 
grade 4 
 
Permanent discontinuation – 
CTCAE = Common Terminology Criteria for Adverse Events; BP = Blood pressure 
a: Not manageable despite optimal antihypertensive treatment. 
b: The lowest dose level is 30mg. 
 
 


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109 
APPENDIX H 
ABEMACICLIB MEDICATION DIARIES 
 
Today’s Date:    
 
Agent:  Abemaciclib – Daily Dosing 
Cycle:    
 
Study ID#:   
 
   
INSTRUCTIONS TO THE PATIENT: 
1. Complete one form for each month.  Take _____mg ( ___tablets) of abemaciclib at approximately the same time twice a 
day each day.  Swallow the tablets whole and do not chew them. 
2. Take abemaciclib with or without food. 
3. Record the date, the number of tablets taken, and when you took them. 
4. If you forgot to take your dose, then skip the dose and start taking at the next dosing time. 
5. If you have any questions or notice any side effects, please record them in the comments section.  Record the time if you 
should vomit.  If you vomit after taking a dose, DO NOT retake the dose.  Take the next dose at the usual time.  If you 
mistakenly take an extra dose, DO NOT take the next day’s dose. 
6. At the first sign of loose stools, start antidiarrheal medication (such as loperamide), increase your fluid intake, and tell 
your doctor.  
7. Please return the forms to your physician or your study coordinator when you go to your next appointment.  Please bring 
your unused study medications and/or empty bottles with you to each clinic visit so that a pill count can be done. 
8. Avoid St. John’s Wort, Seville oranges, grapefruit, grapefruit juice, grapefruit hybrids, pummelos, and exotic citrus fruits 
from 7 days before you start taking abemaciclib and throughout the entire study.   
Day 
Date 
What time was dose taken? 
# of capsules 
taken 
Comments 
AM dose 
PM dose 
1 
 
 
 
 
 
2 
 
 
 
 
 
3 
 
 
 
 
 
4 
 
 
 
 
 
5 
 
 
 
 
 
6 
 
 
 
 
 
7 
 
 
 
 
 
8 
 
 
 
 
 
9 
 
 
 
 
 
10 
 
 
 
 
 
11 
 
 
 
 
 
12 
 
 
 
 
 
13 
 
 
 
 
 
14 
 
 
 
 
 
15 
 
 
 
 
 
16 
 
 
 
 
 
17 
 
 
 
 
 
18 
 
 
 
 
 
19 
 
 
 
 
 
20 
 
 
 
 
 
21 
 
 
 
 
 
22 
 
 
 
 
 
23 
 
 
 
 
 
24 
 
 
 
 
 
25 
 
 
 
 
 
26 
 
 
 
 
 
27 
 
 
 
 
 
28 
 
 
 
 
 
 


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110 
APPENDIX H 
ABEMACICLIB MEDICATION DIARIES 
 
Today’s Date:    
 
Agent:  Abemaciclib – 5 Days On/2 Days Off  
Cycle:    
    Study ID#:    
 
 
INSTRUCTIONS TO THE PATIENT: 
1. Complete one form for each month.  Take _____mg ( ___tablets) of abemaciclib at approximately the same time twice a 
day each day for 5 days, then do not take any pills for 2 days. Repeat the 5 days of dosing followed by 2 days off 
throughout the cycle.  Swallow the tablets whole and do not chew them. 
2. Take abemaciclib with or without food. 
3. Record the date, the number of tablets taken, and when you took them. 
4. If you forgot to take your dose, then skip the dose and start taking at the next dosing time. 
5. If you have any questions or notice any side effects, please record them in the comments section.  Record the time if you 
should vomit.  If you vomit after taking a dose, DO NOT retake the dose.  Take the next dose at the usual time.  If you 
mistakenly take an extra dose, DO NOT take the next day’s dose. 
6. At the first sign of loose stools, start antidiarrheal medication (such as loperamide), increase your fluid intake, and tell your 
doctor.  
7. Please return the forms to your physician or your study coordinator when you go to your next appointment.  Please bring 
your unused study medications and/or empty bottles with you to each clinic visit so that a pill count can be done. 
8. Avoid St. John’s Wort, Seville oranges, grapefruit, grapefruit juice, grapefruit hybrids, pummelos, and exotic citrus fruits 
from 7 days before you start taking abemaciclib and throughout the entire study.   
Day 
Date 
What time was dose taken? 
# of tablets 
taken 
Comments 
AM dose 
PM dose 
1 
 
 
 
 
 
2 
 
 
 
 
 
3 
 
 
 
 
 
4 
 
 
 
 
 
5 
 
 
 
 
 
6 
 
 
 
 
 
7 
 
 
 
 
 
8 
 
 
 
 
 
9 
 
 
 
 
 
10 
 
 
 
 
 
11 
 
 
 
 
 
12 
 
 
 
 
 
13 
 
 
 
 
 
14 
 
 
 
 
 
15 
 
 
 
 
 
16 
 
 
 
 
 
17 
 
 
 
 
 
18 
 
 
 
 
 
19 
 
 
 
 
 
20 
 
 
 
 
 
21 
 
 
 
 
 
22 
 
 
 
 
 
23 
 
 
 
 
 
24 
 
 
 
 
 
25 
 
 
 
 
 
26 
 
 
 
 
 
27 
 
 
 
 
 
28 
 
 
 
 
 


 
 
 
 
 
NCI Protocol #:  10287 
Version Date:  June 13, 2024 
 
 
APPENDIX I  
PK SAMPLING MANUAL 
 
 
 
NorthEast BioAnalytical Laboratories 
 
 
 
 
 
Pharmacokinetic (PK) Sampling Manual 
 
 
Study Title  
 
A randomized phase II trial of fulvestrant and abemaciclib in 
combination with copanlisib (FAC) versus fulvestrant and 
abemaciclib alone (FA) for endocrine resistant, hormone receptor 
positive, HER2 negative metastatic breast cancer (FAC vs FA)  
 
 
Study Number: NCI Protocol #: 10287 
 
 
 
 
 
 
Version 1.0 
Dated: Nov 17, 2018 
 
 
 


 
 
 
 
 
NCI Protocol #:  10287 
Version Date:  June 13, 2024 
 
 
Table of Contents 
1.  Introduction…………………………………………………………………….……...……3 
2.  Laboratory Equipment and Supplies………………………………………….………...…..3 
2.1  Required Site Equipment and Supplies………………….………………....….3 
2.2  Pharmacokinetic Sample Collection Kit.…………………………………...…3 
3.  Sample Collection, Storage and Shipment…………………………………….………...….4 
3.1  Plasma Sample Collection and Processing for Pharmacokinetic Analysis…...…...4 
3.2  Sample Shipments…………………………………………………………………5 
 
ATTACHMENTS 
Sample Shipment Cover Sheet………………..…………………………………..……………8 
Sample Shipment Form for Pharmacokinetic Plasma...…………………………..……………9 
 
 


 
 
 
 
 
NCI Protocol #:  10287 
Version Date:  June 13, 2024 
 
 
1. Introduction 
The purpose of this laboratory manual is to specify all the instructions for the 
collection, processing, storing and shipping of plasma samples for drug 
concentration / pharmacokinetic measurements. 
 
2. Laboratory Equipment and Supplies 
 
1.1 Required Site Equipment and Supplies: 
 
• –70C freezers to store all samples until shipment and a temperature control log 
to ensure stable storage conditions.  
• Refrigerated centrifuge (4 C) for centrifuging blood samples to obtain plasma.   
• Dry ice. 
Notify vipin.agarwal@nebiolab.com or jonathan.quick@nebiolab.com if you do not 
have any of the above supplies. 
 
2.2  Pharmacokinetic Sample Collection Kits  
 
Kits will be provided by NorthEast Bioanalytical Laboratories and will contain the 
following supplies: 
➢ Pharmacokinetic blood sample draw tubes ( 4 ml Li-Heparin BD vacutainers,  
green cap, Cat. No.367884) – (19 count) 
➢ 2 mL cryovials – (19 count) 
➢ Labels for blood draw tubes and cryovials – 1 sheet 
➢ A cardboard box to place tubes – 1 count 
➢ Requisitions (Sample Shipment Form) – 1 count 
➢ Styrofoam boxes and shipping containers – 1 count 
➢ Disposable plastic transfer pipettes – (Phase Ib-12 count/Phase II 6 count) 
➢ KPA/biohazard bags, Saf-T Pak bag – 1 count 
➢ FedEx shipping labels 
For Re-ordering of Supplies please contact vipin.agarwal@nebiolab.com or 
jonathan.quick@nebiolab.com at least one week in advance to ensure that 
supplies are shipped in time.  
 
3. Plasma Sample Collection, Storage and Shipment 
 
3.1 Plasma Sample Collection for Pharmacokinetic Analysis 
 
• Collect one 4 mL blood sample for analysis by venipuncture at the 
following time points:  
 
Visit 
Scheduled time point   
Cycle 1 Day 1 (C1D1) 
Pre-infusion (up to 30 minutes prior to the start of the infusion) 
Cycle 1 Day 1 
10 minutes (± 2 minutes after the start of the infusion) 


 
 
 
 
 
NCI Protocol #:  10287 
Version Date:  June 13, 2024 
 
 
Cycle 1 Day 1 
1 hour (± 5 minutes after the start of the infusion) 
Cycle 1 Day 1 
2 hour (± 5 minutes after the start of the infusion) 
Cycle 1 Day 1 
3 hour (± 5 minutes after the start of the infusion) 
Cycle 1 Day 1 
5 hour (± 5 minutes after the start of the infusion) 
Cycle 1 Day 2 (C1D2) 
24 hour (± 1 hr after the start of the infusion; prior to the first dose of 
palbo and fulvestrant) 
Cycle 1 Day 15 (C1D15) 
Pre-infusion (up to 30 minutes prior to the start of the infusion) 
Cycle 1 Day 15 
10 minutes (± 2 minutes after the start of the infusion) 
Cycle 1 Day 15 
1 hour (± 5 minutes after the start of the infusion) 
Cycle 1 Day 15 
2 hour (± 5 minutes after the start of the infusion) 
Cycle 1 Day 15 
3 hour (± 5 minutes after the start of the infusion) 
Cycle 1 Day 15 
5 hour (± 5 minutes after the start of the infusion) 
Cycle 1 Day 16 (C1D16) 
24 hour (± 1 hr after the start of C1D15 infusion; prior to the C1D16 
palbo and fulvestrant) 
Cycle 1  Day 22 (C1D22) 
Prior to the morning dose of abemaciclib 
Cycle 1 Day 22 
1 hour after taking the morning dose of abemaciclib 
Cycle 1 Day 22 
2 hour after taking the morning dose of abemaciclib 
Cycle 1 Day 22 
4 hour after taking the morning dose of abemaciclib 
Cycle 1 Day 22 
23 hour (1 hour before C1D23’s abemaciclib) 
 
• Pharmacokinetic Plasma Sample Processing 
Note:  Read instructions entirely before processing samples.  Keep vacutainer 
tubes on ice when not being used. 
1. Collect 4 mL blood in a vacutainer tube (as specified above) at each time 
point using adequately labeled vacutainer tubes containing Li-Heparin 
(green top tube).   
2. Gently invert vacutainer tubes several times to mix with anticoagulant.   
3. Immediately place vacutainer tubes on ice (baggie, cup or basin with ice). 
4. Within 10-15 minutes after collecting blood, centrifuge each vacutainer 
tube at 4ºC for 10 minutes at 1000 g to separate the plasma.  If a 
refrigerated centrifuge is not available, it is imperative that the 
vacutainer tubes are placed on ice for a minimum of 10 minutes prior 
to centrifugation. 
5. Using disposable plastic transfer pipettes, aspirate off the plasma layer 
from one vacutainer tube.  (If you are processing samples collected from 
more than one time point, use a new pipette for each vacutainer tube.) 
6. Pipette the plasma into a 2-ml screw cap polypropylene cryovial.   
7. Complete sample label for “PK-Plasma” and affix to the cryovial.  


 
 
 
 
 
NCI Protocol #:  10287 
Version Date:  June 13, 2024 
 
 
8. Freeze samples in cryovial upright at -60 C to  -80 C in the cardboard 
storage box provided no later than 60 minutes after blood draw.  
9.  If you have successfully processed the samples according to the above 
instructions, appropriately dispose of vacutainers and prepare to ship 
samples within 24 hours of completing Cycle 1 Day 22.   
10. Note:  Document any significant deviations from the collection or 
processing instructions in the space provided on the Sample Shipment 
Form.  
 
3.2  Sample Shipments: 
 
The site will complete the FedEx shipping airway bill and e-mail or fax a copy of 
the completed sample shipment cover (pg. 8) to NEBA as a pre-shipment 
notification. Then, the site will arrange sample pick up by courier. The site is 
responsible for obtaining  dry ice for shipment.  
The following instructions need to be followed for sample pick up and shipment.  
1. 
Verify that each sample is labeled properly, the label is completed and 
affixed to the cryovial, and the corresponding Sample Shipment Form has 
been completed. Please make sure that samples are organized in boxes 
by Patient and collection time points. 
2. 
Remove cardboard storage box containing cryovials from freezer.  
3. 
Place box into large biohazard bag.  Seal bag completely. 
4. 
Insert sealed biohazard bag into white “Saf-T-Pak” envelope. 
5. 
Place original Sample Shipment Forms into the “Saf-T-Pak” envelope, 
between the plastic biohazard bag and envelope.   Retain a copy in your 
site file. 
6. 
Place envelope containing storage box inside cooler.  
7. 
Fill cooler completely with dry ice. 
8. 
Place cover on the cooler.  
9. 
Place cooler in the fiberboard container, close the cardboard flaps and 
secure with tape. 
10. Complete Shipper’s Information and Dry Ice Information on the outside of 
the container (name, address, phone, amount of Dry Ice). 
11. Affix completed Airbill on top of container in designated area. 
The package is now ready for shipping.  
 
• Batch ship frozen samples on Monday, Tuesday or Wednesday for overnight 
delivery after all samples for a subject have been obtained.  Do not ship samples 
on Thursday or Friday.   
• Notify recipient via e-mail or Fax at least one day in advance of shipping the 
samples by faxing Sample Shipment Cover. 
• Ship samples to: 


 
 
 
 
 
NCI Protocol #:  10287 
Version Date:  June 13, 2024 
 
 
 
Vipin Agarwal, PhD 
NorthEast Bioanalytical Laboratories 
925 Sherman Avenue 
Hamden, CT 06514 
USA 
Tel: +1-203-361-3768 
Fax: +1-203-407-0703 
E-mail: vipin.agarwal@nebiolab.com or jonathan.quick@nebiolab.com  
 
Prior to shipment, please ensure: 
• all cryovials  are stored in a cardboard storage box.  Each box can 
accommodate  81 2 mL cryovials; up to two cardboard storage boxes 
may be included in each styrofoam shipping container filled with dry 
ice. 
• all tubes are packaged according to the instructions in section 3.2. 
• all tubes are labeled appropriately and match shipping forms 
•  all corresponding Sample Shipment Forms and Sample Shipment Cover 
are included 
• Provide notification of shipment along with FedEx tracking number to : 
▪ vipin.agarwal@nebiolab.com and 
jonathan.quick@nebiolab.com 
 
 


 
 
 
 
 
NCI Protocol #:  10287 
Version Date:  June 13, 2024 
 
 
Sample Shipment Cover 
Key Study Data 
Study Identifier : NCI Protocol 10287 (FAC vs FA) 
 
FedEx Tracking Number:_____________________________ 
Responsibilities/Contacts  
Function: Investigator  
Study Manager 
Other 
(e.g.CRO) 
Receiving Lab 
 
Name: 
 
 
 
Vipin Agarwal, PhD 
Address:  
 
 
 
 
 
NorthEast 
Bioanalytical 
Laboratories 
925 Sherman Ave 
Hamden, CT  06514 
 
 
Site ID: 
 
 
N/A 
 
Phone: 
 
 
 
203-361-3768 
Fax: 
 
 
 
203-407-0703 
Email: 
 
 
 
Vipin.agarwal@nebiolab.com 
 
Key Shipment Data  
 
Analyte*: N/A 
Shipment from this site: First:    Interim:     Last shipment:   
No. of Boxes ____ 
No. of shipped samples: Plasma ____ ____ Aliqout 1/Aliqout 2 (circle one)_____________ 
Samples with known infectious agents (Yes / No):  
If Yes, which infectious agents: HIV___ Hepatitis ___ Other ______________________ 
Additional Info: 
Name of Shipper: 
Date of Shipment: 
Signature: 
Confirmation of Receipt (to be faxed to Investigator/Shipper and XXXX-US)  
Comments: Shipment OK ? (Yes  / No ) 
If No, specify: Some Samples thawed   . Some Samples broken/open   . Other:____________ 
Total no. of samples received (N= __) deviates from schedule (N= ___). Sample lists missing  . 
Further Comments: 
 
Name of Recipient: 
Date: 
Signature: 
Distribution:  
 
Original: Please attach at top inside of the shipment container 
Fax: Send in parallel to 203-407-0703 
Copy: Retain in Investigator Site Fil


NCI Protocol #:  10287 
Version Date:  June 13, 2024 
118 
Sample Shipment Form  
For Pharmacokinetic Samples 
Key Study Data 
Study Identifier: NCI Protocol 10287 (FAC vs FA) 
Investigator Name:  
 
Date of Shipment: ____/____/200__ 
                                (mm/dd/yyyy) 
Matrix: Plasma 
Analyte:  
 
Additional Info for all shipped samples: 
 
Sample Details 
Site Number:  ___ ___  
Subject Number ___ ___ ___ ___  
Sample 
Visit  
Planned Collection Time 
Collection date 
(mm/dd/yyyy) 
Actual 
Collection time 
(Per Clock) 
Rec’d at 
NEBL 
1 
Cycle 1 Day 1 
Pre-infusion (up to 30 minutes prior to the start of infusion) 
 
 
 
2 
Cycle 1 Day 1 
10 minutes (± 2 minutes after the start of the infusion) 
 
 
 
3 
Cycle 1 Day 1 
1 hour (± 5 minutes after the start of the infusion) 
 
 
 
4 
Cycle 1 Day 1 
2 hour (± 5 minutes after the start of the infusion) 
 
 
 
5 
Cycle 1 Day 1 
3 hour (± 5 minutes after the start of the infusion) 
 
 
 
6 
Cycle 1 Day 1 
5 hour (± 5 minutes after the start of the infusion) 
 
 
 
7 
Cycle 1 Day 2  
24 hour (± 1 hr after the start of the infusion; prior to the 
first dose of palbo and fulvestrant) 
 
 
 
8 
Cycle 1 Day 15 Pre-infusion (up to 30 minutes prior to the start of infusion) 
 
 
 
9 
Cycle 1 Day 15 10 minutes (± 2 minutes after the start of the infusion) 
 
 
 
10 
Cycle 1 Day 15 1 hour (± 5 minutes after the start of the infusion) 
 
 
 
11 
Cycle 1 Day 15 2 hour (± 5 minutes after the start of the infusion) 
 
 
 
12 
Cycle 1 Day 15 3 hour (± 5 minutes after the start of the infusion) 
 
 
 
13 
Cycle 1 Day 15 5 hour (± 5 minutes after the start of the infusion) 
 
 
 
14 
Cycle 1 Day 16  24 hour (± 1 hr after the start of C1D15 infusion; prior to 
the C1D16 palbo and fulvestrant) 
 
 
 
15 
Cycle 1  Day 22 
(C1D22) 
Prior to the morning dose of abemaciclib 
 
 
 
16 
Cycle 1 Day 22 1 hour (± 5 minutes) after taking the morning dose of 
abemaciclib 
 
 
 
17 
Cycle 1 Day 22 2 hour (± 5 minutes) after taking the morning dose of 
abemaciclib 
 
 
 
18 
Cycle 1 Day 22 4 hour (± 5 minutes) after taking the morning dose of 
abemaciclib 
 
 
 
19 
Cycle 1 Day 22 23 hour (± 1 hr) after the morning dose of 
abemaciclib 
 
 
 


 
 
 
 
 
NCI Protocol #:  10287 
Version Date:  June 13, 2024 
 
 
 
Distribution: 
 
 
 
 
Signature: __________________________ 
 
Original: Please attach at top inside of the shipment container  
Fax: Send to (203)- 407-0703 
Copy: Retain in Investigator Site File 
 
 


 
 
 
 
 
NCI Protocol #:  10287 
Version Date:  June 13, 2024 
 
 
APPENDIX J 
TISSUE BIOPSY VERIFICATION 
A copy of the diagnostic pathology report must be shipped with all tissue specimens sent 
to the EET Biobank. 
If the corresponding pathology report is not available for the biopsy, then a copy 
of the radiology report or operative report from the biopsy procedure and the 
diagnostic pathology report must be sent to the EET Biobank. A completed copy 
of this appendix (i.e., Tissue Biopsy Verification) must also be submitted to the 
EET Biobank. 
Note: If this information is not provided with the biopsy specimen, then it will not be 
accepted by the EET Biobank. 
 
Please have the Clinician* responsible for signing out this patient’s case complete the 
following: 
ETCTN Universal Patient ID:  
 
ETCTN Patient Study ID:   
 
Date of Procedure (mm/dd/yyyy):   
 
Tissue Type (circle one): 
Primary 
Metastatic 
Time point (circle one):  Archival       Pre-treatment      C1D15       Progression  
 
Site Tissue Taken From:   
 
Diagnosis:   
 
I agree that this tissue may be released for research purposes only and that the release 
of this tissue will not have any impact on the patient’s care. 
Clinician Signature 
Date 
Clinician Printed Name 
 
*Note: For the purposes of this form, Clinician could include the Nurse Practitioner, Registered 
Nurse, Pathologist, Radiologist, Interventional Radiologist, Surgeon, Oncologist, Internist, or 
other medical professional responsible for the patient’s care.  
Version: 1 
Effective Date: 9/2019 
 
 

ICF_002.pdf: 
i 
 
SUMMARY OF CHANGES – Consent 
 
NCI Protocol #:  10287 
Local Protocol #:  201911082 
Protocol Version Date:  June 13, 2024 
 
Protocol Title:  A randomized Phase I/II trial of fulvestrant and abemaciclib in combination 
with copanlisib (FAC) versus fulvestrant and abemaciclib alone (FA) for endocrine-resistant, 
hormone receptor positive, HER2 negative metastatic breast cancer (FAC vs FA) 
 
Informed Consent Version Date:  June 13, 2024 
 
I. 
Summary of Changes with Protocol Version June 13, 2024 
 
Section 
Comments 
1. 
Global 
Protocol version updated.  
 
II. 
CIRB Letter, 11/21/2023, CIRB Approval Pending Modification of Amendment 
Review 
# 
Section 
Comments 
1. 
 What will 
happen if I 
decide to take 
part in this 
study? 
Incorporate language regarding the recent copanlisib FDA approval 
withdrawal into the Protocol and Consent Form. 
 
PI Response: This has been updated as requested. 
 
 
III. 
Disapproval Letter, 09/27/2023, Review of Amendment #11 of Protocol #10287* 
*Of note, protocol version dated 09/07/2023 was titled Amendment 8a. 
# 
Section 
Comments 
2. 
 Consent form 
Genetic Testing Risks 
The genetic tests used in this study will test your tumor and normal 
tissue for genetic changes. Changes found in your normal tissue may 
be passed down in families. For example, these genetic changes may 
be passed down to your children in the same way that eye and hair 
color are passed down. Genetic tests of normal tissue can reveal 
information about you and also about your relatives. Your doctor will 
talk with you about what the test results may mean for you and your 


ii 
 
# 
Section 
Comments 
family. He or she may also suggest that you talk with a genetics 
counselor to learn more. You or your insurance plan would have to 
pay for visits to a genetic counselor 
There are NO integral genomic studies in this protocol, therefore no 
genomic results can be returned to patients or their doctors. This 
section must be removed. 
PI Response: This has been updated as requested. 
3. 
 Study Calendar 
Day 22 was removed from days of assessments for cycles 2 and 
beyond, in accordance with previous protocol calendar updates. 
 
IV. 
Disapproval Letter, 08/02/2023, Review of Amendment #10 of Protocol #10287* 
*Of note, protocol version reviewed was Amendment #8 dated July 10, 2023 
 
Section 
Comments 
1. 
Global 
Protocol version updated.  
2. 
Samples for 
known future 
studies 
Results will not be returned as stated under “Optional studies you can 
chose to take part in”  
Please delete the following language under “Samples for known future 
studies”  
I agree that my study doctor, or someone on the study team, may 
contact me or my doctor to see if I wish to learn about results from 
this study.  
YES        NO 
PI Response: This has been updated as requested. 
3. 
ICD  
Pg 19 
Study Calendar – remove the X for copanlisib on Day 8 as Day 8 and 
day 22 are removed from cycles 2 and beyond. 
PI Response: Only applicable to Phase II. 
4. 
ICD  
Pg 19, 20 0f 19 
Please correct page numbers 
PI Response: This has been updated as requested. 
 
V. 
Summary of Changes in Amendment #8 of Protocol #10287, dated July 10, 2023 
 


iii 
 
# 
Section 
Comments 
1. Global 
Protocol version date updated. 
Minor typographical and formatting issues fixed throughout. 
2. Study 
Calendar 
Updated the scan schedule to be every 3 cycles instead of every 12 weeks. 
 
 


Protocol Version Date: June 13, 2024 
Page 1 of 18 
10287 
Research Study Informed Consent Document – Phase 1 
 
Study Title for Study Participants:  Testing the addition of copanlisib to usual 
treatment (fulvestrant and abemaciclib) in metastatic breast cancer – Phase 1 
dose-finding study 
 
Official Study Title for Internet Search on http://www.ClinicalTrials.gov: 
10287, A randomized phase I/II trial of fulvestrant and abemaciclib in 
combination with copanlisib (FAC) versus fulvestrant and abemaciclib alone 
(FA) for endocrine resistant, hormone receptor positive, HER2 negative 
metastatic breast cancer (FAC vs FA) 
 
Overview and Key Information 
 
What am I being asked to do? 
We are asking you to take part in a research study.  This study has public funding from the 
National Cancer Institute (NCI), part of the National Institutes of Health (NIH) in the United 
States Department of Health and Human Services.  We do research studies to try to answer 
questions about how to prevent, diagnose, and treat diseases like cancer.  We are asking you to 
take part in this study because you have metastatic breast cancer that is hormone receptor (HR) 
positive and HER2 negative. 
 
Taking part in this study is your choice. 
You can choose to take part or you can choose not to take part in this study.  You also can 
change your mind at any time.  Whatever choice you make, you will not lose access to your 
medical care or give up any legal rights or benefits. 
 
This document has important information to help you make your choice.  Take time to read it.  
Talk to your doctor, family, or friends about the risks and benefits of taking part in the study.  
It’s important that you have as much information as you need and that all your questions are 
answered.  See the “Where can I get more information?” section for resources of more clinical 
trials and general cancer information. 
 
 
Why is this study being done? 
This study is being done to answer the following question: what are the effects (good and bad) of 
adding a specific drug, copanlisib, to the usual therapy of fulvestrant and abemaciclib?  The 
usual approach is defined as care most people get for metastatic breast cancer that is HR positive 
and HER2 negative. 
 
What is the usual approach to my metastatic breast cancer? 
People who are not in a study are usually treated with the combination including a drug like 
fulvestrant, which breaks down the estrogen receptor of the cancer cells, and a drug like 
abemaciclib, which interferes with cell growth.  This combination has received Food and Drug 
Administration (FDA) approval.  Fulvestrant and abemaciclib are FDA-approved because 


Protocol Version Date: June 13, 2024 
Page 2 of 18 
10287 
patients taking this combination have no cancer growth for longer duration than patients taking 
fulvestrant alone. 
 
What are my other choices if I decide not to take part in this study? 
• You may choose to have the usual approach described above. 
• You may choose to take part in a different research study, if one is available. 
• You may choose not to be treated for cancer. 
• You may choose to only get comfort care to help relieve your symptoms and not get 
treated for your cancer. 
 
What will happen if I decide to take part in this study? 
If you decide to take part in this study, you will get copanlisib along with abemaciclib and 
fulvestrant until your disease gets worse or the side effects become too severe. 
 
After you finish your treatment, your doctor and study team will watch you for side effects.  
They will also check on you every 3 months for 5 years after treatment. 
 
In November 2023, results from another ongoing trial with copanlisib in patients with lymphoma 
did not demonstrate an improvement in efficacy in comparison to the standard of care treatment. 
Therefore, Bayer, manufacturer of copanlisib, decided to stop further studies with copanlisib. 
Since you have already enrolled to the trial, you may continue if your doctor feels it is providing 
clinical benefit, and if you consent. You should discuss treatment options with your doctor. If 
you and your doctor decide the appropriate treatment option is to continue treatment with 
copanlisib, then you may remain on study.   
 
What are the risks and benefits of taking part in this study? 
There are both risks and benefits to taking part in this study.  It is important for you to think 
carefully about these as you make your decision. 
 
Risks 
 
We want to make sure you know about a few key risks right now.  We give you more 
information in the “What risks can I expect from taking part in this study?” section. 
 
If you choose to take part in this study, there is a risk that the study approach may not be as good 
as the usual approach for your cancer at shrinking or stabilizing your cancer. 
There is also a risk that you could have side effects from the study drugs.  These side effects may 
be worse and may be different than you would get with the usual approach for your cancer.  
Some side effects may be mild.  Other side effects may be serious and even result in death. 
 
Some of the most common side effects that the study doctors know about are:  
• nausea   
• fatigue 
• elevated blood sugar. 
 
There may be some risks that the study doctors do not yet know about. 


Protocol Version Date: June 13, 2024 
Page 3 of 18 
10287 
 
Benefits 
 
It is however not known if the study drugs will extend your life compared to the usual approach.  
This study will help the study doctors learn things that will help people in the future. 
 
If I decide to take part in this study, can I stop later? 
Yes, you can decide to stop taking part in the study at any time. 
 
If you decide to stop, let your study doctor know as soon as possible.  It’s important that you stop 
safely.  If you stop, you can decide if you want to keep letting the study doctor know how you 
are doing. 
 
Your study doctor will tell you about new information or changes in the study that may affect 
your health or your willingness to continue in the study. 
 
Are there other reasons why I might stop being in the study? 
Yes.  The study doctor may take you off the study if: 
• Your health changes and the study is no longer in your best interest 
• New information becomes available and the study is no longer in your best interest 
• You do not follow the study rules 
• You become pregnant while on the study 
• The study is stopped by the Institutional Review Board (IRB), or Food and Drug 
Administration (FDA), or study sponsor (National Cancer Institute (NCI)). The study 
sponsor is the organization who oversees the study. 
 
It is important that you understand the information in the informed consent before making 
your decision.  Please read, or have someone read to you, the rest of this document.  If there is 
anything you don’t understand, be sure to ask your study doctor or nurse. 
 
What is the purpose of this study? 
The purpose of this study is to test the good and bad effects of adding a specific drug, copanlisib, 
to the usual therapy of fulvestrant and abemaciclib.  The addition of copanlisib to fulvestrant and 
abemaciclib could shrink your cancer and prevent tumor growth based on studies done in the 
laboratory but it could also cause side effects.  This study will allow the researchers to know 
whether this different approach is better, the same, or worse than the usual approach.  To be 
better, the addition of copanlisib should increase the amount of time before a person’s disease 
progresses by six months or more compared to the usual approach.  This drug, copanlisib, stops a 
protein called phosphoinositide 3-kinase (PI3K) that is often changed (or mutated) in cancer cells 
and causes resistance to treatment.  It is already FDA-approved for use in follicular lymphoma 
but is not FDA-approved for the treatment of breast cancer.  There will be about 194 people 
taking part in this study 24 people in the first part of the study and about 170 people in the 
second part of the study. 
 
What are the study groups? 


Protocol Version Date: June 13, 2024 
Page 4 of 18 
10287 
This consent form covers the first part of the study.  During this part of this study, different doses 
of the study drug, copanlisib, and one of the standard of care drugs, abemaciclib, along with 
standard dose of fulvestrant, will be given to several study participants to determine the 
appropriate drug doses.   
 
Copanlisib and fulvestrant will be administered in the clinic.  Copanlisib is given as an 
intravenous (IV) infusion on Days 1 and 15 or Days 1, 8, and 15 of each 28-day cycle; the 
number of doses of copanlisib you receive will depend on when you enroll in the study and what 
side effects other study participants have experienced.  Fulvestrant is given as an intramuscular 
injection on Days 2 and 16 of the first cycle and on Day 1 of every cycle after that.  Abemaciclib 
is an oral drug which you will take at home either twice a day for 5 days followed by a two day 
rest period each week.  Abemaciclib will start on Day 2 through Day 5 during the first week, 
then Day 1 through 5 with two day rest period each week after that.   
 
The first several study participants will receive a low dose of copanlisib.  If the drugs cause 
serious side effects, the dose of copanlisib will be lowered for the next group of study 
participants.  If the drugs do not cause serious side effects, the dose of copanlisib will be 
increased for the next group of study participants.  Once the best dose of copanlisib is found, 
recruitment to the first part of the study will be stopped.  This dose will be used in the second 
part of the study.  You will be able to receive treatment with copanlisib, fulvestrant, and 
abemaciclib for as long as you are benefitting. 
 
We recommend that, on the days when copanlisib is admistered, you bring your abemaciclib 
with you and not to take the morning dose of abemaciclib until 1 hour after completing the 
infusion of copanlisib.  Do not eat within 4 hours of each copanlisib dose.  You made need to 
discuss with your dietician if you need to change your normal diet to avoid foods that raise your 
blood sugar.  Take the evening dose of abemaciclib approximately 12 hours from the morning 
dose. 
 
What exams, tests, and procedures are involved in this study? 
Before you begin the study, your doctor will review the results of your exams, tests, and 
procedures.  This helps your doctor decide if it is safe for you to take part in the study.  If you 
join the study, you will have more exams, tests, and procedures to closely monitor your safety 
and health.  Most of these are included in the usual care you would get even if you were not in a 
study. 
 
Listed below are exams, tests, and procedures that need to be done as part of this study to 
monitor your safety and health, but may not be included in the usual care.  We will use them to 
carefully follow the effects of the study treatment, including preventing and managing side 
effects. 
 
• 
Blood tests to see how your blood is clotting before you begin the study 
• 
Blood test to check your average blood sugar over the last few months before you begin 
the study 
• 
Blood tests to see whether you have hepatitis before you begin the study 


Protocol Version Date: June 13, 2024 
Page 5 of 18 
10287 
• 
Echocardiogram or MUGA scan to check how your heart is functioning before you begin 
the study 
• 
Electrocardiogram to check how your heart is functioning before you begin the study 
• Blood tests to monitor blood sugar before administration of copanlisib, 60 minutes after 
the start of the copanlisib infusion, 1 hour after the end of the infusion (Day 1 only), and 
2 hours after the end of the infusion (Day 1 only) 
• Monitoring of blood pressure on each dosing day 
 
Some exams, tests, and procedures are a necessary part of the research study, but would not be 
included in usual care.  Listed below are procedures that will be done for research purposes only. 
 
Tumor biopsy for research:  Small pieces of cancer tissue removed by surgery (biopsies) will 
be taken for the study before you begin treatment.  This sample is required if there are cancer 
sites that can be biopsied safely, in order for you to take part in this study because the research 
on the sample is an important part of the study.  There is also an optional research biopsy on 
Cycle 1 Day 15 and again if your disease progresses.  The research biopsy is done in a similar 
way to biopsies done for diagnosis.  The tissue collected will be used for research to look for 
some specific genetic mutations or markers in the cancer cell that might predict response to 
treatment.  If you agree, any specimen leftover will be stored for biobanking.  This will be 
discussed in the section on optional studies.  In addition, pieces of cancer tissue removed from 
your previous biopsies or surgeries for the breast cancer will be tested for mutations or markers 
that may predict response to therapy.   
 
Blood collection for research:  Blood samples will be taken for the study before you begin 
treatment and at the following time points: 
* Cycle 1 Day 8 (a cycle is 28 days of treatment) 
* Cycle 1 Day 15 
* Cycle 2 Day 1 
* Cycle 4 Day 1 
* Every 3 cycles 
* Before you begin your next treatment after you come off study treatment 
 
In addition, research blood draws to look at how your body processes copanlisib and abemaciclib 
will be done; these blood draws will take place at 6 different time points on Cycle 1 Day 1, one 
time point on Cycle 1 Day 2, and again at 6 different time points on Cycle 1 Day 15, and one 
time point on Cycle 1 Day 16; then again at 4 different time point on Cycle 1 Day 22 and one 
time point on Cycle 1 Day 23 
 
The samples described above are required in order for you to take part in this study because the 
research on the sample is an important part of the study.  The blood will be collected at the same 
time as routine blood draws when possible to minimize the number of extra needlesticks you 
have.  The blood collected will be used for research to study whether specific markers in the 
blood may be associated with treatment response.  If you agree, any specimen leftover will be 
stored for biobanking.  This will be discussed in the section on optional studies. 
 


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A study calendar that shows how often these tests and procedures will be done is attached 
to the end of this consent form. 
 
What risks can I expect from taking part in this study? 
If you choose to take part in this study, there is a risk that the study approach may not be as good 
as the usual approach for your cancer at shrinking or stabilizing your cancer.  The schedule of 
taking abemaciclib for 5 days and then having a 2-day rest period is a change from the standard 
daily dosing schedule; this may result in your disease not responding as well to treatment, even 
when copanlisib is added. 
 
You may also have the following discomforts: 
• Spend more time in the hospital or doctor’s office than usual 
• Be asked sensitive or private questions about things you do not normally discuss 
• May not be able to take part in future studies 
 
The treatment used in this study could be very harmful to an unborn or newborn baby.  There 
may be some risks that doctors do not yet know about.  It is very important that you check with 
your study doctor about what types of birth control or pregnancy prevention to use during the 
study and for 3 months after you have completed the study if you have child bearing potential.   
 
If any of the research leads to new tests, drugs, or other commercial products, you will not share 
in any profits 
 
Biopsy Risks 
 
Common side effects of a biopsy are a small amount of bleeding at the time of the procedure, 
bruising, and pain at the biopsy site.  Pain can be treated with regular pain medications.  Rarely, 
an infection can occur.  You may sign a separate consent form for the study biopsy that describes 
the risks in more detail.   
 
Blood Draw Risks 
 
Some of the risks from drawing blood from your arm may include pain, bruising, light-
headedness, and rarely, infection.  For most people, needle punctures to get blood samples do not 
cause any serious harm.  The frequent research blood draws to look at how your body processes 
copanlisib and abemaciclib can cause some discomfort and maybe inconvenient to your 
schedule.   
 
Risk of Radiation Exposure from MUGA 
 
To determine whether you are eligible to participate in the study, a MUGA scan may be used to 
check your heart function (if this is the test your physician prefers over an echocardiogram).  
MUGA scan involves exposure to radiation. The risk of this procedure is small and is similar to 
that received from clinical x-ray and nuclear medicine studies. The amount of radiation exposure 
that you will receive from this procedure is equivalent to a uniform whole body exposure of 700 


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millirem. This is equal to 2.33 times the amount of natural background radiation that the average 
person in the United States receives each year (300 millirem).              
 
Side Effect Risks 
 
The drugs used in this study may affect how different parts of your body work such as your liver, 
kidneys, heart, and blood. The study doctor will be testing your blood and will let you know if 
changes occur that may affect your health. 
 
There is also a risk that you could have side effects from the study drugs.  Some side effects may 
be mild.  Other side effects may be serious and even result in death. 
 
Here are important points about side effects: 
• The study doctors do not know who will or will not have side effects. 
• Some side effects may go away soon, some may last a long time, or some may never go 
away. 
• Some side effects may make it hard for you to have children. 
• Some side effects may be mild.  Other side effects may be serious and even result in 
death. 
 
You can ask your study doctor questions about side effects at any time:   
• If you notice or feel anything different, tell your study doctor.  He or she can check to see 
if it is a side effect. 
• Your study doctor will work with you to treat your side effects. 
• Your study doctor may adjust the study drugs to try to reduce side effects. 
 
This study is looking at a combination of the usual drugs used to treat this type of cancer plus a 
study drug.  This different combination of drugs may increase your side effects or may cause 
new side effects. 
 
Drug Risks 
 
The tables below show the most common and the most serious side effects doctors know about. 
Keep in mind that there might be other side effects doctors do not yet know about. If important 
new side effects are found, the study doctor will discuss these with you. 
 
Possible Side Effects of Abemaciclib 
 
COMMON, SOME MAY BE SERIOUS   
In 100 people receiving abemaciclib (LY2835219), more than 20 and up to 100 may have: 
• 
Anemia which may require blood transfusion 
• 
Diarrhea, nausea, vomiting 
• 
Tiredness 
• 
Bruising, bleeding 
• 
Loss of appetite 
 


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OCCASIONAL, SOME MAY BE SERIOUS   
In 100 people receiving abemaciclib (LY2835219), from 4 to 20 may have: 
• Belly pain 
• Dry mouth 
• Sores in the mouth which may cause difficulty swallowing 
• Infection, especially when white blood cell count is low 
• Changes in taste 
• Headache 
• Hair loss 
 
RARE, AND SERIOUS 
In 100 people receiving abemaciclib (LY2835219), 3 or fewer may have: 
• Damage to the lungs which may cause shortness of breath 
• Blood clot which may cause swelling, pain, shortness of breath 
 
 
Possible Side Effects of Fulvestrant 
 
COMMON, SOME MAY BE SERIOUS 
In 100 people receiving fulvestrant, more than 20 and up to 100 may have: 
• Pain 
• Tiredness 
• Increased sweating 
• Hot flashes, flushing 
• Swelling and redness at the site of the medication injection 
 
OCCASIONAL, SOME MAY BE SERIOUS 
In 100 people receiving fulvestrant, from 4 to 20 may have: 
• Constipation, diarrhea, nausea, vomiting, loss of appetite, heartburn 
• Swelling of the body 
• Loss of bone tissue, broken bone, or decreased height 
• Dizziness, headache 
• Difficulty sleeping 
• Fluid around lungs 
• Swelling of the liver which may cause belly pain 
• Worry, depression, mood swings 
• Hair thinning 
• Cough 
 
RARE, AND SERIOUS 
In 100 people receiving fulvestrant, 3 or fewer may have: 
• Allergic reaction which may cause rash, low blood pressure, wheezing, shortness of 
breath, swelling of the face or throat 
• Liver damage which may cause yellow eyes and skin 


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RARE, AND SERIOUS 
In 100 people receiving fulvestrant, 3 or fewer may have: 
• Vaginal bleeding 
• Blood clot which may cause swelling, pain, shortness of breath 
• Heart attack or heart failure which may result in chest pain, shortness of breath, swelling 
of ankles, and tiredness 
• Stroke which may cause weakness, paralysis 
 
Possible Side Effects of Copanlisib dihydrochloride 
(Table Version Date: April 2, 2023) 
COMMON, SOME MAY BE SERIOUS   
In 100 people receiving copanlisib dihydrochloride (BAY 80-6946 dihydrochloride), more 
than 20 and up to 100 may have: 
• 
Diarrhea 
• 
Tiredness 
• 
Infection, especially when white blood cell count is low 
• 
High blood pressure which may cause headaches, dizziness, blurred vision 
 
OCCASIONAL, SOME MAY BE SERIOUS   
In 100 people receiving copanlisib dihydrochloride (BAY 80-6946 dihydrochloride), from 
4 to 20 may have: 
• Anemia which may require blood transfusion 
• Sores in the mouth which may cause difficulty swallowing 
• Nausea, vomiting 
• Bruising, bleeding 
• Loss of appetite 
• Pain 
• Damage to the lungs which may cause shortness of breath 
• Rash 
 
RARE, AND SERIOUS 
In 100 people receiving copanlisib dihydrochloride (BAY 80-6946 dihydrochloride), 3 or 
fewer may have: 
• Change in the heart rhythm 
• Swelling and redness of the skin 
• Itching 
 
 
Patients with diabetes may need to increase or change their diabetic medications to better 
control their diabetes. 
 
Additional Drug Risks 
 


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Abemaciclib has been known to cause inflammation of the lungs. Copanlisib in combination 
with the other two drugs (FA) could cause an exacerbation of any side effect currently known to 
be caused by the other drug, or the combination of drugs and may result in side effects never 
previously associated with either of the three drugs.   
 
What are my responsibilities in this study? 
If you choose to take part in this study you will need to: 
 
• Keep your study appointments. 
• Tell your doctor about: 
o all medications and supplements you are taking 
o any side effects  
o any doctors’ visits or hospital stays outside of this study  
o if you have been or are currently in another research study. 
• Write down in your medication diary when you take the abemaciclib at home.   
 
Ways to keep from getting pregnant: 
 
Do not get pregnant or breastfeed while taking part in this study.  Tell your study doctor right 
away if you think that you become pregnant during the study or within 3 months after your last 
dose of study drug.  Use barrier method (condoms, diaphragms, or cervical caps) of birth control 
or abstinence for the duration of your study participation and for 6 months after your last day of 
study treatment. 
 
For men:  Do not father a baby while taking part in this study, or donate sperm for three (3) 
months following the last dose of your study drugs.   
 
Acceptable Birth Control Methods:  
 
• Condoms with spermicide AND one of the following: 
o Oral contraceptive or hormonal therapy (e.g., hormone implants, skin patches, 
intravaginal device, hormone shots). 
o Placement of an intra-uterine device (IUD; e.g., Mirena®). 
o Vasectomy, with participant assurance that the vasectomy was successful. 
o Tubal occlusion (i.e., getting your tubes tied). 
• Total sexual abstinence, when this is in line with your usual and/or preferred lifestyle.  
Periodic abstinence (e.g., calendar, ovulation), the rhythm method, and withdrawal are 
not acceptable methods of contraception. 
 
 
 
What are the costs of taking part in this study? 
You and/or your insurance plan will need to pay for the costs of medical care you get as part of 
this study, just as you would if you were getting the usual care for your cancer.  This includes: 
• 
the cost of tests, exams, procedures, and drugs that you get during the study to 
monitor your safety and prevent and treat side effects 


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• 
the costs of getting the copanlisib, abemaciclib, and fulvestrant ready and giving it to 
you 
• 
ECG 
• 
Echo/MUGA 
• 
your insurance co-pays and deductibles 
 
Talk to your insurance provider and make sure that you understand what your insurance pays for 
and what it doesn’t pay for if you take part in this clinical trial.  Also, find out if you need 
approval from your plan before you can take part in the study.  
 
Ask your doctor or nurse for help finding the right person to talk to if you are unsure which costs 
will be billed to you or your insurance provider.  
 
You and/or your insurance provider will not have to pay for exams, tests, and procedures done 
for research purposes only or that are covered by the study.  These include:   
• 
the research biopsies and research blood draws 
 
You or your insurance provider will not have to pay for the copanlisib while you take part in the 
study. 
 
Neither you nor your health care plan/insurance carrier will be billed for the collection of the 
tissue and blood that will be used for this study. 
 
Taking part in this study may mean that you need to make more visits to the clinic or hospital 
than if you were getting the usual approach to treat your cancer.  You may: 
 
• Have more travel costs. 
• Need to take more time off work. 
• Have other additional personal costs. 
 
You will not be paid for taking part in this study.  The research may lead to new tests, drugs, or 
other products for sale.  If it does, you will not get any payment. 
 
What happens if I am injured because I took part in this study? 
If you are injured as a result of taking part in this study and need medical treatment, please talk 
with your study doctor right away about your treatment options.  The study sponsors will not pay 
for medical treatment for injury.  Your insurance company may not be willing to pay for study-
related injury.  Ask them if they will pay.  If you do not have insurance, then you would need to 
pay for these medical costs. 
 
If you feel this injury was caused by medical error on the part of the study doctors or others 
involved in the study, you have the legal right to seek payment, even though you are in a study.  
Agreeing to take part in this study does not mean you give up these rights. 
 
Who will see my medical information? 


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Your privacy is very important to us.  The study doctors will make every effort to protect it.  The 
study doctors have a privacy permit to help protect your records if there is a court case.  
However, some of your medical information may be given out if required by law.  If this should 
happen, the study doctors will do their best to make sure that any information that goes out to 
others will not identify who you are. 
 
Some of your health information, such as your response to cancer treatment, results of study 
tests, medicines you took, and the results of any tumor and blood genetic testing will be kept by 
the study sponsor in a central research database. If information from this study is published or 
presented at scientific meetings, your name and other personal information will not be used. 
 
There are organizations that may look at or receive copies of some of the information in your 
study records. Your health information in the research database may also be shared with these 
organizations.  They must keep your information private, unless required by law to give it to 
another group. 
 
Some of these organizations are: 
• Bayer Pharmaceuticals (makers of copanlisib) or any drug company supporting the study 
now or in the future.  This would include any organization helping the company with the 
study. 
• The NCI Central IRB, which is a group of people who review the research with the goal 
of protecting the people who take part in the study. 
• The FDA and the groups it works with to review research 
• The NCI and the groups it works with to review research 
 
In addition to storing data in the study database, data from studies that are publicly funded may 
also be shared broadly for future research with protections for your privacy.  The goal of this 
data sharing is to make more research possible that may improve people’s health.  Your study 
records may be stored and shared for future use in public databases.  However, your name and 
other personal information will not be used.   
 
Some types of future research may include looking at information and information from other 
patients to see who had side effects across many studies or comparing new study data with older 
study data.  However, right now we don’t know what research may be done in the future using 
your information.  This means that: 
 
• You will not be asked if you agree to take part in the specific future research studies 
using your health information.   
• You and your study doctor will not be told when or what type of research will be done. 
• You will not get reports or other information about any research that is done using your 
information.  
• Because it may be possible to re-identify de-identified genomic data, even if access to 
data is controlled and data security standards are met, confidentiality cannot be 
guaranteed, and re-identified data could potentially be used to discriminate against or 
stigmatize participants, their families, or groups.  In addition, there may be unknown 
risks. 


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There are laws that protect your genetic information.  However, there is a risk that someone 
could get access to your genetic information and identify you by name.  In some cases, 
employers could use your genetic information to decide whether to hire or fire you.  The study 
doctors believe the risk of this happening is very small.  However, the risk may increase in the 
future as people find new ways of tracing information.  For more information about the laws that 
protect you, ask your study doctor. 
 
Where can I get more information? 
You may visit the NCI Web site at http://cancer.gov/ for more information about studies or 
general information about cancer. You may also call the NCI Cancer Information Service to get 
the same information at: 1-800-4-CANCER (1-800-422-6237). 
 
A description of this clinical trial will be available on http://www.ClinicalTrials.gov, as required 
by U.S. Law. This Web site will not include information that can identify you. At most, the Web 
site will include a summary of the results. You can search this Web site at any time. 
 
You can talk to the study doctor about any questions or concerns you have about this study or to 
report side effects or injuries. Contact the study doctor __________________ (insert name of 
study doctor[s]) at __________________ (insert telephone number). 
 
For questions about your rights while in this study, call the (*insert name of organization or 
center*) Institutional Review Board at (*insert telephone number*).  
 
Optional studies you can choose to take part in 
This part of the consent form is about optional studies that you can choose to take part in. They 
are separate from the main study described above.  These optional studies will not benefit your 
health. The researchers leading these optional studies hope the results will help other people with 
cancer in the future.  The results will not be added to your medical records and you or your study 
doctor will not know the results. 
 
Taking part in these optional studies is your choice.  You can still take part in the main study 
even if you say “no” to any or all of these studies. There is no penalty for saying “no.”  You and 
your insurance company will not be billed for these optional studies.  If you sign up for but 
cannot complete any of the studies for any reason, you can still take part in the main study. 
 
Circle your choice of “yes” or “no” for each of the following studies. 
 
Optional Sample Collections for known Laboratory Studies and/or storage for 
Possible Future Studies 
Researchers are trying to learn more about cancer and other health problems using blood and 
tissue samples from people who take part in clinical trials.  By studying these samples, 
researchers hope to find new ways to prevent, detect, treat, or cure diseases. 
 
Some of these studies may be about how genes affect health and disease.  Other studies may look 
at how genes affect a person’s response to treatment.  Genes carry information about traits that 


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are found in you and your family. Examples of traits are the color of your eyes, having curly or 
straight hair, and certain health conditions that are passed down in families.  Some of the studies 
may lead to new products, such as drugs or tests for diseases. 
 
Known Future Studies 
 
If you choose to take part in this optional study, leftover tissue and blood from other research 
collections will be collected.  The researchers ask your permission to store and use your samples 
and related health information (for example, your response to cancer treatment, results of study 
tests and medicines you are given) for medical research.  The research that may be done is 
unknown at this time.  Storing samples for future studies is called “biobanking”.  The Biobank is 
being run by Nationwide Children’s Hospital in Columbus, Ohio, and is supported by the NCI. 
 
Unknown Future Studies 
 
If you choose to take part in this optional study, leftover tissue and blood will be collected and 
stored.  Storing samples for future studies is called “biobanking.”  The biobank is being run by 
Nationwide Children’s Hospital in Columbus, Ohio, and is supported by the NCI.  This is a 
publicly funded study. Samples from publicly funded studies are required to be shared as broadly 
as possible. However, we will protect your privacy. The goal of this is to make more research 
possible that may improve people’s health.  
 
The biobank is a public research resource. It has controlled access.  This means that researchers 
who want to get samples and data from it must submit a specific research request. The request 
identifies who they are and what their planned research project is. Before getting the samples and 
data, the researchers must agree to keep the data private, only use it for their planned research 
project, and never use it to try to identify you.  
 
Right now, we don’t know what research may be done in the future using your blood and tissue 
samples.  This means that: 
 
• 
You will not be asked if you agree to take part in the future research studies.   
• 
You and your study doctor will not be told when or what type of research will be done. 
• 
You will not get reports or other information about any research that is done using your 
samples. 
 
What is involved in this optional sample collection? 
 
If you agree to take part, here is what will happen next: 
1) A sample from the tissue that was collected at the time of your research biopsies and 
blood that was collected at the time of your research blood draws will be sent to the 
Biobank, as well as the additional biopsies that will be performed on Cycle 1 Day 15 
and at the time of disease progression.   
2) Your sample and some related health information may be stored in the Biobank, 
along with samples and information from other people who take part.  The samples 


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will be kept until they are used up.  Information from your medical record will be 
updated from time to time. 
3) Qualified researchers can submit a request to use the materials stored in the Biobanks.  
A science committee at the clinical trials organization, and/or the National Cancer 
Institute, will review each request.  There will also be an ethics review to ensure that 
the request is necessary and proper.  Researchers will not be given your name or any 
other information that could directly identify you.  
4) Neither you nor your study doctor will be notified when research will be conducted or 
given reports or other information about any research that is done using your samples.  
5) Some of your genetic and health information may be placed in central databases that 
may be public, along with information from many other people.  Information that 
could directly identify you will not be included. 
 
What are the risks in this optional sample collection? 
• Generally, hospitals will keep some of your tissue.  This tissue may be used to help 
treat your cancer in the future.  There is a small risk that when this tissue sample is 
submitted to the biobank for this optional sample collection, your tissue could be used 
up. 
• Common side effects of a biopsy are a small amount of bleeding at the time of the 
procedure, bruising, and pain at the biopsy site.  Pain can be treated with regular 
pain medications.  Rarely, an infection, significant bleeding, or collapsing of the 
lung can occur.  You may sign a separate consent form for the study biopsy that 
describes the risks in more detail. 
• Your medical and genetic information is unique to you.  There is a risk that someone 
outside of the research study could get access to your study records or trace 
information in a database back to you.  They could use that information in a way that 
could harm you.  Researchers believe that the chance that someone could access and 
misuse your information is very small.  However, the risk may increase in the future 
as people find new ways of tracing information. 
• In some cases, this information could be used to make it harder for you to get or keep 
a job or insurance.  There are laws against the misuse of genetic information, but they 
may not give full protection. For more information about the laws that protect you, 
ask your study doctor or visit: https://www.genome.gov/10002328/ 
 
How will information about me be kept private? 
Your privacy is very important to the researchers and the biobank.  They will make every effort 
to protect it. Here are just a few of the steps they will take: 
1. They will remove identifiers, such as your initials, from your sample and information.  
They will replace them with a code number.  There will be a master list linking the code 
numbers to names, but they will keep it separate from the samples and information. 
2. Researchers who study your sample and information will not know who you are.  They 
also must agree that they will not try to find out who you are. 
3. Your personal information will not be given to anyone unless it is required by law.  
4. If research results are published, your name and other personal information will not be 
used. 
 


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What are the possible benefits to taking part in this optional sample collection? 
You will not benefit from taking part.  The researchers, using the samples from you and others, 
might make discoveries that could help people in the future. 
 
Are there any costs or payments to this optional sample collection? 
There are no costs to you or your insurance.  You will not be paid for taking part in this study.  
The research may lead to new tests, drugs, or other products for sale.  If it does, you will not get 
any payment. 
 
What if I change my mind about this optional sample collection? 
If you decide you no longer want your samples to be used, you can call the study doctor, (*insert 
name of study doctor for main trial*), at (*insert telephone number of study doctor for main 
trial*), who will let the biobank know.  Then, any sample that remains in the biobank will be 
destroyed or returned to your study doctor.  This will not apply to any samples or related health 
information that have already been given to or used by researchers. 
   
What if I have questions about this optional sample collection? 
If you have questions about the use of your samples for research, contact the study doctor, 
________________, (insert name of study doctor for main trial), at _____________________ 
(insert telephone number of study doctor for main trial). 
 
Please circle your answer below to show whether or not you would like to take part in each 
optional study: 
 
Additional (2nd) Tumor Biopsy  
 
Please circle your answer:  I choose to permit an additional tumor biopsy on Cycle 1 Day 15  
 
YES 
 
NO 
 
Additional (3rd) Tumor Biopsy  
 
Please circle your answer:  I choose to permit an additional tumor biopsy if the study treatment 
appears to help me, but my cancer later starts to grow.  
 
YES 
 
NO 
 
 
 
 
Samples for known future studies 
 
I agree that my samples and related health information may be used for the laboratory study 
described above. 
 
 
YES 
 
NO 


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Samples for unknown future studies 
 
I agree that my samples and related health information may be kept in a biobank for use in future 
health research. 
 
 
YES 
 
NO 
 
Contact for Future Research 
 
I agree that my study doctor, or someone on the study team, may contact me or my doctor to see 
if I wish to participate in other research in the future. 
 
 
YES 
 
NO 
 
This is the end of the section about optional studies. 
 
My Signature Agreeing to Take Part in the Study 
I have read this consent form or had it read to me.  I have discussed it with the study doctor and 
my questions have been answered.  I will be given a signed and dated copy of this form.  I agree 
to take part in the main study.  I also agree to take part in any additional studies where I circled 
‘yes’. 
 
_________________________________________________________________ 
Participant’s signature 
 
 
 
_________________________________________________________________ 
Date of signature 
 
 
 
 
 
 
 
_________________________________________________________________ 
Signature of person(s) conducting the informed consent discussion 
 
 
 
_________________________________________________________________ 
Date of signature 
  


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STUDY CALENDAR 
 
 
Screening* 
Pre-
treatment 
ACycle 1 
Day 1* 
Cycle 1 
Day 2* 
Cycle 1 
Day 8* 
ACycle 1 
Day 15* 
Cycle 1 
Day 16* 
Cycle 1 
Day 22* 
Cycle 1 
Day 23* 
Cycles after Cycle 1* 
End of 
TreatmentB* 
Day 1 
Day 8 
Day 
15 
Physical exam 
X 
 
X 
 
X 
X 
 
 
 
X 
 
 
 
Disease 
Assessment 
ImagingE 
X 
 
 
 
 
 
 
 
 
 
 
 
X 
Blood for 
safety labs 
X 
 
X 
 
X 
X 
 
X 
 
X 
 
X 
 
Echo/MUGA 
X 
 
 
 
 
 
 
 
 
 
 
 
 
ECG 
X 
As clinically indicated 
Pregnancy test 
XC 
 
 
 
 
 
 
 
 
 
 
 
 
Hepatitis panel 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Urinalysis 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Blood pressure 
 
 
X 
 
X 
X 
 
 
 
X 
X 
X 
 
Fulvestrant 
 
 
XA 
 
 
XA 
 
 
 
X 
 
 
 
Abemaciclib 
 
 
 
D2-5 the first week followed by 5 days with 2 days rest each week  
5 days with 2 days rest 
each week 
 
Copanlisib 
 
 
X 
 
X 
X 
 
 
 
X 
X 
X 
 
Archival tumor 
tissue 
 
X 
 
 
 
 
 
 
 
 
 
 
 
Fresh tumor 
biopsy 
 
X 
 
 
 
X** 
 
 
 
 
 
 
X** 
Blood for 
research 
 
X 
XA 
X 
X 
XA 
X 
X 
X 
XD 
 
 
X 
A. Note that the first dose (C1D1) of abemaciclib and fulvestrant will be delayed to C1D2 following the 24 hour PK blood draw.  In addition, the C1D15 dose 
of fulvestrant will be administered on C1D16 following the 24 hour PK draw.. 
B. Follow up for survival status occurs every 3 months (+/- 7 days) for 5 years after removal from the study or until death, whichever occurs first.  In addition, 
patients removed from study due to unacceptable adverse event(s) will be followed until resolution or stabilization of the adverse event. 
C. Pregnancy test is only applicable for patients with pregnancy potential.  It will be performed at screening, and then every 3 cycles on study. 
D. On Day 1 of Cycles 2 and 4 and then every 3 cycles after that. 
E.    Disease Assessment Imaging will be performed at screening, at the end of Cycle 3 (+/- 7 days), then every 3 cycles (+/- 7 days). 
**Optional 
*Visits can occur in ± 2 day window to allow for holidays, inclement weather, etc 
 

ICF_003.pdf: 
i 
 
SUMMARY OF CHANGES – Consent 
 
NCI Protocol #:  10287 
Local Protocol #:  201911082 
Protocol Version Date:  June 13, 2024 
 
Protocol Title:  A randomized Phase I/II trial of fulvestrant and abemaciclib in combination 
with copanlisib (FAC) versus fulvestrant and abemaciclib alone (FA) for endocrine-resistant, 
hormone receptor positive, HER2 negative metastatic breast cancer (FAC vs FA) 
 
Informed Consent Version Date:  June 13, 2024 
 
I. 
Summary of Changes with Protocol Version June 13, 2024 
 
Section 
Comments 
1. 
Global 
Protocol version updated.  
 
II. 
CIRB Letter, 11/21/2023, CIRB Approval Pending Modification of Amendment 
Review 
# 
Section 
Comments 
1. 
 Footer 
Updated version date. Due to study closure, this phase II consent will 
no longer be used. 
 
III. 
Disapproval Letter, 09/27/2023, Review of Amendment #11 of Protocol #10287* 
*Of note, protocol version dated 09/07/2023 was titled Amendment 8a. 
# 
Section 
Comments 
2. 
Genetic 
Testing 
Risks 
Genetic Testing Risks 
The genetic tests used in this study will test your tumor and normal tissue for 
genetic changes. Changes found in your normal tissue may be passed down in 
families. For example, these genetic changes may be passed down to your children 
in the same way that eye and hair color are passed down. Genetic tests of normal 
tissue can reveal information about you and also about your relatives. Your doctor 
will talk with you about what the test results may mean for you and your family. 
He or she may also suggest that you talk with a genetics counselor to learn more. 
You or your insurance plan would have to pay for visits to a genetic counselor 
There are NO integral genomic studies in this protocol, therefore no genomic 
results can be returned to patients or their doctors. This section must be removed. 
PI Response: This has been updated as requested. 


ii 
 
 
IV. 
Disapproval Letter, 08/02/2023, Review of Amendment #10 of Protocol #10287* 
*Of note, protocol version reviewed was Amendment #8 dated July 10, 2023 
 
Section 
Comments 
1. 
Global 
Protocol version updated.  
2. 
Samples for 
known future 
studies 
Results will not be returned as stated under “Optional studies you can 
chose to take part in”  
Please delete the following language under “Samples for known future 
studies”  
I agree that my study doctor, or someone on the study team, may 
contact me or my doctor to see if I wish to learn about results from 
this study.  
YES        NO 
PI Response: This has been updated as requested. 
3. 
Study Calendar  
Pg 19 
Study Calendar – remove the X for copanlisib on Day 8 as Day 8 and 
day 22 are removed from cycles 2 and beyond. 
PI Response: This has been updated as requested. 
4. 
ICD  
Pg 19, 20 0f 19 
Please correct page numbers 
PI Response: This has been updated as requested. 
 
V. 
Summary of Changes in Amendment #8 of Protocol #10287, dated July 10, 2023 
 
# 
Section 
Comments 
1. Global 
Protocol version date updated. 
Minor typographical and formatting issues fixed throughout. 
Any references to Abemaciclib Days 1-28 day dosing removed due to RP2D 
dosing regimen of 5 days on, 2 days off. 
2. What are 
the study 
groups? 
Clarified that the RP2D dosing regimen chosen was abemaciclib on a 5 days 
on, 2 days off schedule, and that for the first 4 patients randomized to FAC, the 
C1D1 dose is skipped due to PKs. 
3. Study 
Calendar 
Day 8 and Day 22 removed in cycles 2 and beyond. Abemaciclib dosing 
updated to be regimen of 5 days on, 2 days off. Removed erroneous mention of 
PKs in screening. Clarified that scans will be performed every 3 cycles, not 
every 12 weeks. 


iii 
 
 
 


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Research Study Informed Consent Document – Phase 2 
 
Study Title for Study Participants: A Phase 2 Study Testing the addition of 
copanlisib to usual treatment (fulvestrant and abemaciclib) in metastatic 
breast cancer 
 
Official Study Title for Internet Search on http://www.ClinicalTrials.gov: 10287 A 
randomized phase I/II trial of fulvestrant and abemaciclib in combination 
with copanlisib (FAC) versus fulvestrant and abemaciclib alone (FA) for 
endocrine resistant, hormone receptor positive, HER2 negative metastatic 
breast cancer (FAC vs FA) 
 
Overview and Key Information 
 
What am I being asked to do? 
We are asking you to take part in a research study.  This study has public funding from the 
National Cancer Institute (NCI), part of the Nationsl Institutes of Health (NIH) in the United 
States Department of Health and Human Services.  We do research studies to try to answer 
questions about how to prevent, diagnose, and treat diseases like cancer.  We are asking you to 
take part in this study because you have metastatic breast cancer that is hormone receptor (HR) 
positive and HER2 negative. 
 
Taking part in this study is your choice. 
You can choose to take part or you can choose not to take part in this study.  You also can 
change your mind at any time.  Whatever choice you make, you will not lose access to your 
medical care or give up any legal rights or benefits. 
 
This document has important information to help you make your choice.  Take time to read it.  
Talk to your doctor, family, or friends about the risks and benefits of taking part in the study.  
It’s important that you have as much information as you need and that all your questions are 
answered.  See the “Where can I get more information?” section for resources of more clinical 
trials and general cancer information. 
 
Why is this study being done? 
This study is being done to answer the following question: what are the effects (good and bad) of 
adding a specific drug, copanlisib, to the usual therapy of fulvestrant and abemaciclib?  We are 
doing this study because we want to find out if adding copanlisib is better or worse than the usual 
approach for your metastatic breast cancer that is HER2 negative.  The usual approach is defined 
as care most people get for metastatic breast cancer that is HR positive and HER2 negative. 
 
What is the usual approach to my metastatic breast cancer? 
People who are not in a study are usually treated with the combination of fulvestrant, which 
breaks down the estrogen receptor of the cancer cells, and a drug like abemaciclib, which 
interferes with cell growth.  This combination has received Food and Drug Administration 


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(FDA) approval.  Fulvestrant and abemaciclib are FDA approved because patients taking this 
combination have no cancer growth for longer duration than patients taking fulvestrant alone. 
 
What are my other choices if I decide not to take part in this study? 
• You may choose to have the usual approach described above. 
• You may choose to take part in a different research study, if one is available. 
• You may choose not to be treated for cancer. 
• You may choose to only get comfort care to help relieve your symptoms and not get 
treated for your cancer. 
 
What will happen if I decide to take part in this study? 
If you decide to take part in this study, you will either get copanlisib along with abemaciclib and 
fulvestrant or you will get abemaciclib and fulvestrant alone, until your disease gets worse or the 
side effects become too severe. 
 
After you finish your treatment, your doctor and study team will watch you for side effects.  
They will also check on you for every 3 months for 5 years after treatment. 
 
What are the risks and benefits of taking part in this study? 
There are both risks and benefits to taking part in this study.  It is important for you to think 
carefully about these as you make your decision.     
 
Risks 
 
We want to make sure you know about a few key risks right now.  We give you more 
information in the “What risks can I expect from taking part in this study?” section. 
 
If you choose to take part in this study, there is a risk that the study approach may not be as good 
as the usual approach for your cancer at shrinking or stabilizing your cancer. 
 
There is also a risk that you could have side effects from the study drugs.  These side effects may 
be worse and may be different than you would get with the usual approach for your cancer.  
Some side effects may be mild.  Other side effects may be serious and even result in death. 
 
Some of the most common side effects that the study doctors know about are:  
• Nausea 
• fatigue 
• elevated blood sugar. 
 
There may be some risks that the study doctors do not yet know about. 
 
Benefits 
 
It is however, not known if the study drugs will extend your life compared to the usual approach.  
This study will help the study doctors learn things that will help people in the future. 
 


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If I decide to take part in this study, can I stop later? 
Yes, you can decide to stop taking part in the study at any time. 
 
If you decide to stop, let your study doctor know as soon as possible.  It’s important that you stop 
safely. If you stop, you can decide if you want to keep letting the study doctor know how you are 
doing. 
 
Your study doctor will tell you about new information or changes in the study that may affect 
your health or your willingness to continue in the study. 
 
Are there other reasons why I might stop being in the study? 
Yes.  The study doctor may take you off the study if: 
• Your health changes and the study is no longer in your best interest 
• New information becomes available and the study is no longer in your best interest 
• You do not follow the study rules 
• You become pregnant while on the study 
• The study is stopped by the Institutional Review Board (IRB), or Food and Drug 
Administration (FDA), or study sponsor (National Cancer Institute (NCI)). The study 
sponsor is the organization who oversees the study. 
 
It is important that you understand the information in the informed consent before making 
your decision.  Please read, or have someone read to you, the rest of this document.  If there is 
anything you don’t understand, be sure to ask your study doctor or nurse. 
 
What is the purpose of this study? 
The purpose of this study is to test the good and bad effects of adding a specific drug, copanlisib, 
to the usual therapy of fulvestrant and abemaciclib.  The addition of copanlisib to fulvestrant and 
abemaciclib could shrink your cancer and prevent tumor growth based on studies done in the 
laboratory but it could also cause side effects.  This study will allow the researchers to know 
whether this different approach is better, the same, or worse than the usual approach.  To be 
better, the addition of copanlisib should increase the amount of time before a person’s disease 
progresses by six months or more compared to the usual approach.  This drug, copanlisib, stops a 
protein called phosphoinositide 3-kinase (PI3K) that is often changed (or mutated) in cancer cells 
and causes resistance to treatment.  It is already FDA-approved for use in follicular lymphoma 
but is not FDA-approved for the treatment of breast cancer.  There will be about 194 people 
taking part in this study 24 people in the first part of the study and about 170 people in the 
second part of the study. 
 
What are the study groups? 
The first part of the study determined the best dose of copanlisib that would be used in the 
second part.  This consent form covers the second part of the study.   
 
During the second part of this study, now that the appropriate doses of copanlisib and 
abemaciclib have been determined, participants will be assigned to one of two study groups.  
 


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Group 1 will receive the usual treatment for this type of cancer (abemaciclib and fulvestrant) 
along with the study drug, copanlisib.  Group 2 will receive the usual treatment for this type of 
cancer on its own. 
 
Copanlisib and fulvestrant will be administered in the clinic.  Copanlisib is given as an 
intravenous (IV) infusion on Days 1 and 15 of each 28-day cycle in patients assigned to Group 1.   
Fulvestrant is given as intramuscular injections on Days 1 and 15 of the first cycle and on Day 1 
of every cycle after that. Abemaciclib is an oral drug which you will take at home twice a day for 
5 days followed by a two day rest period each week.   
 
For the first 4 patients in Group 1, in Cycle 1 only, the schedule for fulvestrant and abemaciclib 
is altered by one to test the study treatment assignment interactions in your blood.  In these 
patients, fulvestrant is given Days 2 and 16 of the first cycle and on Day 1 of every cycle after 
that. The first 2 doses of abemaciclib on Day 1 will be skipped and dosing will start on Day 2 
and continue through Day 5, and then Days 8-12, 15-19, and 22-26.   
 
We recommend that, on the days when copanlisib is admistered (if receiving fulvestrant, 
abemaciclib and copanlisib), you bring your abemaciclib with you and not to take the morning 
dose of abemaciclib until 1 hour after completing the infusion of copanlisib.  Do not eat within 4 
hours of each copanlisib dose.  You made need to discuss with your dietician if you need to 
change your normal diet to avoid foods that raise your blood sugar.  Take the evening dose of 
abemaciclib approximately 12 hours from the morning dose.   
 
We will use a computer to assign you to one of the study groups.  This process is called 
“randomization.”  It means that your doctor will not choose and you cannot choose which study 
group you are in.  You will be put into a group by chance.  You will have an equal chance of 
being in Group 1 or Group 2. 
 
Another way to find out what will happen to you if you enroll during the second part of this 
study is to read the chart below.  Start reading at the left side and read across to the right, 
following the lines and arrows. 
 
 
 
You will be expected to complete a medication diary when you take abemaciclib at home.  
 
What exams, tests, and procedures are involved in this study? 
Randomize 
(The computer will 
randomly put you in 
a study group) 
Group 2 
Abemaciclib + Fulvestrant 
(Usual Treatment group) 
You agree to take 
part in the study 
and sign this 
consent form 
Group 1 
Copanlisib + Abemaciclib 
+ Fulvestrant 
(Study Group) 


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10287 
Before you begin the study, your doctor will review the results of your exams, tests, and 
procedures.  This helps your doctor decide if it is safe for you to take part in the study.  If you 
join the study, you will have more exams, tests, and procedures to closely monitor your safety 
and health.  Most of these are included in the usual care you would get even if you were not in a 
study. 
 
Listed below are exams, tests, and procedures that need to be done as part of this study to 
monitor your safety and health, but may not be included in the usual care.  We will use them to 
carefully follow the effects of the study treatment, including preventing and managing side 
effects. 
 
• 
Blood tests to see how your blood is clotting before you begin the study 
• 
Blood test to check your average blood sugar over the last few months before you begin 
the study 
• 
Blood tests to see whether you have hepatitis before you begin the study 
• 
Echocardiogram or multigated acquisition (MUGA) scan to check how your heart is 
functioning before you begin the study 
• 
Electrocardiogram to check how your heart is functioning before you begin the study 
• Blood tests to monitor blood sugar for all patients receiving copanlisib before 
administration of copanlisib, 60 minutes after the start of the copanlisib infusion, 1 hour 
after the end of the infusion (Day 1 only), and 2 hours after the end of the infusion (Day 1 
only) 
• Monitoring of blood pressure for all patients receiving copanlisib on each dosing day 
 
Some exams, tests, and procedures are a necessary part of the research study, but would not be 
included in usual care.  Listed below are procedures that will be done for research purposes only. 
 
Tumor biopsy for research:  Small pieces of cancer tissue removed by surgery (biopsies) will 
be taken for the study before you begin treatment.  This sample is required if there are cancer 
sites that can be biopsied safely, in order for you to take part in this study because the research 
on the sample is an important part of the study.  There is also an optional research biopsy on 
Cycle 1 Day 15 and again if your disease progresses.  The research biopsy is done in a similar 
way to biopsies done for diagnosis.  The tissue collected will be used for research to look for 
some specific genetic mutations or markers in the cancer cell that might predict response to 
treatment.  If you agree, any specimen leftover will be stored for biobanking.  This will be 
discussed in the section on optional studies.  In addition, pieces of cancer tissue removed from 
your previous biopsies or surgeries for the breast cancer will be tested for mutations or markers 
that may predict response to therapy.   
 
Blood collection for research: A blood sample will be taken for the study before you begin 
treatment and at the following time points: 
• Cycle 1 Day 8 (a cycle is 28 days of treatment)  
• Cycle 1 Day 15 
• Cycle 2 Day 1 
• Cycle 4 Day 1 
• Every 3 cycles 


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• Before you begin your next treatment after you come off study treatment 
 
In addition, research blood draws to look at how your body processes copanlisib and abemaciclib 
will be done for the first 4 patients in Group 1; these blood draws will take place at 6 different 
time points on Cycle 1 Day 1, one time point on Cycle 1 Day 2, and again at 6 different time 
points on Cycle 1 Day 15, and one time point on Cycle 1 Day 16; then again at 4 different time 
point on Cycle 1 Day 22 and one time point on Cycle 1 Day 23. 
 
The samples described above are required in order for you to take part in this study because the 
research on the sample is an important part of the study.  The blood will be collected at the same 
time as routine blood draws when possible to minimize the number of extra needlesticks you 
have.  The blood collected will be used for research to study whether specific markers in the 
blood may be associated with treatment response.  If you agree, any specimen leftover will be 
stored for biobanking.  This will be discussed in the section on optional studies. 
 
A study calendar that shows how often these tests and procedures will be done is attached 
to the end of this consent form. 
 
What risks can I expect from taking part in this study? 
If you choose to take part in this study, there is a risk that the study approach may not be as good 
as the usual approach for your cancer at shrinking or stabilizing your cancer.  The schedule of 
taking abemaciclib for 5 days and then having a 2-day rest period is a change from the standard 
daily dosing schedule; this may result in your disease not responding as well to treatment, even 
when copanlisib is added. 
 
You may also have the following discomforts: 
• Spend more time in the hospital or doctor’s office than usual 
• Be asked sensitive or private questions about things you do not normally discuss 
• May not be able to take part in future studies 
 
The treatment used in this study could be very harmful to an unborn or newborn baby.  There 
may be some risks that doctors do not yet know about.  It is very important that you check with 
your study doctor about what types of birth control or pregnancy prevention to use during the 
study and for 3 months after you have completed the study if you have child bearing potential. 
 
Biopsy Risks 
 
Common side effects of a biopsy are a small amount of bleeding at the time of the procedure, 
bruising, and pain at the biopsy site.  Pain can be treated with regular pain medications.  Rarely, 
an infection can occur.  You may sign a separate consent form for the study biopsy that describes 
the risks in more detail.   
 
Blood Draw Risks 
 
Some of the risks from drawing blood from your arm may include pain, bruising, light-
headedness, and rarely, infection.  For most people, needle punctures to get blood samples do not 


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cause any serious harm.  The frequent research blood draws to look at how your body processes 
copanlisib and abemaciclib can cause some discomfort and maybe inconvenient to your schedule 
 
Risk of Radiation Exposure from MUGA 
 
To determine whether you are eligible to participate in the study, a MUGA scan may be used to 
check your heart function (if this is the test your physician prefers over an echocardiogram).  
MUGA scan involves exposure to radiation. The risk of this procedure is small and is similar to 
that received from clinical x-ray and nuclear medicine studies. The amount of radiation exposure 
that you will receive from this procedure is equivalent to a uniform whole body exposure of 700 
millirem. This is equal to 2.33 times the amount of natural background radiation that the average 
person in the United States receives each year (300 millirem).              
 
 
Side Effect Risks 
 
The drugs used in this study may affect how different parts of your body work such as your liver, 
kidneys, heart, and blood.  The study doctor will be testing your blood and will let you know if 
changes occur that may affect your health. 
 
There is also a risk that you could have side effects from the study drugs.  Some side effects may 
be mild.  Other side effects may be serious and even result in death. 
 
Here are important points about side effects: 
 
• The study doctors do not know who will or will not have side effects. 
• Some side effects may go away soon, some may last a long time, or some may never go 
away. 
• Some side effects may make it hard for you to have children. 
• Some side effects may mild.  Other side effects may be serious and even result in death. 
 
You can ask your study doctor questions about side effects at any time:   
• If you notice or feel anything different, tell your study doctor.  He or she can check to see 
if it is a side effect. 
• Your study doctor will work with you to treat your side effects. 
• Your study doctor may adjust the study drugs to try to reduce side effects. 
 
This study is looking at a combination of the usual drugs used to treat this type of cancer plus a 
study drug.  This different combination of drugs may increase your side effects or may cause 
new side effects. 
 
Drug Risks 
 
The tables below show the most common and the most serious side effects doctors know about.  
Keep in mind that there might be other side effects doctors do not yet know about.  If important 
new side effects are found, the study doctor will discuss these with you. 


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Study Group 1 and Group 2 – Possible side effects of abemaciclib + fulvestrant 
 
Possible Side Effects of Abemaciclib 
 
COMMON, SOME MAY BE SERIOUS   
In 100 people receiving abemaciclib (LY2835219), more than 20 and up to 100 may have: 
• 
Anemia which may require blood transfusion 
• 
Diarrhea, nausea, vomiting 
• 
Tiredness 
• 
Bruising, bleeding 
• 
Loss of appetite 
 
OCCASIONAL, SOME MAY BE SERIOUS   
In 100 people receiving abemaciclib (LY2835219), from 4 to 20 may have: 
• Belly pain 
• Dry mouth 
• Sores in the mouth which may cause difficulty swallowing 
• Infection, especially when white blood cell count is low 
• Changes in taste 
• Headache 
• Hair loss 
 
RARE, AND SERIOUS 
In 100 people receiving abemaciclib (LY2835219), 3 or fewer may have: 
• Damage to the lungs which may cause shortness of breath 
• Blood clot which may cause swelling, pain, shortness of breath 
 
Possible Side Effects of Fulvestrant 
 
COMMON, SOME MAY BE SERIOUS 
In 100 people receiving fulvestrant, more than 20 and up to 100 may have: 
• Pain 
• Tiredness 
• Increased sweating 
• Hot flashes, flushing 
• Swelling and redness at the site of the medication injection 
 
OCCASIONAL, SOME MAY BE SERIOUS 
In 100 people receiving fulvestrant, from 4 to 20 may have: 
• Constipation, diarrhea, nausea, vomiting, loss of appetite, heartburn 
• Swelling of the body 
• Loss of bone tissue, broken bone, or decreased height 
• Dizziness, headache 


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10287 
OCCASIONAL, SOME MAY BE SERIOUS 
In 100 people receiving fulvestrant, from 4 to 20 may have: 
• Difficulty sleeping 
• Fluid around lungs 
• Swelling of the liver which may cause belly pain 
• Worry, depression, mood swings 
• Hair thinning 
• Cough 
 
RARE, AND SERIOUS 
In 100 people receiving fulvestrant, 3 or fewer may have: 
• Allergic reaction which may cause rash, low blood pressure, wheezing, shortness of 
breath, swelling of the face or throat 
• Liver damage which may cause yellow eyes and skin 
• Vaginal bleeding 
• Blood clot which may cause swelling, pain, shortness of breath 
• Heart attack or heart failure which may result in chest pain, shortness of breath, swelling 
of ankles, and tiredness 
• Stroke which may cause weakness, paralysis 
 
Study Group 1 – in addition to side effects outlined above, people who are in the first part of the 
study or in Group 1 of the second part of the study may also experience the possible side effects 
of copanlisib listed below. 
 
Possible Side Effects of Copanlisib dihydrochloride 
(Table Version Date: April 2, 2023) 
COMMON, SOME MAY BE SERIOUS   
In 100 people receiving copanlisib dihydrochloride (BAY 80-6946 dihydrochloride), more 
than 20 and up to 100 may have: 
• 
Diarrhea 
• 
Tiredness 
• 
Infection, especially when white blood cell count is low 
• 
High blood pressure which may cause headaches, dizziness, blurred vision 
 
OCCASIONAL, SOME MAY BE SERIOUS   
In 100 people receiving copanlisib dihydrochloride (BAY 80-6946 dihydrochloride), from 
4 to 20 may have: 


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• Anemia which may require blood transfusion 
• Sores in the mouth which may cause difficulty swallowing 
• Nausea, vomiting 
• Bruising, bleeding 
• Loss of appetite 
• Pain 
• Damage to the lungs which may cause shortness of breath 
• Rash 
 
RARE, AND SERIOUS 
In 100 people receiving copanlisib dihydrochloride (BAY 80-6946 dihydrochloride), 3 or 
fewer may have: 
• Change in the heart rhythm 
• Swelling and redness of the skin 
• Itching 
 
 
 
Patients with diabetes may need to increase or change their diabetic medications to better 
control their diabetes. 
 
Additional Drug Risks 
 
Abemaciclib has been known to cause inflammation of the lungs.  Copanlisib in combination 
with the other two drugs (FA) could cause an exacerbation of any side effect currently known to 
be caused by the other drug, or the combination of drugs and may result in side effects never 
previously associated with either of the three drugs. 
 
What are my responsibilities in this study? 
If you choose to take part in this study you will need to: 
 
• Keep your study appointments. 
• Tell your doctor about: 
o all medications and supplements you are taking 
o any side effects  
o any doctors’ visits or hospital stays outside of this study  
o if you have been or are currently in another research study. 
• Write down in your medication diary when you take the abemaciclib at home.   
 
Ways to keep from getting pregnant: 
 
Do not get pregnant or breastfeed while taking part in this study.  Tell your study doctor right 
away if you think that you have become pregnant during the study or within 3 months after your 
last dose of study drug.  Use barrier method (condoms, diaphragms, or cervical caps) of birth 


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control or abstinence for the duration of your study participation and for 6 months after your last 
day of study treatment. 
 
For men:  Do not father a baby while taking part in this study, or donate sperm for three (3) 
months following the last dose of your study drugs.   
 
Acceptable Birth Control Methods:  
 
• Condoms with spermicide AND one of the following: 
o Oral contraceptive or hormonal therapy (e.g., hormone implants, skin patches, 
intravaginal device, hormone shots). 
o Placement of an intra-uterine device (IUD; e.g., Mirena®). 
o Vasectomy, with participant assurance that the vasectomy was successful. 
o Tubal occlusion (i.e., getting your tubes tied). 
• Total sexual abstinence, when this is in line with your usual and/or preferred lifestyle.  
Periodic abstinence (e.g., calendar, ovulation), the rhythm method, and withdrawal are 
not acceptable methods of contraception. 
 
 
What are the costs of taking part in this study? 
You and/or your insurance plan will need to pay for the costs of medical care you get as part of 
this study, just as you would if you were getting the usual care for your cancer.  This includes: 
• 
the cost of tests, exams, procedures, and drugs that you get during the study to 
monitor your safety and prevent and treat side effects 
• 
the costs of getting the copanlisib, abemaciclib, and fulvestrant ready and giving it to 
you 
• 
ECG 
• 
Echo/MUGA 
• 
your insurance co-pays and deductibles 
 
Talk to your insurance provider and make sure that you understand what your insurance pays for 
and what it doesn’t pay for if you take part in this clinical trial.  Also, find out if you need 
approval from your plan before you can take part in the study.  
 
Ask your doctor or nurse for help finding the right person to talk to if you are unsure which costs 
will be billed to you or your insurance provider.  
 
You and/or your insurance provider will not have to pay for exams, tests, and procedures done 
for research purposes only or that are covered by the study.  These include:   
• 
the research biopsies and research blood draws 
 
You or your insurance provider will not have to pay for the copanlisib while you take part in the 
study. 
 
Neither you nor your health care plan/insurance carrier will be billed for the collection of the 
tissue and blood that will be used for this study. 


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Taking part in this study may mean that you need to make more visits to the clinic or hospital 
than if you were getting the usual approach to treat your cancer.  You may: 
 
• Have more travel costs. 
• Need to take more time off work. 
• Have other additional personal costs. 
 
You will not be paid for taking part in this study.  The research may lead to new tests, drugs, or 
other products for sale.  If it does, you will not get any payment. 
 
What happens if I am injured because I took part in this study? 
If you are injured as a result of taking part in this study and need medical treatment, please talk 
with your study doctor right away about your treatment options.  The study sponsors will not pay 
for medical treatment for injury.  Your insurance company may not be willing to pay for study-
related injury.  Ask them if they will pay.  If you do not have insurance, then you would need to 
pay for these medical costs. 
 
If you feel this injury was caused by medical error on the part of the study doctors or others 
involved in the study, you have the legal right to seek payment, even though you are in a study.  
Agreeing to take part in this study does not mean you give up these rights. 
 
Who will see my medical information? 
Your privacy is very important to us.  The study doctors will make every effort to protect it.  The 
study doctors have a privacy permit to help protect your records if there is a court case.  
However, some of your medical information may be given out if required by law.  If this should 
happen, the study doctors will do their best to make sure that any information that goes out to 
others will not identify who you are. 
 
Some of your health information, such as your response to cancer treatment, results of study 
tests, medicines you took, and the results of any tumor and blood genetic testing will be kept by 
the study sponsor in a central research database.If information from this study is published or 
presented at scientific meetings, your name and other personal information will not be used. 
 
There are organizations that may look at or receive copies of some of the information in your 
study records. Your health information in the research database may also be shared with these 
organizations.  They must keep your information private, unless required by law to give it to 
another group.  
 
Some of these organizations are: 
• Bayer Pharmaceuticals (makers of copanlisib) or any drug company supporting the study 
now or in the future.  This would include any organization helping the company with the 
study. 
• The NCI Central IRB, which is a group of people who review the research with the goal 
of protecting the people who take part in the study. 
• The FDA and the groups it works with to review research 


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• The NCI and the groups it works with to review research 
 
In addition to storing data in the study database, data from studies that are publicly funded may 
also be shared broadly for future research with protections for your privacy.  The goal of this 
data sharing is to make more research possible that may improve people’s health.  Your study 
records may be stored and shared for future use in public databases.  However, your name and 
other personal information will not be used.  Some types of future research may include looking 
at your records and those of other patients to see who had side effects across many studies or 
comparing new study data with older study data.  However, we don’t know what research may 
be done in the future using your information.  This means that: 
 
• You will not be asked if you agree to take part in the specific future research studies 
using your health information.   
• You and your study doctor will not be told when or what type of research will be done. 
• You will not get reports or other information about any research that is done using your 
information.  
• Because it may be possible to re-identify de-identified genomic data, even if access to 
data is controlled and data security standards are met, confidentiality cannot be 
guaranteed, and re-identified data could potentially be used to discriminate against or 
stigmatize participants, their families, or groups.  In addition, there may be unknown 
risks. 
 
 
There are laws that protect your genetic information.  However, there is a risk that someone 
could get access to your genetic information and identify you by name.  In some cases, 
employers could use your genetic information to decide whether to hire or fire you.  The study 
doctors believe the risk of this happening is very small.  However, the risk may increase in the 
future as people find new ways of tracing information.  For more information about the laws that 
protect you, ask your study doctor. 
 
Where can I get more information? 
You may visit the NCI Web site at http://cancer.gov/ for more information about studies or 
general information about cancer. You may also call the NCI Cancer Information Service to get 
the same information at: 1-800-4-CANCER (1-800-422-6237). 
 
A description of this clinical trial will be available on http://www.ClinicalTrials.gov, as required 
by U.S. Law. This Web site will not include information that can identify you. At most, the Web 
site will include a summary of the results. You can search this Web site at any time. 
 
You can talk to the study doctor about any questions or concerns you have about this study or to 
report side effects or injuries. Contact the study doctor __________________ (insert name of 
study doctor[s]) at __________________ (insert telephone number). 
 
For questions about your rights while in this study, call the (*insert name of organization or 
center*) Institutional Review Board at (*insert telephone number*).  
 


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Optional studies you can choose to take part in 
This part of the consent form is about optional studies that you can choose to take part in.  They 
are separate from the main study described above.  These optional studies will not benefit your 
health.  The researchers leading these optional studies hope the results will help other people 
with cancer in the future.  The results will not be added to your medical records and you or your 
study doctor will not know the results. 
 
Taking part in these optional studies is your choice.  You can still take part in the main study 
even if you say “no” to any or all of these studies.  There is no penalty for saying “no.”  You and 
your insurance company will not be billed for these optional studies.  If you sign up for but 
cannot complete any of the studies for any reason, you can still take part in the main study. 
 
Circle your choice of “yes” or “no” for each of the following studies. 
 
Optional Sample Collections for known Laboratory Studies and/or Storage for 
Possible Future Studies 
Researchers are trying to learn more about cancer and other health problems using blood and 
tissue samples from people who take part in clinical trials.  By studying these samples, 
researchers hope to find new ways to prevent, detect, treat, or cure diseases. 
 
Some of these studies may be about how genes affect health and disease.  Other studies may look 
at how genes affect a person’s response to treatment.  Genes carry information about traits that 
are found in you and your family.  Examples of traits are the color of your eyes, having curly or 
straight hair, and certain health conditions that are passed down in families.  Some of the studies 
may lead to new products, such as drugs or tests for diseases. 
 
Known Future Studies 
 
If you choose to take part in this optional study, leftover tissue and blood from other research 
collections will be collected.  The researchers ask your permission to store and use your samples 
and related health information (for example, your response to cancer treatment, results of study 
tests and medicines you are given) for medical research.  The research that may be done is 
unknown at this time.  Storing samples for future studies is called “biobanking”.  The Biobank is 
being run by Nationwide Children’s Hospital in Columbus, Ohio, and is supported by the NCI.. 
 
Unknown Future Studies 
 
If you choose to take part in this optional study, leftover tissue and blood will be collected and 
stored.  Storing samples for future studies is called “biobanking.”  The biobank is being run by 
Nationwide Children’s Hospital in Columbus, Ohio, and is supported by the NCI.  This is a 
publicly funded study. Samples from publicly funded studies are required to be shared as broadly 
as possible. However, we will protect your privacy. The goal of this is to make more research 
possible that may improve people’s health.  
 
The biobank is a public research resource. It has controlled access.  This means that researchers 
who want to get samples and data from it must submit a specific research request. The request 


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identifies who they are and what their planned research project is. Before getting the samples and 
data, the researchers must agree to keep the data private, only use it for their planned research 
project, and never use it to try to identify you.  
 
Right now, we don’t know what research may be done in the future using your blood and tissue 
samples.  This means that: 
 
• 
You will not be asked if you agree to take part in the future research studies.   
• 
You and your study doctor will not be told when or what type of research will be done. 
• 
You will not get reports or other information about any research that is done using your 
samples. 
 
 
What is involved in this optional sample collection? 
 
If you agree to take part, here is what will happen next: 
1) A sample from the tissue that was collected at the time of your research biopsies and 
blood that was collected at the time of your research blood draws will be sent to the 
Biobank, as well as the additional biopsies that will be performed on Cycle 1 Day 15 
and at the time of disease progression.   
2) Your sample and some related health information may be stored in the Biobank, 
along with samples and information from other people who take part.  The samples 
will be kept until they are used up.  Information from your medical record will be 
updated from time to time. 
3) Qualified researchers can submit a request to use the materials stored in the Biobanks.  
A science committee at the clinical trials organization, and/or the National Cancer 
Institute, will review each request.  There will also be an ethics review to ensure that 
the request is necessary and proper.  Researchers will not be given your name or any 
other information that could directly identify you.  
4) Neither you nor your study doctor will be notified when research will be conducted or 
given reports or other information about any research that is done using your samples.  
5) Some of your genetic and health information may be placed in central databases that 
may be public, along with information from many other people.  Information that 
could directly identify you will not be included. 
 
What are the risks in this optional sample collection? 
• Generally, hospitals will keep some of your tissue.  This tissue may be used to help 
treat your cancer in the future.  There is a small risk that when this tissue sample is 
submitted to the biobank for this optional sample collection, your tissue could be used 
up. 
• Common side effects of a biopsy are a small amount of bleeding at the time of the 
procedure, bruising, and pain at the biopsy site.  Pain can be treated with regular pain 
medications.  Rarely, an infection, significant bleeding, or collapsing of the lung can 
occur.  You may sign a separate consent form for the study biopsy that describes the 
risks in more detail. 


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• Your medical and genetic information is unique to you.  There is a risk that someone 
outside of the research study could get access to your study records or trace 
information in a database back to you.  They could use that information in a way that 
could harm you.  Researchers believe that the chance that someone could access and 
misuse your information is very small.  However, the risk may increase in the future 
as people find new ways of tracing information. 
• In some cases, this information could be used to make it harder for you to get or keep 
a job or insurance.  There are laws against the misuse of genetic information, but they 
may not give full protection.  For more information about the laws that protect you, 
ask your study doctor or visit: https://www.genome.gov/10002328/ 
 
How will information about me be kept private? 
Your privacy is very important to the researchers and the biobank.  They will make every effort 
to protect it.  Here are just a few of the steps they will take: 
1. They will remove identifiers, such as your initials, from your sample and information.   
They will replace them with a code number.  There will be a master list linking the code 
numbers to names, but they will keep it separate from the samples and information. 
2. Researchers who study your sample and information will not know who you are.  They 
also must agree that they will not try to find out who you are. 
3. Your personal information will not be given to anyone unless it is required by law.  
4. If research results are published, your name and other personal information will not be 
used. 
 
What are the possible benefits to taking part in this optional sample collection? 
You will not benefit from taking part. The researchers, using the samples from you and others, 
might make discoveries that could help people in the future. 
 
Are there any costs or payments to this optional sample collection? 
There are no costs to you or your insurance.  You will not be paid for taking part in this study.  
The research may lead to new tests, drugs, or other products for sale.  If it does, you will not get 
any payment 
 
What if I change my mind about this optional sample collection? 
If you decide you no longer want your samples to be used, you can call the study doctor, (*insert 
name of study doctor for main trial*), at (*insert telephone number of study doctor for main 
trial*), who will let the biobank know.  Then, any sample that remains in the biobank will be 
destroyed or returned to your study doctor.  This will not apply to any samples or related health 
information that have already been given to or used by researchers. 
 
What if I have questions about this optional sample collection? 
If you have questions about the use of your samples for research, contact the study doctor, 
________________, (insert name of study doctor for main trial), at _____________________ 
(insert telephone number of study doctor for main trial). 
 
Please circle your answer below to show whether or not you would like to take part in each 
optional study: 


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Additional (2nd) Tumor Biopsy  
 
Please circle your answer:  I choose to permit an additional tumor biopsy on Cycle 1 Day 15  
 
YES 
 
NO 
 
Additional (3rd) Tumor Biopsy  
 
Please circle your answer:  I choose to permit an additional tumor biopsy if the study treatment 
appears to help me, but my cancer later starts to grow.  
 
YES 
 
NO 
 
Samples for known future studies 
 
I agree that my samples and related health information may be used for the laboratory study 
described above. 
 
 
YES 
 
NO 
 
Samples for unknown future studies 
 
I agree that my samples and related health information may be kept in a biobank for use in future 
health research. 
 
 
YES 
 
NO 
 
Contact for Future Research 
 
I agree that my study doctor, or someone on the study team, may contact me or my doctor to see 
if I wish to participate in other research in the future. 
 
 
YES 
 
NO 
 
This is the end of the section about optional studies. 
 
 
 
My Signature Agreeing to Take Part in the Study 
I have read this consent form or had it read to me.  I have discussed it with the study doctor and 
my questions have been answered.  I will be given a signed and dated copy of this form. I agree 
to take part in the main study.  I also agree to take part in any additional studies where I circled 
‘yes’. 
 
_________________________________________________________________ 


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Participant’s signature 
 
 
 
 
_________________________________________________________________ 
Date of signature 
 
 
 
 
_________________________________________________________________ 
Signature of person(s) conducting the informed consent discussion 
 
 
 
 
_________________________________________________________________ 
Date of signature 
  


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STUDY CALENDAR 
 
Screening 
Pre-
treatment 
Cycle 1* 
Cycles after 
Cycle 1* 
End of 
TreatmentC* 
Day 1 
Day 2 
Day 8 
Day 15 
Day 16 
Day 22 
Day 23 
Day 1 
Day 15 
Physical exam 
X 
 
X 
 
XB 
XB 
 
 
 
X 
 
 
Disease Assessment 
Imaging† 
X 
 
 
 
 
 
 
 
 
 
 
X 
Blood for safety 
labs 
X 
 
X 
 
XB 
X 
 
X 
 
X 
X 
 
Echo/MUGA 
X 
 
 
 
 
 
 
 
 
 
 
 
ECG 
X 
As clinically indicated thereafter 
Pregnancy test 
XD 
 
 
 
 
 
 
 
 
 
 
 
Hepatitis panel 
X 
 
 
 
 
 
 
 
 
 
 
 
Urinalysis 
X 
 
 
 
 
 
 
 
 
 
 
 
Blood pressure 
(group 1) 
 
 
X 
 
XB 
X 
 
 
 
X 
 
X 
 
Randomization 
 
X 
 
 
 
 
 
 
 
 
 
 
Fulvestrant 
 
 
XA 
 
 
XA 
 
 
 
X 
 
 
Abemaciclib 
 
 
5 days with 2 days rest each week A 
 
Copanlisib (if 
applicable) 
 
 
X 
 
 
X 
 
 
 
X 
 
X 
 
Archival tumor 
tissue 
X 
 
 
 
 
 
 
 
 
 
 
 
Fresh tumor biopsy 
X 
 
 
 
 
X** 
 
 
 
 
 
X** 
Blood for research 
X 
 
X 
X 
X 
X A 
X 
 
 
XE 
 
X 
A. Note that in patients who participate in the copanlisib PK studies (the first 4 patients randomized to FAC in this Phase II portion), the first two doses of 
abemaciclib on C1D1 are skipped and fulvestrant is delayed to C1D2 following the 24 h blood draw for copanlisib PK.  Abemciclib is therefore 
administered on C1D2-5 (4 days) the first week due to the 5 days on and 2 days off schedule each week. C1D15 fulvestrant dose is delayed to C1D16 
following the 24 h blood draw for copanlisib PK.  
B. Only if receiving copanlisib.  
C. Follow up for survival status occurs every 3 months (+/- 7 days) for 5 years after removal from the study or until death, whichever occurs first.  In 
addition, patients removed from study due to unacceptable adverse event(s) will be followed until resolution or stabilization of the adverse event. 
D. Pregnancy test is only applicable for patients with pregnancy potential.  Pregnancy tests will be performed at screening and every 3 cycles on study. 
E. On Day 1 of Cycles 2 and 4 and then every 3 cycles after that. 
** Optional 
*Visits can occur in ± 2 day window to allow for holidays, inclement weather, etc 
† Disease Assessment Imaging will be performed at screening, at the end of Cycle 3 (+/- 7 days), then every 3 cycles (+/- 7 days).