Clinical trial NCT04750941
Conditions: Follicular Lymphoma Endometrial Cancer
Keywords: Keto diet Copanlisib
Sponsor: Columbia University
Start date: 2022-02-10; Completion date: 2023-06-09
Enrollment: 1 participants; Allocation: NON_RANDOMIZED; Intervention model: PARALLEL

Brief summary:
This is a multicenter, open label, pilot phase II study of the PI3K inhibitor copanlisib in combination with a ketogenic diet in the treatment of patients with one of the following malignancies: (a) relapsed or refractory (R/R) follicular lymphoma (FL), (b) R/R endometrial cancer (EC) with a documented activating mutation in PIK3CA or loss of phosphatase and tensin homolog (PTEN).

Detailed description:
As the investigators recently reported ketogenic diet can suppress hyperinsulinemia associated with PI3K inhibitors, leading to potentiation of the anti-tumor effects of PI3K inhibitors. Copanlisib potently inhibits PI3Kα and PI3Kδ. It has been approved for the treatment of relapsed follicular lymphoma, based on ORR of 59% (84 of 142 patients). The CR rate in FL was 14%, and the median progression-free survival was 11.2 months. Copanlisib demonstrated encouraging clinical activity in marginal zone lymphoma (ORR 70% including 9% CR). While these results are clinically meaningful, FL and MZL inevitably develop resistance to copanlisib with time, even in those patients who initially respond to the therapy. Novel strategies to improve the efficacy of copanlisib in FL and MZL, by improving CR and PFS, may transform how to manage these incurable malignancies.

Arms: arm 1: The lymphoma study group will enroll 23 patients with FL.

In cycle 1, patients will first start ketogenic diet for 7 days (Day -6 to Day 0). Only patients who demonstrate compliance and tolerance with the ketogenic diet for all 7 days, as confirmed by pertinent blood and urine tests, will be allowed to continue the study and treatment using copanlisib and the ketogenic diet starting on Day 1. In cycle 2 and beyond, patients will start the ketogenic diet and copanlisib on day 1. arm 2: The solid tumor group will enroll 19 patients with EC.

In cycle 1, patients will first start ketogenic diet for 7 days (Day -6 to Day 0). Only patients who demonstrate compliance and tolerance with the ketogenic diet for all 7 days, as confirmed by pertinent blood and urine tests, will be allowed to continue the study and treatment using copanlisib and the ketogenic diet starting on Day 1. In cycle 2 and beyond, patients will start the ketogenic diet and copanlisib on day 1.
Interventions: intervention 1: Copanlisib intervention 2: Ketogenic Diet
Intervention descriptions: intervention 1: Copanlisib will be infused intravenously on days 1, 8, 15 of each cycle, over 1 hour, of 28-day cycles. intervention 2: In cycle 1, patients will first start the ketogenic diet for 7 days (Day -6 to Day 0).

Only the patients who demonstrate compliance and tolerance with the ketogenic diet, as confirmed by pertinent blood and urine tests and a diary of diet, will be allowed to continue the study and start copanlisib on Day 1. The ketogenic diet will continue daily throughout the treatment days.

In cycle 2 and beyond, patients will start the ketogenic diet and copanlisib on day 1.

The ketogenic diet will then continue daily throughout the treatment days.

Protocol documents:
Prot_SAP_000.pdf: 
 
 
 
 
 
 
 
 
 
 
 
PILOT PHASE II MULTICENTER STUDY OF THE 
PI3K INHIBITOR COPANLISIB IN 
COMBINATION WITH A KETOGENIC DIET IN 
THE TREATMENT OF PATIENTS WITH 
RELAPSED OR REFRACTORY FOLLICULAR 
LYMPHOMA OR ENDOMETRIAL CANCER 
 
 
NCT04750941 
 
Protocol date: 9/23/2024 
 
 


 
 
PROTOCOL SYNOPSIS 
 
Study Design: This is a multi-institution, open label, pilot phase II study of the PI3K inhibitor 
copanlisib in combination with a ketogenic diet in the treatment of patients with one of the 
following malignancies: (a) relapsed or refractory (R/R) follicular lymphoma (FL), (b) R/R 
endometrial cancer (EC) with a documented activating mutation in PIK3CA or loss of PTEN. 
The FL arm will enroll 23 subjects and the EC arm will enroll 19 subjects. The study will be 
stopped if the safety trigger is activated at the pre-specified times of interim safety analysis upon 
enrollment of 12 and 24 patients. 
The two arms will enroll patients in parallel and independently. Safety analysis will be done by 
pooling patients from the two arms together. Efficacy analysis will be conducted independently 
within each arm. 
 
Objectives: 
Primary Objectives 
• Determine the objective response rate (ORR) (complete response [CR] + partial response 
[PR]) in FL. 
• Determine the ORR in EC. 
 
Secondary Objectives: 
• Determine the CR and PR rates in FL upon completion of the study protocol. 
• Determine the CR and PR rates in EC upon completion of the study protocol. 
• Determine the ORR in FL and EC at the Simon stage I analysis 
• Determine patient compliance with the ketogenic diet. 
 
Exploratory Objectives: 
• Determine the PD markers including blood levels of insulin, c-Peptide, BHB (beta- 
hydroxybutyrate), triglyceride, and glucose, and urine ketones. 
• Determine the PD markers including levels of pINSR, INSR, pAKT, AKT, pS6, S6, Ki-67, 
TUNEL, caspase, and actin in paired pre- and post-treatment tumor tissues in patients who 
consented for the optional post-treatment biopsy of the tumors (blood and bone marrow are 
acceptable if they are known to be involved by lymphoma). 
• Explore the correlation of disease response and the PD markers described above. 
• Explore the correlation of disease response and gene alternations in tumor tissues. 
• Explore the correlation of insulin response and gene alternations in normal buccal 
fibroblasts. 
• Determine the change in body weight and body mass index (BMI) over time. 
• Determine the change in computed tomography-based body composition metrics including 
measures of adipose tissue and skeletal muscle. 
• Determine the change in 18F-fluorodeoxyglucose uptake/PET-based adipose tissue and 
skeletal muscle peak standardized uptake value. 
 
Target Population: 


 
 
(a) R/R FL, (b) R/R EC with a documented activating mutation in PIK3CA or loss of PTEN. 
 
Inclusion Criteria: 
• Be willing and able to provide written informed consent for the trial. 
• Be  18 years of age on day of signing informed consent. 
• For lymphoma, patients should have measurable disease based on the Lugano Criteria 
(Cheson et al., 2014). 
• For FL patients must have received at least two lines of prior therapy. There is no upper limit 
for the number of prior therapies. Tumor tissues of all patients are encouraged to be 
submitted (optional) prospectively for whole or targeted exome sequencing of key cancer 
related genes, using the Columbia Combined Cancer Panel (CCCP) or a comparable 
sequencing platform, such as the MSK-IMPACT 468-gene oncopanel. However, the results 
of tumor sequencing by themselves are not inclusion criteria for FL. The test should be 
submitted as per standard of care; however, if the coverage is denied by patients’ insurance 
plans the test will be waivered or if possible paid for by the research protocol. 
• For EC the patients must have recurrent/advanced tumor for which surgical or the systemic 
curative treatments, or standard therapeutic approaches are not available. The following 
histologic subtypes are eligible: endometrioid, serous, clear cell, undifferentiated/de- 
differentiated, mucinous, squamous, transitional, not-otherwise specified, and mixed cell- 
type. EC must have PI3K pathway activation confirmed in mutational profiling using the 
MSK-IMPACT 468-gene oncopanel or an equivalent platform, as defined below: 
(1) Genomic alteration resulting in loss of PTEN function including a) whole or partial 
gene deletion, frame shift mutations, or non-sense mutations. Missense mutations in 
PTEN will not be considered qualifying; OR 
(2) A previously characterized activating mutation in any component of the pathway 
including: PIK3CA, AKT1, PIK3R1, PIK3R2, and mTOR. 
However, EC must NOT have a known concurrent activating RAS/RAF mutation or loss 
of function alternation in NF1 of NF2 resulting in MAP kinase pathway activation. 
• Fresh and or archived tumor tissues must be available to (a) establish the diagnosis of the 
respective malignancies as described in Inclusion Criteria, and (b) be investigated for 
biomarkers. Patients without historical material or fresh tissue biopsy that is adequate for 
both diagnosis and biomarker studies will not be eligible for the clinical trial. For the 
lymphoma cohort, bone marrow biopsy can be used for histological confirmation of the 
diagnosis and for biomarker analyses. 
• Left Ventricular Ejection Fraction (LVEF) > 50%. 
• A performance status of 0-2 on the ECOG Performance Scale. 
• Demonstrate adequate organ function, as described below. All screening labs should be 
performed within 21 days of initiation of Copanlisib.
 
 
 
 
 


 
 
Laboratory criteria for inclusion 
 
Laboratory Test 
Criteria 
Glucose 
Hemoglobin 
ANC 
Platelets 
ALT 
AST 
Total bilirubin 
GFR (MDRD) 
< 160 mg/dL (fasting) or < 200 mg/dL (non-fasting) 
≥ 8 g/dL a 
≥ 1,500/mm3 
≥ 75,000/mm3 b 
<2.5 x ULN c 
<2.5 x ULN d 
within normal limits e 
≥ 35 mL/min/1.73 m2 f 
ALT = Alanine aminotransferase; ANC = Absolute neutrophil count; AST = Aspartate aminotransferase; GFR = 
Glomerular filtration rate; MDRD = Modification of Diet in Renal Disease; ULN = Upper limit of normal. 
a: If hemoglobin is < 8 g/dL but ≥ 6 g/dL on the day of planned study drug administration it is permissible to give the 
study drug dose as scheduled and transfuse within 48 hours after the dose, if the patient is hemodynamically stable 
and in opinion of investigator benefits outweigh risks. Rationale and treatment should be recorded in source 
document and Electronic case report form (eCRF). 
b: For patients with lymphomatous bone marrow infiltration at study entry (local assessment), platelet count ≥ 
50,000/mm3. This value should be used throughout the study irrespective of bone marrow status changes. Platelet 
transfusion should not be given less than 7 days before the exam collection. 
c: < 5 x ULN in patients with documented liver involvement by lymphoma or with biliary obstruction due to 
lymphoma. 
d: < 5 x ULN in patients with documented liver involvement by lymphoma or with biliary obstruction due to 
lymphoma. 
e: < 3 x ULN in patients with Gilbert-Meulengracht syndrome, patients with cholestasis due to compressive 
adenopathies of the hepatic hilum or documented liver involvement by lymphoma. 
f: If not on target, this evaluation may be repeated once after at least 24 hours either according to the MDRD 
abbreviated formula or by 24 hour sampling. If the latter result is within acceptable range, it may be used to fulfill 
the inclusion criteria instead. 
 
 
Exclusion Criteria: 
• 
The following treatments are prohibited: (a) Chemotherapy (including PI3K inhibitors and 
other approved or investigational drugs) and monoclonal antibody within 3 weeks; (b) 
radiotherapy within 2 weeks prior to entering the study; (c) systemic steroids that have not 
been stabilized (≥ 5 days) to the equivalent of ≤10 mg/day prednisone prior to the start of the 
study drugs. 
• 
Patients that have not recovered from adverse events due to chemotherapy agents 
administered more than 3 weeks earlier. 
• 
Hypersensitivity to copanlisib or any of its excipients. 
• 
Type I diabetes 
• 
Uncontrolled Type II diabetes mellitus (HbA1c> 7.5%). 
• 
Type II diabetes requiring treatment with a sulfonylurea, meglitinide, or insulin. 
• 
Patients that received major surgery and have not recovered adequately from the toxicity 


 
 
and/or complications from the intervention prior to starting therapy. 
• 
Patients with active, clinically serious infections > CTCAE version 5 Grade 2. 
• 
Patients with known active concurrent malignancy with the following exception: non- 
melanoma skin cancer, prostatic intraepithelial neoplasia, or carcinoma in situ of the cervix, 
prostate cancer that responds to androgen deprivation therapy and has no progression of 
disease for at least 12 months. If there is a history of prior malignancy, the patient must be 
disease-free for ≥ 3 years. 
• 
Uncontrolled hypertension, i.e., blood pressure (BP) of ≥ 150/90; patients who have a history 
of hypertension controlled by medication must be on a stable dose (for at least one month) 
and meet all other inclusion criteria. 
• 
Concomitant use of strong CYP3A4 inhibitors. 
• 
Uncontrolled moderate to severe hypertriglyceridemia (TG>300 mg/dL). 
• 
Myocardial infarction within 6 months of cycle 1, day 1. [Subjects with a history of 
myocardial infarction between 6 and 12 months prior to cycle 1, day 1, who are 
asymptomatic and have had a negative cardiac risk assessment (treadmill stress test, nuclear 
medicine stress test, or stress echocardiogram) since the event, may participate]. 
• 
Symptomatic coronary artery disease (CAD), e.g., angina Canadian Class II-IV (see 
Appendix 5). In any patient in whom there is doubt whether the symptoms are truly due to 
CAD, the patient should have a stress imaging study and, if abnormal, angiography to define 
whether or not CAD is present. If the work up is negative the patient may participate in the 
clinical trial. 
• 
An ECG recorded at screening showing evidence of cardiac ischemia (ST depression of ≥ 2 
mm, measured from isoelectric line to the ST segment). In any patient in whom there is  
doubt whether the ECG changes is accurate and clinically significant, the patient should have 
a stress imaging study and, if abnormal, angiography to define whether or not CAD is 
present. If further work up is negative the patient may participate in the clinical trial. 
• 
Congestive heart failure (CHF) that meets New York Heart Association (NYHA) Class II to 
IV definitions and/or ejection fraction < 40% by multigated acquisition (MUGA) scan or < 
50% by echocardiogram and/or magnetic resonance imaging (MRI); 
• 
Arterial or venous thrombotic or embolic events such as cerebrovascular accident (including 
transient ischemic attacks) within 6 months before the start of study medication. 
• Patients who are pregnant or breastfeeding, or expecting to conceive or father children within 
the projected duration of the trial, starting with the pre-screening or screening visit through at 
least 30 days after the last dose of trial treatment. History of nephrolithiasis or nephrolithiasis 
incidentally discovered during CT screening. Known selenium deficiency. 
• Body mass index (BMI) less than 20. 
• An allergy or intolerance to egg, gluten, tree nuts, peanuts, or milk protein. 
• History of serious or uncontrolled gout or hyperuricemia. 
• Any other disease, metabolic dysfunction, physical examination finding, or clinical 
laboratory finding that, in the investigators’ opinion, gives reasonable suspicion of a disease 
or condition that contraindicates the use of an investigational drug or that may affect the 
interpretation of the results or render the patient at high risk from treatment complications. 
• Major surgical procedure or significant traumatic injury within 28 days prior to Day 1 or 
anticipation of the need for major surgery during the course of study treatment. 
 


 
 
Cycle 2 and beyond 
Start day 1 and subsequent treatments using 
copanlisib and the ketogenic diet 
Stay on protocol. Start cycle 1 
day 1 of copanlisib. Continue 
the ketogenic diet 
Off protocol. Patient 
will be replaced 
Acceptable 
Unacceptable 
Cycle 1: Day -6 to day 0: ketogenic diet 
Tolerance & 
compliance 
EC (n=19) 
Two-stage 
design. 
Enroll 11: If 2 
or more 
responders 
then enroll 8 
more 
FL (n=23) 
Two-stage 
design. 
Enroll 13: If 6 
or more 
responders 
then enroll 10 
more 
Phase II (N = 42) 
Study Scheme 
Interim safety analysis: Pool 
data in 2 arms upon enrollment of 
12 and 24 patients 
Study flow chart 
 
 
The Phase II study will enroll 42 patients in two study groups. The lymphoma study group will 
enroll 23 patients with FL, and the solid tumor group will enroll 19 patients with EC. 
 
In cycle 1, patients will first start ketogenic diet for 7 days (Day -6 to Day 0). Only patients who 
demonstrate compliance and tolerance with the ketogenic diet for all 7 days during the run-in 
phase, as confirmed by pertinent blood and urine tests, will be allowed to continue the study and 
treatment using copanlisib and the ketogenic diet starting on day 1. In cycle 2 and beyond, 
patients will start the ketogenic diet and copanlisib on day 1. 
 
Treatment Plan: 
• Copanlisib: Copanlisib will be infused intravenously on days d1, 8, 15 of each cycle, over 1 
hour, of 28-day cycles. 
• Ketogenic diet: 
o Prior to the first treatment patients will start the ketogenic diet for 6 days (Day -5 to 
Day 0). Patients who demonstrate compliance and tolerance with the ketogenic diet, as 
confirmed by pertinent blood and urine tests and recorded dietary intake, will be 
allowed to continue the study and start copanlisib on Day 1. The ketogenic diet will 
continue daily throughout the treatment days. 
o In cycle 2 and beyond, patients will start the ketogenic diet and copanlisib on day 1. 
The ketogenic diet will then continue daily throughout the treatment days. 
o All patients will be eligible to receive the ketogenic diet as long as the patients remain 
on the trial. If patients want to remain on the trial to receive Copanlisib but wish to 
discontinue the ketogenic diet, they should do so at the following time: (a) when they 
have achieved a complete response, or (b) when they have completed 4 cycles of 
treatment. In the rare case when a patient wants to discontinue the ketogenic diet after 
having completed only 2 or 3 cycles of therapy but having not achieved a CR, the 
patient will be allowed to remain in the study and receive copanlisib without having to 
take the ketogenic diet. However, if a patient wishes to stop the ketogenic diet before 


 
 
cycle 2 is completed, when the response will be first evaluated, the patient will not be 
allowed to continue this trial but will be replaced. 
 
 
REGIMEN DESCRIPTION 
Agent 
Premedications/Precautions 
Dose 
Route 
Cycle 
Length 
Copanlisib 
IV Hydration (Normal Saline 
500 cc IV in 30 minutes after 
copanlisib infusion) 
60 mg 
IV over 60 
minutes 
28 days 
Ketogenic 
diet 
 
Three 
times 
daily 
Oral, three 
times daily 
 
 
 
Dose Modification: 
Dose Modification of copanlisib is described in Section 6.6. 
 
Duration of Treatment: 
Patients will be treated until one of the following events: disease progression, unacceptable 
adverse event(s), withdrawal of consent, general or specific changes in the patient's condition 
that render the patient unacceptable for further treatment in the judgment of the investigator. 
Sample Size and Statistical Consideration: 
The study will enroll 42 patients. The two arms will enroll patients in parallel and independently. 
Safety analysis will be done by pooling patients from the two arms together. Efficacy analysis 
will be conducted independently within each of the two arms (lymphoma, solid tumor). 
Patients who do not complete the planned cycle 2 cycles of treatment, which is required for the 
first evaluation of response, will be replaced. 
(a) The lymphoma arm will enroll 23 patients with FL. 
• Simon's two-stage design (Simon, 1989) will be used. The null hypothesis that the true 
ORR rate is 41% will be tested against a one-sided alternative. In the first stage, 13 
patients will be accrued. If there are 5 or fewer ORRs (To be assessed after completing 
4 cycles of the treatment) in these 13 patients, the study will be stopped for futility. 
Otherwise, 10 additional patients will be accrued for a total of 23. The null hypothesis 
will be rejected if 14 or more ORRs are observed in 23 patients. This design yields a type 
I error rate of 5% and power of 80% when the true ORR rate is 67%. Assuming that the 
CR rate is 0.09 (2 out 23), with 23 subjects we will have 80% power to claim that the true 
CR is at least 30%. 
• The reference range of ORR in FL is 40% (n = 16. Dreyling et al, Ann Oncol. 2017) to 


 
 
59% (n = 104. Dreyling et al, J Clin Oncol. 2017). 
• The reference CR rate is 14% (n = 104. Dreyling et al, J Clin Oncol. 2017). 
(b) The solid tumor arm will enroll 19 patients with EC. 
• Simon's two-stage design (Simon, 1989) will be used. The null hypothesis that the true 
ORR rate is 0.10 will be tested against a one-sided alternative. In the first stage, 11 
patients will be accrued. If there are 1 or fewer ORRs (To be assessed after completing 
4 cycles of treatment) in these 11 patients, the study will be stopped for futility. 
Otherwise, if >=2/11 responses are observed, then 8 additional patients will be accrued 
for a total of 19. The null hypothesis will be rejected if 4 or more ORRs are observed in 
19 patients. This design yields a type I error rate of 10% and power of 81% when the true 
ORR rate is 30%. 
 
Safety: 
Patients will be monitored carefully for the development of adverse events (AEs). AE will be 
evaluated according to criteria outlined in the National Cancer Institute (NCI) Common 
Terminology Criteria for Adverse Events (CTCAE), version 5. 
 
Safety Trigger 
There will be ongoing safety monitoring. 
 
Interim safety analysis will be performed upon enrollment of 12 and 24 subjects. Safety analysis 
will be done by pooling patients from the two arms together. 
 
The safety trigger will be activated if any of the following Safety Trigger Events (STE) happens 
during the first cycle of treatment: 
• During the interim analysis of the first 12 subjects: 3 incidents of STE excluding 
mortality, or 2 incidents of mortality deemed not likely to be due to progression of the 
cancer but possibly related to the treatment. The study will be stopped. 
• During the interim analysis of the first 24 subjects: 5 incidents of STE excluding 
mortality, or 3 incidents of mortality deemed not likely to be due to progression of the 
cancer but possibly related to the treatment. The study will be stopped. 
Safety Trigger Events (STE) will defined as the following: 
• Any non-hematologic toxicity grade 3-4 that require delay of treatment by more than 7 
days despite optimal management. 
o Note that a patient who experiences a STE may be allowed to continue the study, 
as long as the patient can safely resume therapy within 21 days. 
• Any hematologic toxicity grade 3-4 that require delay of treatment by more than 7 days 
despite optimal management including blood products and growth factors. 
o Note that a patient who experiences a STE may be allowed to continue the study, 
as long as the patient can safely resume therapy within 21 days. 


 
 
• Any mortality. 
 
Efficacy Outcome: 
Patients will be monitored for clinical and/or radiographic evidence of disease response. 
Response will be evaluated using clinical parameters, CT or PET/CT scan (PET/CT scan is 
preferred), and bone marrow or other tissue biopsy (when applicable for lymphoma), according 
to the Updated Recommendations for Evaluation, Staging, and Response Assessment for 
Hodgkin and Non-Hodgkin Lymphoma: The Lugano Classification. For solid tumor the response 
will be determined in accordance with the revised Response Evaluation Criteria in Solid Tumors 
(RECIST) guideline. CT or PET/CT scan will be performed after every two 28-day cycles of. 
After cycle 4, if the patient has achieved CR, scans will be done every 3 cycles. 
 
Data analysis: 
All patients receiving at least one dose of copanlisib will be evaluable for toxicity and all patients 
completing at least one 28-day cycle of therapy (copanlisib plus ketogenic diet) will be evaluable 
for response and time-to-endpoint analyses. 
 
Response will be estimated with exact 95% confidence intervals (CIs). We will estimate overall 
survival, progression-free survival, and duration of response using the Kaplan-Meier method. 
Group comparisons, between groups associated with different biomarkers described below, will 
be made using a two-sided log-rank test, and the estimated hazard ratios and 95% CIs will be 
calculated using Cox regression. Overall survival will be assessed post hoc in the trial patients. 
In the exploratory correlative biomarker analyses, any patients with assessable biological 
samples (blood, tumor etc) will be included. An association between disease outcome (complete 
response, partial response, stable disease, progression of disease, duration of response, and 
progression-free survival) and changes from baseline in biomarker concentrations as a function 
of treatment over time will be assessed. Because of sample size considerations, we will base 
group comparisons for these analyses on two-sample t test. We will do correlative studies 
including all enrolled patients that have adequate biological samples available for analysis. We 
plan to assess changes over time and estimate odds ratios using mixed-effects logistic regression 
models or a linear model if the sample sizes for comparison are too small. We will summarize 
continuous variables as means and SDs, and categorical variables as counts with percentages.  
We will not do multiple testing adjustments. All the analyses will be done with SAS version 9.4. 
Study Rationale 
As we recently reported ketogenic diet can suppress hyperinsulinemia associated with PI3K 
inhibitors, leading to potentiation of the anti-tumor effects of PI3K inhibitors[79]. Copanlisib 
potently inhibits PI3Kα and PI3Kδ. It has been approved for the treatment of relapsed follicular 
lymphoma, based on ORR of 59% (84 of 142 patients)[83]. The CR rate in FL was 14%, and the 
median progression-free survival was 11.2 months. Copanlisib demonstrated encouraging 
clinical activity in marginal zone lymphoma (ORR 70% including 9% CR). While these results 
are clinically meaningful, FL and MZL inevitably develop resistance to copanlisib with time, 
even in those patients who initially respond to the therapy. Novel strategies to improve the 
efficacy of copanlisib in FL and MZL, by improving CR and PFS, may transform how we 
manage these incurable malignancies. 


 
 
 
(A) Wildtype c57/bl6 mice treated with copanlisib (BAY 80-6946), ketogenic diet, and the combination. c- 
Peptide levels were accessed from serum samples taken from these animals at the end of the time course, 240 
min. (B) Mice with the Kras-Tp53-Pdx-Cre (KPC) tumor allografts were treated as indicated, and the survival of 
the animals were depicted. 
Interestingly, copanlisib has also demonstrated clinical activity in aggressive lymphomas in a 
smaller study of heavily pre-treated patients[84]. Objective responses were achieved in patients 
with DLBCL (one PR; ORR 6.7%), PTCL (two CRs, one PR; ORR 21.4%), MCL (two uCRs, 
five PRs; ORR 63.6%), and transformed FL (both PRs; ORR 33.3%). These results suggest that 
copanlisib warrants further investigation in aggressive lymphomas such as PTCL and DLBCL. 
In a Phase I study of both solid tumors and lymphoma, sixteen of 20 patients treated at the MTD 
had reduced (18)FDG-PET uptake; 7 (33%) had a reduction >25%. One patient achieved a 
complete response (CR; endometrial carcinoma exhibiting both PIK3CA and PTEN mutations 
and complete PTEN loss) and two had a partial response (PR; both metastatic breast cancer). 
Among the nine NHL patients, all six with follicular lymphoma (FL) responded (one CR and 
five PRs) and one patient with diffuse large B-cell lymphoma had a PR by investigator 
assessment; two patients with FL who achieved CR (per post hoc independent radiologic review) 
were on treatment >3 years. 
The exact mechanism of resistance to copanlisib in various lymphomas and solid tumors remain 
poorly understood. As described above, we have reported that PI3K inhibitors can induce 
hyperinsulinemia, which in turn leads to activated survival pathway in cancer cells[79]. Our 
preliminary results demonstrate that in mice copanlisib stimulated the blood level of insulin, 
which is effectively mitigated by the ketogenic diet. Importantly, the ketogenic diet markedly 
improves the survival of KPC mice treated with copanlisib (BAY 80-6946). 
 
 
 
Collectively, the results presented above suggest that copanlisib may have encouraging clinical 
activity in indolent B-cell NHL such as FL and MZL, aggressive lymphomas such as PTCL and 
DLBCL, and solid tumors such as endometrial cancer. Furthermore, ketogenic diet may mitigate 
hyperinsulinemia associated with copanlisib in many patients, leading to improved treatment 
response to copanlisib and prolonged patient survival. 
 
 
 


 
 
Fasting requirements and pre-dose glucose levels 
 
Period 
Fasting ≥ 8 h required 
before 
first 
glucose 
measurement 
Pre-dose glucose levels 
(first glucose measurement) 
Day 1 Cycle 1 
Yes 
≤125 
mg/dL 
(non-diabetic 
patients) 
<160 
mg/dL 
(diabetic 
patients) 
Subsequent Infusion after Day 
1 Cycle 1 
No a 
<160 mg/dL (fasting) 
< 200 mg/dL (non-fasting) 
aThe decision regarding meal timing and fasting can be made by the investigator based on 
glucose response patterns during prior treatment days 
 
The investigator will accurately document fasting/non-fasting for each glucose measurement 
done at the site. 
▪ Fasting refers to no caloric intake for ≥ 8 h. 
▪ Non-fasting status includes any caloric intake such as meals and also juice, snacks, and other 
caloric intake not consistently called a meal. 
 
From Cycle 1 Day 1 onwards, glucose measurements at the site may be done either by laboratory 
analysis or in capillary blood using a hand-held glucose meter. If hand-held capillary glucose 
meters are chosen, the appropriate calibration of glucose meters will be documented. Any 
capillary or plasma glucose of > 250 mg/dL should be confirmed by repeated laboratory analysis. 
 
Laboratory criteria for dosing of copanlisib 
Blood glucose must be performed and assessed on the day of infusion. Glucose lowering 
medication can be used to optimize pre-infusion glucoses. 
 
Laboratory tests must be performed and assessed prior to each infusion of copanlisib. The results 
can be done +/- 2 days. 
 
 
 
 
 
 
 
 
 
 
 
 
 


 
 
Laboratory criteria for day 1 of each cycle 
 
Laboratory Test 
Criteria 
Glucose 
Hemoglobin 
ANC 
Platelets 
ALT 
AST 
Total bilirubin 
GFR (MDRD) 
< 160 mg/dL (fasting) or < 200 mg/dL (non-fasting) 
≥ 8 g/dL a 
≥ 1,000/mm3 
≥ 75,000/mm3 b 
<2.5 x ULN c 
<2.5 x ULN d 
within normal limits e 
≥ 35 mL/min/1.73 m2 
ALT = Alanine aminotransferase; ANC = Absolute neutrophil count; AST = Aspartate aminotransferase; GFR = 
Glomerular filtration rate; MDRD = Modification of Diet in Renal Disease; ULN = Upper limit of normal. 
a: If hemoglobin is < 8 g/dL but ≥ 6 g/dL on the day of planned study drug administration it is permissible to give the 
study drug dose as scheduled and transfuse within 48 hours after the dose, if the patient is hemodynamically stable 
and in opinion of investigator benefits outweigh risks. Rationale and treatment should be recorded in source 
document and Electronic case report form (eCRF). 
b: For patients with lymphomatous bone marrow infiltration at study entry (local assessment), platelet count ≥ 
50,000/mm3. This value should be used throughout the study irrespective of bone marrow status changes. Platelet 
transfusion should not be given less than 7 days before the exam collection. 
c: < 5 x ULN in patients with documented liver involvement by lymphoma or with biliary obstruction due to 
lymphoma. 
d: < 5 x ULN in patients with documented liver involvement by lymphoma or with biliary obstruction due to 
lymphoma. 
e: < 3 x ULN in patients with Gilbert-Meulengracht syndrome, patients with cholestasis due to compressive 
adenopathies of the hepatic hilum or documented liver involvement by lymphoma. 
 
On Days 8 and 15 of each cycle, the dose of copanlisib will be administered only if, on the day 
of scheduled dosing, the following laboratory test criteria are met (blood tests from the previous 
day is acceptable): 
• ANC ≥ 500/mm3 (and G-CSF/GM-CSF is mandatory if ANC<1000/mm3 and should 
be administered as per label) 
• Hemoglobin ≥ 8 g/Dl (Transfusion is allowed) 
• Platelet ≥ 75,000/mm3 (Transfusion is allowed) 
 
Doses of copanlisib may be delayed by up to 2 days. The minimal time between each infusion 
of copanlisib is 5 days. 
 
A delay of more than 2 days will be considered a missed dose. Missed doses will not be 
replaced. If a dose is missed by 8-21 days, the patient will start a new cycle at the dose 
described in Section 6.6 “Dose modification”. If the dose is delayed by more than 21 days, the 
patient will not be allowed to continue the study. Details were described in Section 5.6 
“Withdrawal criteria”. 


 
 
 
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