Study of Copanlisib and Ketogenic Diet
Study of Copanlisib and Ketogenic Diet
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).
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.
Inclusion Criteria:

 -  Be willing and able to provide written informed consent for the trial.

 -  Be 18 years of age or older on day of signing informed consent.

 -  For lymphoma, patients should have measurable disease based on the Lugano Criteria.

 -  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.

 -  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 /dedifferentiated, mucinous, squamous, transitional, not-otherwise
 specified, and mixed celltype.

 -  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 correlative studies will not be
 eligible for the clinical trial.

 -  Left Ventricular Ejection Fraction (LVEF) > 50%.

 -  A performance status of 0-2 on the Eastern Cooperative Oncology Group (ECOG)
 Performance Scale.

 -  Demonstrate adequate organ function. All screening labs should be performed within 14
 days of treatment initiation.

 -  HIV positive patients will be eligible as long as the viral load by polymerase chain
 reaction (PCR) testing is undetectable.

 -  Female patients of childbearing potential must have a negative pregnancy test within 7
 days prior to treatment start.

 -  Adequate contraception.

 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:
 nonmelanoma 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 (defined in the protocol).

 -  Uncontrolled moderate to severe hypertriglyceridemia (TG>300 mg/dL).

 -  Myocardial infarction within 6 months of cycle 1, day 1.

 -  Symptomatic coronary artery disease (CAD), e.g., angina Canadian Class II-IV (see
 Appendix 5).

 -  An ECG recorded at screening showing evidence of cardiac ischemia.

 -  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 or milk protein.

 -  History of serious or uncontrolled gout or hyperuricemia.

 -  Pregnancy, lactation, or breastfeeding.

 -  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.