Copanlisib and a Ketogenic Diet for the Treatment of Relapsed or Refractory Follicular Lymphoma or Endometrial Cancer

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
• 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 Memorial Sloan Kettering (MSK)-integrated mutation profiling of actionable cancer targets (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: * 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 * 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 Eastern Cooperative Oncology Group (ECOG) performance scale
• Glucose < 160 mg/dL (fasting) or < 200 mg/dL (non-fasting) (performed within 21 days of initiation of copanlisib)
• Hemoglobin >= 8 g/dL (performed within 21 days of initiation of copanlisib) * 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)
• Absolute neutrophil count (ANC) >= 1,500/mm^3 (performed within 21 days of initiation of copanlisib)
• Platelets >= 75,000/mm^3 (performed within 21 days of initiation of copanlisib) * For patients with lymphomatous bone marrow infiltration at study entry (local assessment), platelet count >= 50,000/mm^3. 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
• Alanine aminotransferase (ALT) < 2.5 x upper limit of normal (ULN) (performed within 21 days of initiation of copanlisib) * < 5 x ULN in patients with documented liver involvement by lymphoma or with biliary obstruction due to lymphoma
• Aspartate aminotransferase (AST) < 2.5 x upper limit of normal (ULN) (performed within 21 days of initiation of copanlisib) * < 5 x ULN in patients with documented liver involvement by lymphoma or with biliary obstruction due to lymphoma
• Total bilirubin within normal limits (performed within 21 days of initiation of copanlisib) * < 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
• Glomerular filtration rate (GFR) ( modification of diet in renal disease [MDRD]) >= 35 mL/min/1.73 m^2 (performed within 21 days of initiation of copanlisib) * 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
• Human immunodeficiency virus (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 as described below: * Female subject of childbearing potential should have a negative urine or serum pregnancy within 72 hours prior to receiving the first dose of study medication. If the urine test is positive or cannot be confirmed as negative, a serum pregnancy test will be required * Female subjects of childbearing potential must be willing to use an adequate method of contraception – contraception for the course of the study through 120 days after the last dose of study medication. Note: Abstinence is acceptable if this is the usual lifestyle and preferred contraception for the subject * Male subjects of childbearing potential must agree to use an adequate method of contraception - contraception, starting with the first dose of study therapy through 120 days after the last dose of study therapy * Note: Abstinence is acceptable if this is the usual lifestyle and preferred contraception for the subject

Exclusion Criteria

• The following treatments are prohibited: * Chemotherapy (including PI3K inhibitors and other approved or investigational drugs) and monoclonal antibody within 3 weeks; * Radiotherapy within 2 weeks prior to entering the study; * 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 (glycosylated hemoglobin [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 > Common Terminology Criteria for Adverse Events (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 (triglyceride [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. 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 electrocardiogram (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