Study of Copanlisib and Ketogenic Diet

Pilot Phase II 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

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.