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Study of Copanlisib and Ketogenic Diet

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ClinicalTrials.gov Identifier: NCT04750941
Recruitment Status : Recruiting
First Posted : February 11, 2021
Last Update Posted : December 8, 2021
Sponsor:
Collaborator:
Bayer
Information provided by (Responsible Party):
Jennifer Amengual, Columbia University

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).

Condition or disease Intervention/treatment Phase
Follicular Lymphoma Endometrial Cancer Drug: Copanlisib Other: Ketogenic Diet Phase 2

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.

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 42 participants
Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: 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
Estimated Study Start Date : December 2021
Estimated Primary Completion Date : June 2022
Estimated Study Completion Date : December 2022

Resource links provided by the National Library of Medicine

MedlinePlus related topics: Lymphoma
Drug Information available for: Copanlisib

Arm Intervention/treatment
Experimental: Follicular Lymphoma (FL)

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.

Drug: Copanlisib
Copanlisib will be infused intravenously on days 1, 8, 15 of each cycle, over 1 hour, of 28-day cycles.

Other: Ketogenic Diet

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.


Experimental: Endometrial Cancer (EC)

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.

Drug: Copanlisib
Copanlisib will be infused intravenously on days 1, 8, 15 of each cycle, over 1 hour, of 28-day cycles.

Other: Ketogenic Diet

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.





Primary Outcome Measures :
  1. Objective response rate (ORR) [ Time Frame: Up to 58 weeks or 4 weeks after the last dose ]
    ORR will be determined from the number of individuals with a complete response (CR) and number of individuals with a partial response (PR)


Secondary Outcome Measures :
  1. Complete Response (CR) Rate [ Time Frame: Up to 58 weeks or 4 weeks after the last dose ]
    Total number of participants with a CR.

  2. Partial Response (PR) Rate [ Time Frame: Up to 58 weeks or 4 weeks after the last dose ]
    Total number of participants with a PR.

  3. ORR at the Simon stage I analysis [ Time Frame: Up to 58 weeks or 4 weeks after the last dose ]
    ORR will be determined from the number of individuals with a complete response (CR) and number of individuals with a partial response (PR).

  4. Patient compliance with the ketogenic diet [ Time Frame: Up to 58 weeks or 4 weeks after the last dose ]
    Total # of patients who are compliant with the ketogenic diet.



Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.


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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

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.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT04750941


Contacts
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Contact: Jennifer E. Amengual, MD (212) 326 - 5720 jea2149@cumc.columbia.edu

Locations
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United States, New York
Columbia University Irving Medical Center Recruiting
New York, New York, United States, 10032
Contact: Jennifer E. Amengual, MD    212-326-5720    jea2149@cumc.columbia.edu   
Principal Investigator: Jennifer E. Amengual, MD         
Weill Cornell Medical Center Not yet recruiting
New York, New York, United States, 10065
Contact: Peter Martin, MD         
Principal Investigator: Peter Martin, MD         
Memorial Sloan Kettering Cancer Center Not yet recruiting
New York, New York, United States, 10604
Contact: Vicky Makker, MD         
Principal Investigator: Vicky Makker, MD         
Sponsors and Collaborators
Columbia University
Bayer
Investigators
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Principal Investigator: Jennifer E. Amengual, MD Columbia University
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Responsible Party: Jennifer Amengual, Principal Investigator, Assistant Professor of Medicine, Columbia University
ClinicalTrials.gov Identifier: NCT04750941    
Other Study ID Numbers: AAAS4953
First Posted: February 11, 2021    Key Record Dates
Last Update Posted: December 8, 2021
Last Verified: November 2021
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Product Manufactured in and Exported from the U.S.: No
Keywords provided by Jennifer Amengual, Columbia University:
Keto diet
Copanlisib
Additional relevant MeSH terms:
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Lymphoma
Lymphoma, Follicular
Endometrial Neoplasms
Neoplasms by Histologic Type
Neoplasms
Lymphoproliferative Disorders
Lymphatic Diseases
Immunoproliferative Disorders
Immune System Diseases
Lymphoma, Non-Hodgkin
Uterine Neoplasms
Genital Neoplasms, Female
Urogenital Neoplasms
Neoplasms by Site
Uterine Diseases