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Copanlisib With Dose-Adjusted EPOCH-R in Relapsed and Refractory Burkitt Lymphoma and Other High-Grade B-cell Lymphomas

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ClinicalTrials.gov Identifier: NCT04933617
Recruitment Status : Not yet recruiting
First Posted : June 22, 2021
Last Update Posted : December 1, 2021
Sponsor:
Information provided by (Responsible Party):
National Institutes of Health Clinical Center (CC) ( National Cancer Institute (NCI) )

Brief Summary:

Background:

Burkitt Lymphoma (BL) and diffuse large B-cell lymphoma (DLBCL) are aggressive B cell lymphomas. Frontline treatment does not always work. Researchers want to see if a combination of drugs can help.

Objective:

To learn if it is safe to give people with certain cancers copanlisib together with rituximab and combination chemotherapy (DA-EPOCH-R).

Eligibility:

People ages 18 and older with relapsed and/or refractory highly aggressive B-cell lymphomas such as BL and certain types of DLBCL.

Design:

Participants will be screened with:

Medical history

Physical exam

Bone marrow aspiration and biopsy. A needle will be put into their hipbone. Marrow will be removed.

Imaging scans of the chest, abdomen, pelvis, and/or brain

Tumor biopsy (if needed)

Blood and urine tests

Heart function tests

Treatment will be given in 21-day cycles for up to 6 cycles. Participants will get copanlisib by intravenous (IV) infusion. They will also get a group of medicines called DA-EPOCH-R, as follows. They will get rituximab by IV infusion. Doxorubicin, etoposide, and vincristine will be mixed together in an IV bag and given by continuous IV infusion over 4 days. They will get cyclophosphamide by IV infusion. They will take prednisone by mouth.

Participants will have frequent study visits. At these visits, they will repeat some screening tests. They may give tissue, saliva, and cheek swab samples. They will have at least one spinal tap. For this, a needle will be inserted into the spinal canal. Fluid will be removed.

Participants will have a visit 30 days after treatment ends. They will have follow-up visits for at least 5 years.


Condition or disease Intervention/treatment Phase
Burkitt Lymphoma High-grade B-cell Lymphoma T-cell/Histocyte-rich Large B-cell Lymphoma Diffuse Large B-Cell Lymphoma (DLBCL) Germinal Center B-cell Type (GCB) Biological: Rituximab Drug: Etoposide Biological: Copanlisib Drug: Cyclophosphamide Drug: Doxorubicin Drug: Vincristine Drug: Prednisone Phase 1

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 34 participants
Allocation: Non-Randomized
Intervention Model: Sequential Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: Phase 1 Study of Copanlisib With Dose-adjusted EPOCH-R in Relapsed and Refractory Burkitt Lymphoma and Other High-Grade B-cell Lymphomas
Estimated Study Start Date : December 6, 2021
Estimated Primary Completion Date : July 1, 2025
Estimated Study Completion Date : July 1, 2025


Arm Intervention/treatment
Experimental: 1- Dose Escalation
Copanlisib (IV) per dose level (30 mg, 45 mg, or 60 mg) on days 1 and 5 of each 21-day cycle in combination with standard dosing DA-EPOCH-R to determine RP2D and MTD of copanlisib. Up to 6 cycles total.
Biological: Rituximab
Rituximab 375 mg/m2 IV per protocol on Day 1 of each cycle up to 6 cycles

Drug: Etoposide
Etoposide 50 mg/m2/day CIVI on Days 1-4 of each cycle up to 6 cycles

Biological: Copanlisib
Copanlisib IV is administered at a fixed dose (30 mg, 45 mg, or 60 mg) on days 1 and 5 of each 21-day cycle for up to 6 cycles

Drug: Cyclophosphamide
Cyclophosphamide 750 mg/m2 IV on Day 5 of each cycle up to 6 cycles

Drug: Doxorubicin
Doxorubicin 10 mg/m2/day CIVI on Days 1-4 of each cycle up to 6 cycles

Drug: Vincristine
Vincristine 0.4 mg/m2/day (no cap) CIVI on Days 1-4 of each cycle up to 6 cycles

Drug: Prednisone
Prednisone 60 mg/m2 PO BID Days 1-5 (total 120mg/m2/day)

Experimental: 2 - Dose Expansion
Copanlisib (IV) at the RP2D or MTD on days 1 and 5 of each 21-day cycle in combination with standard dosing DA-EPOCH-R. Up to 6 cycles total.
Biological: Rituximab
Rituximab 375 mg/m2 IV per protocol on Day 1 of each cycle up to 6 cycles

Drug: Etoposide
Etoposide 50 mg/m2/day CIVI on Days 1-4 of each cycle up to 6 cycles

Biological: Copanlisib
Copanlisib IV is administered at a fixed dose (30 mg, 45 mg, or 60 mg) on days 1 and 5 of each 21-day cycle for up to 6 cycles

Drug: Cyclophosphamide
Cyclophosphamide 750 mg/m2 IV on Day 5 of each cycle up to 6 cycles

Drug: Doxorubicin
Doxorubicin 10 mg/m2/day CIVI on Days 1-4 of each cycle up to 6 cycles

Drug: Vincristine
Vincristine 0.4 mg/m2/day (no cap) CIVI on Days 1-4 of each cycle up to 6 cycles

Drug: Prednisone
Prednisone 60 mg/m2 PO BID Days 1-5 (total 120mg/m2/day)




Primary Outcome Measures :
  1. Maximum tolerated dose (MTD) and Recommended Phase II dose (RP2D) [ Time Frame: 21 days ]
    Frequency (number and percentage) of treatment emergent adverse events


Secondary Outcome Measures :
  1. Overall Response Rate [ Time Frame: 6 cycles ]
    The response rate will be determined and reported along with a 95% confidence interval

  2. Progression-free survival [ Time Frame: every 3 months for 2 years, every 6 months for years 2-5 ]
    The response rate will be determined and reported along with a 95% confidence interval

  3. Complete Response Rate [ Time Frame: every 3 months for 2 years, every 6 months for years 2-5 ]
    The response rate will be determined and reported along with a 95% confidence interval

  4. Overall survival (OS) [ Time Frame: every 2 months for 6 months, every 3 months for 2 years, every 6 months for 2 years, then annually ]
    The response rate will be determined and reported along with a 95% confidence interval

  5. Event-free survival (EFS) [ Time Frame: every 2 months for 6 months, every 3 months for 2 years, every 6 months for 2 years, then annually ]
    The response rate will be determined and reported along with a 95% confidence interval

  6. Safety and tolerability [ Time Frame: 6 cycles ]
    rate and severity of AEs will be summarized by grade and type of toxicity



Information from the National Library of Medicine

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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:
  • Subjects must have a histologic diagnosis, confirmed by the Laboratory of Pathology, NCI with one of the following subtypes and prior therapy, as follows:

    • At least 1 anthracycline-containing regimen:

      • Burkitt lymphoma
      • Burkitt-like lymphoma with 11q aberration
      • High-grade B-cell lymphoma, NOS
      • High-grade B-cell lymphoma, with MYC and BCL2 and/or BCL6 rearrangements

OR

--Must have had at least 2 prior regimens, 1 of which must have been anthracyclinecontaining regimen OR be primary refractory to frontline therapy:

---DLBCL, NOS, Germinal center B-cell type (GCB) type;

NOTE: subjects with coexisting or a history of indolent lymphoma are eligible (i.e., transformed lymphoma )

---T-cell/histocyte-rich large B-cell lymphoma

  • Measurable or evaluable disease on imaging scans or bone marrow
  • No other current systemic anti-lymphoma therapy. NOTE: Recent short-term (less than or equal to 7 days) use of corticosteroids or prior radiation to sites of disease involvement is permitted.
  • Any HIV status will be included in this study as long as infection is controlled; in the opinion of the investigator. Status must be confirmed at screening and the subject must be willing to take any recommended antiretroviral therapy.
  • Greater than or equal to 18 years of age on day of signing informed consent
  • ECOG performance status less than or equal to 2
  • Adequate organ function as evidenced by the following laboratory parameters, unless dysfunction is secondary to lymphoma involvement as determined by the investigator:

    • Absolute neutrophil count (ANC) greater than or equal to 1,000 /mm3
    • Platelets greater than or equal to 75 x 109 /L
    • Hemoglobin greater than or equal to 8 g/dL (unless due to disease itself, transfusion permitted to meet criteria)
    • Renal function Glomerular filtration rate (GFR) >40ml/min/1.73 m2 as estimated by Modification of Diet in Renal Disease

(MDRD) abbreviated formula. If not on target, a 24- hour urine creatinine clearance can be used to directly measure.

  • Total bilirubin less than or equal to 1.5 x ULN OR < 1.5-3.0 x ULN for subjects with liver involvement*
  • AST and ALT less than or equal to 3.0 x ULN OR < 5 x ULN for subjects with liver involvement

    • Acceptable range as long as there is no persistent nausea, vomiting, right upper quadrant pain or tenderness, fever, rash, or eosinophilia

      • Must have fully recovered from all effects of prior surgery. NOTE: Minor procedures requiring Twilight sedation, such as tissue biopsies, endoscopies or mediport placement require a 24-hour waiting period prior to treatment initiation.
      • Women of childbearing potential (WOCBP) and men must agree to use effective contraception when sexually active. This applies for the time period between signing of the informed consent form and for at least 3 months after the last dose of copanlisib and 12 months after the last dose of rituximab, whichever is later. Women of childbearing potential must have a serum pregnancy test performed a maximum of 7 days before start of treatment, and a negative result must be documented before start of treatment.

NOTE: A woman is considered of childbearing potential, (i.e., fertile), following menarche and until becoming post-menopausal unless permanently sterile. Permanent sterilization methods include but are not limited to hysterectomy, bilateral salpingectomy and bilateral oophorectomy. A postmenopausal state is defined as no menses for continuous 12 months without an alternative medical cause. A high follicle stimulating hormone (FSH) level in the postmenopausal range may be used to confirm a postmenopausal state in women not using hormonal contraception or hormonal replacement therapy. The investigator or a designated associate is requested to advise the subject how to achieve highly effective birth control (failure rate of less than 1%), e.g., intrauterine device (IUD), intrauterine hormone-releasing system (IUS), bilateral tubal occlusion, vasectomized partner and sexual abstinence. The use of condoms by male subjects is required unless the female partner is permanently sterile.

  • Willingness to have a central venous access line placed if the subject does not already have one in place
  • Ability of patient to understand and the willingness to sign a written informed consent document

EXCLUSION CRITERIA:

  • Subjects previously exposed to, intolerant of, or ineligible for PI3K inhibitors and/or their combination
  • Brain parenchymal involvement
  • CMV-positive PCR at screening
  • History of diabetic ketoacidosis
  • Uncontrolled intercurrent illness including, but not limited to the following that may limit interpretation of results or that could increase risk to the subject at the discretion of the investigator:

    • Any secondary malignancy that requires active systemic therapy
    • Diabetes mellitus with Hgb A1C > 8.5
    • Clinically significant interstitial lung disease and/or lung disease that severly impairs lung function
    • Uncontrolled HIV
    • Active hepatitis C infection. NOTE: Subjects who are hepatitis C antibody positive will need to have a negative HCV PCR result before enrollment. Those with a positive PCR for hepatitis C are excluded.
    • Active hepatitis B infection. NOTE: Patients who are hepatitis B surface antigen (HbcsAg) or hepatitis B core antibody (HbcAb) positive will need to have a negative HBV PCR result before enrollment. Those with a positive PCR for hepatitis B are excluded. Those who are hepatitis B surface antigen (HbcsAg) or hepatitis B core antibody (HbcAb) positive with a negative PCR for hepatitis B will be treated with antivirals designed to prevent hepatitis B reactivation (e.g., entecavir) throughout therapy and for 12 months after therapy and have monitoring for hepatitis B reactivation with PCR.
    • Clinically significant, uncontrolled heart disease and/or cardiac repolarization abnormalities, including any of the following:

      • History of acute coronary syndromes (including myocardial infarction, unstable angina, coronary artery bypass grafting, coronary angioplasty, or stenting) or symptomatic pericarditis within 6 months prior to screening
      • Congestive heart failure (New York Heart Association functional classification III-IV)
      • Unstable angina
      • Left Ventricular Ejection Fraction (LVEF) <40% as determined by echocardiogram (ECHO) at screening
      • Clinically significant cardiac arrhythmias (e.g., ventricular tachycardia), complete left bundle branch block, high-grade AV block (e.g., bifascicular block, Mobitz type II and third-degree AV block)
      • Long QT syndrome or family history of idiopathic sudden death or congenital long QT syndrome, or any of the following:

        • Long QT syndrome or family history of idiopathic sudden death or congenital long QT syndrome, or any of the following:
        • Inability to determine the QT interval on screening (QTcF, using Fredericia s correction)
        • Long QT syndrome or family history of idiopathic sudden death or congenital long QT syndrome
    • Known mental or physical illness that would interfere with cooperation with the requirements of the trial or confound the results or interpretation of the results of the trial and, in the opinion of the treating investigator, would make the subject inappropriate for entry into the study.
  • Requirement to continue on any of the medications that are excluded
  • Breast-feeding subjects. Because there is an unknown but potential risk for adverse events in nursing infants secondary to treatment of the mother with these agents, breastfeeding should be discontinued if the mother is treated on study.

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): NCT04933617


Contacts
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Contact: NCI Medical Oncology Referral Office (240) 760-6050 ncimo_referrals@nih.gov

Locations
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United States, Maryland
National Institutes of Health Clinical Center
Bethesda, Maryland, United States, 20892
Contact: For more information at the NIH Clinical Center contact National Cancer Institute Referral Office    888-624-1937      
Sponsors and Collaborators
National Cancer Institute (NCI)
Investigators
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Principal Investigator: Mark J Roschewski, M.D. National Cancer Institute (NCI)
Additional Information:
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Responsible Party: National Cancer Institute (NCI)
ClinicalTrials.gov Identifier: NCT04933617    
Other Study ID Numbers: 10000193
000193-C
First Posted: June 22, 2021    Key Record Dates
Last Update Posted: December 1, 2021
Last Verified: October 7, 2021

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Keywords provided by National Institutes of Health Clinical Center (CC) ( National Cancer Institute (NCI) ):
Aliqopa
BAY 80-6946
Monoclonal Antibody
PI3K Target
Additional relevant MeSH terms:
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Burkitt Lymphoma
Lymphoma
Lymphoma, B-Cell
Lymphoma, Large B-Cell, Diffuse
Neoplasms by Histologic Type
Neoplasms
Lymphoproliferative Disorders
Lymphatic Diseases
Immunoproliferative Disorders
Immune System Diseases
Lymphoma, Non-Hodgkin
Epstein-Barr Virus Infections
Herpesviridae Infections
DNA Virus Infections
Virus Diseases
Infections
Tumor Virus Infections
Prednisone
Cyclophosphamide
Rituximab
Doxorubicin
Etoposide
Vincristine
Immunosuppressive Agents
Immunologic Factors
Physiological Effects of Drugs
Antirheumatic Agents
Antineoplastic Agents, Alkylating
Alkylating Agents
Molecular Mechanisms of Pharmacological Action