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

Study Overview
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Brief Summary
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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.

Detailed Description
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Background: Burkitt Lymphoma (BL) is a highly aggressive B cell lymphoma that often involves the bone marrow and central nervous system (CNS) Frontline therapy cures 80-85% of adults with BL but patients with CNS involvement or those who relapse after frontline therapy are at high risk for treatment failure Diffuse large B-cell lymphoma (DLBCL) is a heterogeneous group of aggressive B-cell lymphomas that are successfully cured by frontline therapy in 60-70% of cases A subset of DLBCL that have MYC gene rearrangement as well as those that have transformed from an underlying indolent lymphoma have a lower cure rate Dose-adjusted (DA)-EPOCH-R is an infusional chemotherapy platform often used as frontline therapy for these aggressive B-cell lymphomas and is an effective chemotherapy platform from which to rationally design novel therapies for patients with BL, high grade B-cell lymphomas- double hit/triple hit (HGBCL-DH/TH), DLBCL and MYC rearrangements, and other high-risk DLBCL The phosphoinositide 3-kinase (PI3K) pathway is an important signaling pathway for cellular responses to growth factors and a downstream event of B-cell receptor signaling. Copanlisib targets both PI3K-a and PI3K-d isoforms and is approved for relapsed FL, active as monotherapy in DLBCL, and highly effective in pre-clinical models of BL Copanlisib crosses the blood brain barrier suggesting it may prevent secondary CNS spread in highly aggressive B-cell lymphomas. Copanlisib is a rational targeted agent to be added to DA-EPOCH-R in patients with BL, HGBCL-DH/TH, and other high-risk B-cell lymphomas. Objective: To determine the Maximal tolerated dose (MTD) and Recommended Phase II dose (RP2D) of copanlisib in combination with DA-EPOCH-R in subjects with Burkitt lymphoma (BL) and high grade B-cell lymphomas- double hit/triple hit (HGBCL-DH/TH) relapsed after or refractory to chemo-immunotherapy Eligibility: Subjects must have a histologic diagnosis, confirmed by the Laboratory of Pathology, NCI with one of the following subtypes and prior therapy, as follows: 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 - following at least 1 anthracycline-containing regimen OR DLBCL, NOS, Germinal center B-cell type (GCB) type, T-cell/histocyte-rich large B-cell lymphoma, following at least 1 anthracycline-containing regimen AND at least 2 prior regimens OR be primary refractory to frontline therapy Age >= 18 ECOG performance status 0-2 Adequate bone marrow and organ function Design: Phase 1, open-label, single center, non-randomized 3+3 dosing will be used to determine the RP2D and MTD of dose escalated copanlisib in combination with standard regimen DA-EPOCH-R Maximum 6 cycles (21-day cycles) of combination therapy Dose expansion at the RP2D or MTD to evaluate efficacy and further evaluate safety To explore all dose levels, including further evaluation in dose expansion cohort, the accrual ceiling will be set at 39

Official Title
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Phase 1 Study of Copanlisib With Dose-adjusted EPOCH-R in Relapsed and Refractory Burkitt Lymphoma and Other High-Grade B-cell Lymphomas

Conditions
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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)

Intervention / Treatment
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* Biological: Rituximab
* Drug: Etoposide
* Biological: Copanlisib
* Drug: Cyclophosphamide
* Drug: Doxorubicin
* Drug: Vincristine
* Drug: Prednisone


Participation Criteria
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Eligibility Criteria
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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/mm^3 Platelets greater than or equal to 100 x 10^9 /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) greater than or equal to 50ml/min/1.73 m^2 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 with female partners of childbearing potential must agree to use a highly effective method of contraception when sexually active (intrauterine device, surgical sterilization, contraceptive rod, abstinence) for the time period between signing of the informed consent form and for at least 1 month after the last dose of copanlisib. WOCBP and men with female partners of childbearing potential must agree to use an effective method of contraception (two of the following: diaphragm, cervical cap, contraceptive sponge, condom, hormonal) when sexually active for the time period between signing of the informed consent and for at least 12 months after the last dose of rituximab. 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, asectomized partner and sexual abstinence. 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 Patients who have been treated with prior CAR-T therapy or any regimen containing fludarabine. 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 (HbsAg) 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 (HbsAg) 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.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Non-Randomized
Intervention Model: Sequential Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: 1- Dose Escalation, Original<br>Copanlisib (IV) per dose level (30 mg, 45 mg, or 60 mg) on day 1 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<br>* Rituximab 375 mg/m2 IV per protocol on Day 1 of each cycle up to 6 cycles<br>Drug: Etoposide<br>* Etoposide 50 mg/m2/day CIVI on Days 1-4 of each cycle up to 6 cycles<br>Biological: Copanlisib<br>* 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<br>Drug: Cyclophosphamide<br>* Cyclophosphamide 750 mg/m2 IV on Day 5 of each cycle up to 6 cycles<br>Drug: Doxorubicin<br>* Doxorubicin 10 mg/m2/day CIVI on Days 1-4 of each cycle up to 6 cycles<br>Drug: Vincristine<br>* Vincristine 0.4 mg/m2/day (no cap) CIVI on Days 1-4 of each cycle up to 6 cycles<br>Drug: Prednisone<br>* Prednisone 60 mg/m2 PO BID Days 1-5 (total 120mg/m2/day)<br>|
| Experimental: 2 - Dose Expansion, Modified<br>Copanlisib (IV) at the RP2D or MTD on day 1 of each 21-day cycle in combination with standard dosing DA-EPOCH-R. Up to 6 cycles total. | Biological: Rituximab<br>* Rituximab 375 mg/m2 IV per protocol on Day 1 of each cycle up to 6 cycles<br>Drug: Etoposide<br>* Etoposide 50 mg/m2/day CIVI on Days 1-4 of each cycle up to 6 cycles<br>Biological: Copanlisib<br>* 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<br>Drug: Cyclophosphamide<br>* Cyclophosphamide 750 mg/m2 IV on Day 5 of each cycle up to 6 cycles<br>Drug: Doxorubicin<br>* Doxorubicin 10 mg/m2/day CIVI on Days 1-4 of each cycle up to 6 cycles<br>Drug: Vincristine<br>* Vincristine 0.4 mg/m2/day (no cap) CIVI on Days 1-4 of each cycle up to 6 cycles<br>Drug: Prednisone<br>* Prednisone 60 mg/m2 PO BID Days 1-5 (total 120mg/m2/day)<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Maximum tolerated dose (MTD) and Recommended Phase II dose (RP2D) | Frequency (number and percentage) of treatment emergent adverse events | 21 days | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Overall Response Rate | The response rate will be determined and reported along with a 95% confidence interval | 6 cycles | 
| Progression-free survival | The response rate will be determined and reported along with a 95% confidence interval | every 3 months for 2 years, every 6 months for years 2-5 | 
| Complete Response Rate | The response rate will be determined and reported along with a 95% confidence interval | every 3 months for 2 years, every 6 months for years 2-5 | 
| Overall survival (OS) | The response rate will be determined and reported along with a 95% confidence interval | every 2 months for 6 months, every 3 months for 2 years, every 6 months for 2 years, then annually | 
| Event-free survival (EFS) | The response rate will be determined and reported along with a 95% confidence interval | every 2 months for 6 months, every 3 months for 2 years, every 6 months for 2 years, then annually | 
| Safety and tolerability | rate and severity of AEs will be summarized by grade and type of toxicity | 6 cycles | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Aliqopa, BAY 80-6946, Monoclonal Antibody, PI3K Target