Burkitt LymphomaPhase 1NCT04933617
Copanlisib With Dose-Adjusted EPOCH-R in Relapsed and Refractory Burkitt Lymphoma and Other High-Grade B-cell Lymphomas
A Phase 1 study testing Rituximab, Etoposide and Copanlisib in people with Burkitt Lymphoma and High-grade B-cell Lymphoma, run by National Cancer Institute (NCI) at 1 site in United States.
Trial 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. Read more about this study
- Who is it for?
- Ages 18 years and older
- Conditions the study is for
- Burkitt Lymphoma, High-grade B-cell Lymphoma, T-cell/Histocyte-rich Large B-cell Lymphoma
- What is being tested?
- Rituximab, Etoposide and Copanlisib
- Type of treatment
- Pill or oral medicine, Injection or infusion, Surgery or procedure
- Could I receive a placebo?
- No, everyone receives an active treatment
- How many people
- 8 participants
- Where
- 1 siteUnited States
- Study dates
- 24 Mar 2022to 30 Nov 2023
- Phase
- Phase 1
- Are there results?
- Yes, posted in the registrySummary in the doctors' view
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 18 years and older
- All sexes
- No healthy volunteers
- Adult, Older adult
Who may be able to join
- Subjects must have a histologic diagnosis, confirmed by the Laboratory of Pathology, National Cancer Institute (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, nor otherwise specified (NOS)
- High-grade B-cell lymphoma, with myelocytomatosis (MYC) and B-cell lymphoma 2 (BCL2) and/or B-cell lymphoma 6 (BCL6) rearrangements
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- OR
- --Must have had at least 2 prior regimens, 1 of which must have been anthracycline containing regimen OR be primary refractory to frontline therapy:
- ---Diffuse large B-cell lymphoma (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 human immunodeficiency virus (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
- Eastern Cooperative Oncology Group (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
- 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 upper limit of normal (ULN) OR < 1.5-3.0 x ULN for subjects with liver involvement*
- Aspartate aminotransferase (AST) and alanine aminotransferase (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, vasectomized 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
Who cannot join
- Subjects previously exposed to, intolerant of, or ineligible for phosphoinositide 3-kinases (PI3K) inhibitors and/or their combination
- Brain parenchymal involvement
- Patients who have been treated with prior chimeric antigen receptor (CAR)-T therapy or any regimen containing fludarabine.
- Cytomegalovirus (CMV)-positive polymerase chain reaction (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:
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- Any secondary malignancy that requires active systemic therapy
- Diabetes mellitus with hemoglobin (Hgb) hemoglobin A1C (A1C) > 8.5
- Clinically significant interstitial lung disease and/or lung disease that severely impairs lung function
- Uncontrolled human immunodeficiency virus (HIV)
- Active hepatitis C infection. NOTE: Subjects who are hepatitis C antibody positive will need to have a negative hepatitis C virus (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 atrioventricular (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 Fridericia'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.
Trial locations and contacts
1 site in 1 country.
United States1 site
National Institutes of Health Clinical Center
Bethesda, Maryland, 20892
About this study
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
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.
Read more
Objective:
To learn if it is safe to give people with certain cancers copanlisib together with rituximab and combination chemotherapy dose-adjusted etoposide, prednisone, vincristine, cyclophosphamide, doxorubicin, and rituximab (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 diffuse large B-cell lymphoma (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.
Read the detailed description
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 myelocytomatosis (MYC) gene rearrangement as well as those that have transformed from an underlying indolent lymphoma have a lower cure rate.
Dose-adjusted dose-adjusted etoposide, prednisone, vincristine, cyclophosphamide, doxorubicin, and rituximab (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 myelocytomatosis (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 follicular lymphoma (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, National Cancer Institute (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, not otherwise specified (NOS), High-grade B-cell lymphoma, with MYC and B-cell lymphoma 2 (BCL2) and/or B-cell lymphoma 6 (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
Eastern Cooperative Oncology Group (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 recommended phase 2 dose (RP2D) and maximum tolerated dose (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.
- Conditions
- 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)
- Being tested
- Rituximab, Etoposide, Copanlisib, Cyclophosphamide, Doxorubicin
- Keywords
- Aliqopa, BAY 80-6946, Monoclonal Antibody, PI3K Target
- Medical subject headings
- Burkitt Lymphoma, Lymphoma, Large B-Cell, Diffuse
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
RituximabBiological
Also called Rituxan
Rituximab 375 mg/m^2 intravenous (IV) per protocol on Day 1 of each cycle up to 6 cycles
EtoposideDrug
Also called Toposar, Etopophos
Etoposide 50 mg/m^2/day continuous intravenous infusion (CIVI) on Days 1-4 of each cycle up to 6 cycles
CopanlisibBiological
Also called Aliqopa
Copanlisib intravenous (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
CyclophosphamideDrug
Also called Cytoxan
Cyclophosphamide 750 mg/m^2 intravenous (IV) on Day 5 of each cycle up to 6 cycles
DoxorubicinDrug
Also called Adriamycin
Doxorubicin 10 mg/m^2/day continuous intravenous infusion (CIVI) on Days 1-4 of each cycle up to 6 cycles
VincristineDrug
Also called Marqibo, Vincasar PFS
Vincristine 0.4 mg/m^2/day (no cap) continuous intravenous infusion (CIVI) on Days 1-4 of each cycle up to 6 cycles
PrednisoneDrug
Also called Deltasone, Rayos, Prednisone Intensol
Prednisone 60 mg/m^2 by mouth (PO) twice a day (BID) Days 1-5 (total 120mg/m^2/day)
ECHODiagnostic test
Also called Echocardiogram
At screening.
EKGDiagnostic test
Also called Electrocardiogram
At screening.
MRI BrainDiagnostic test
Also called Magnetic resonance imaging of the brain
At screening.
18F-FDG - PETDiagnostic test
Also called Fludeoxyglucose F18
At screening, baseline, after cycle 1, 3, and 6, and end of treatment.
CT ScanDiagnostic test
Also called Computed tomography scan
At screening, baseline, after cycle 1, 3, and 6, end of treatment and follow-up.
Bone Marrow AspirationProcedure or surgery
At screening and end of treatment.
Bone Marrow BiopsyProcedure or surgery
At screening and end of treatment.
Lumbar Puncture (LP)Diagnostic test
Also called Spinal tap
Baseline and end of treatment.
| Study group | Role | What they receive |
|---|---|---|
| Arm 1- Dose Escalation, Original Copanlisib Intravenous (IV) | Experimental | Copanlisib intravenous (IV) per dose level (30 mg, 45 mg, or 60 mg) on day 1 of each 21-day cycle in combination with standard dosing dose adjusted rituximab, etoposide, prednisolone, vincristine, cyclophosphamide, doxorubicin (DA-EPOCH-R) to determine recommended phase 2 dose (RP2D) and maximum tolerated dose (MTD) of copanlisib. Up to 6 cycles total. Receives: Biological: Rituximab; Drug: Etoposide; Biological: Copanlisib; Drug: Cyclophosphamide; Drug: Doxorubicin; Drug: Vincristine; Drug: Prednisone; Diagnostic Test: ECHO; Diagnostic Test: EKG; Diagnostic Test: MRI Brain; Diagnostic Test: 18F-FDG - PET; Diagnostic Test: CT Scan; Procedure: Bone Marrow Aspiration; Procedure: Bone Marrow Biopsy; Diagnostic Test: Lumbar Puncture (LP) |
| Arm 2 - Dose Expansion, Modified Copanlisib Intravenous (IV) | Experimental | Copanlisib intravenous (IV) at the recommended phase 2 dose (RP2D) or maximum tolerated dose (MTD) on day 1 of each 21-day cycle in combination with standard dosing dose adjusted rituximab, etoposide, prednisolone, vincristine, cyclophosphamide, doxorubicin (DA-EPOCH-R). Up to 6 cycles total. Receives: Biological: Rituximab; Drug: Etoposide; Biological: Copanlisib; Drug: Cyclophosphamide; Drug: Doxorubicin; Drug: Vincristine; Drug: Prednisone; Diagnostic Test: ECHO; Diagnostic Test: EKG; Diagnostic Test: MRI Brain; Diagnostic Test: 18F-FDG - PET; Diagnostic Test: CT Scan; Procedure: Bone Marrow Aspiration; Procedure: Bone Marrow Biopsy; Diagnostic Test: Lumbar Puncture (LP) |
What is being measured
The primary outcome is the main question the study is designed to answer.
Maximum Tolerated Dose (MTD) and Recommended Phase II Dose (RP2D)
MTD and RP2D is defined as the dose level at which no more than 1 of up to 6 participants experience dose limiting toxicity (DLT) during the DLT period, and the dose below that at which at least 2 (of ≤6) participants have DLT as a result of treatment. A DLT is any treatment-emergent, clinically relevant, and related severe (grade ≥ 3) toxicity that is possibly, probably, or definitely related to copanlisib.
Measured: 21 days
Secondary outcomes (6)
Overall Response Rate (ORR)
ORR is the best response recorded from the start of the treatment until disease progression/recurrence determined by Kaplan-Meier method and reported along with a 95% confidence interval. Response was assessed by the Revised Response Criteria for Malignant Lymphoma criteria, and the Lugano Classification Response Criteria for Non-Hodgkin Lymphoma (NHL). Complete response (CR) is complete disappearance of all detectable evidence of disease and disease-related symptoms. Partial response (PR) is a ≥50% decrease in the sum of the product of the diameters of up to 6 of the largest dominant nodes or nodal masses. Progressive disease (PD) is appearance of any new nodal lesion ≥1.6 cm in greatest tumor dimension or ≥1.1 cm in short axis during or after the end of therapy. A participant is considered to have stable disease (SD) when he or she fails to attain the criteria needed for a CR, PR, or Minimal Response (MR) but does not fulfill those for PD.
Measured: Response was assessed after cycles 1, 3 and 6 (each cycle is 21 days), approximately 63 days.
Progression-free Survival (PFS)
PFS is defined as the time from date of study enrollment until time of disease relapse, disease progression, or death, whichever occurs first, assessed every 3-6 months The progression free survival will be determined by the Kaplan-Meier method and reported along with a 95% confidence interval. Response was assessed by the Revised Response Criteria for Malignant Lymphoma criteria, and the Lugano Classification Response Criteria for Non-Hodgkin Lymphoma (NHL). Disease relapse is Progressive disease (PD) is appearance of any new nodal lesion ≥1.6 cm in greatest tumor dimension or ≥1.1 cm in short axis during or after the end of therapy or increase by ≥50% from PPD (cross product of the longest transverse diameter and perpendicular diameter) nadir.
Measured: Time from enrollment to progression or death, approximately 9 months.
Complete Response Rate
Response was assessed by the Revised Response Criteria for Malignant Lymphoma criteria, and the Lugano Classification Response Criteria for Non-Hodgkin Lymphoma (NHL). Complete response (CR) is complete disappearance of all detectable evidence of disease and disease-related symptoms. The response rate will be determined by Kaplan-Meier method and reported along with a 95% confidence interval.
Measured: Response was assessed after cycles 1, 3 and 6 (each cycle is 21 days). Approximately 63 days.
Overall Survival (OS)
OS is defined as the time from the date of study enrollment until death from any cause, assessed every 3-6 months. OS will be determined by the Kaplan-Meier method and reported along with a 95% confidence interval.
Measured: Time from enrollment to death, approximately 1 year
Event-free Survival (EFS)
EFS is defined as the time from the date of study enrollment until time of disease relapse from complete response (CR), disease progression, initiation of subsequent systemic anti-lymphoma therapy for either positron-emission tomography (PET)-positive or biopsy-proven residual disease, or death, whichever occurs first. The EFS will be determined by the Kaplan-Meier method and reported along with a 95% confidence interval. Response was assessed by the Revised Response Criteria for Malignant Lymphoma criteria, and the Lugano Classification Response Criteria for Non-Hodgkin Lymphoma (NHL). Complete response (CR) is complete disappearance of all detectable evidence of disease and disease-related symptoms. Progressive disease (PD) is appearance of any new nodal lesion ≥1.6 cm in greatest tumor dimension or ≥1.1 cm in short axis during or after the end of therapy. Disease relapse is Progressive disease (PD), an appearance of any new nodal lesion ≥1.6 cm in greatest tumor dimension.
Measured: Time from enrollment to next line of anti-lymphoma therapy, progressive disease, or death. Approximately 6 months.
Number of Serious and/or Non-serious Grades 3-5 Adverse Events Related to Copanlisib
Rate and severity of adverse events (AEs) summarized by grade and type of toxicity. AE's were assessed by the Common Terminology Criteria for Adverse Events (CTCAE v5.0). A non-serious adverse event is any untoward medical occurrence. A serious adverse event is an adverse event or suspected adverse reaction that results in death, a life-threatening adverse drug experience, hospitalization, disruption of the ability to conduct normal life functions, congenital anomaly/birth defect or important medical events that jeopardize the patient or subject and may require medical or surgical intervention to prevent one of the previous outcomes mentioned. Grade 3 is severe. Grade 4 is life-threatening. Grade 5 is death related to adverse event.
Measured: An average of 245.5 days
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted22 Jun 2021
- Study start24 Mar 2022
- Primary completion30 Nov 2023
- Study completion30 Nov 2023
Why it stopped: The study was terminated early because copanlisib was removed from the market by the Food and Drug Administration (FDA) and the manufacturer.
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Posted resultsParticipant flow, outcome measures and adverse events reported by the sponsor.
- Other trials for Burkitt LymphomaStudies of the same condition, open and under way.
- More trials run by National Cancer Institute (NCI)The sponsor's other registered studies.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase 1
- Primary purpose
- Treatment
- Allocation
- Non-randomised
- Intervention model
- Sequential
- Masking
- None (open label)
- Enrolment
- 8 participants (actual)
Sponsor and investigators
- Lead sponsor
- National Cancer Institute (NCI)
- Sponsor type
- US National Institutes of Health
- Responsible party
- Principal investigator, Mark Roschewski, M.D., National Cancer Institute (NCI)
- Investigators
- Mark J Roschewski, M.D., Principal investigator, National Cancer Institute (NCI)
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT04933617
- Sponsor's protocol ID
- 10000193
- Other IDs
- 000193-C
- Status last verified
- Jun 2024
- First submitted
- 18 Jun 2021
- Last updated
- 9 Jul 2024
- Results posted
- Yes, on ClinicalTrials.gov
- Data monitoring committee
- No
- FDA-regulated drug
- Yes
- FDA-regulated device
- No
- Individual data sharing
- Yes: All individual participant data (IPD) recorded in the medical record will be shared with intramural investigators upon request. All large- scale genomic sequencing data will be shared with subscribers to the database of Genotypes and Phenotypes (dbGaP).
Study at a glance
From the registry record, last updated by the sponsor on 9 Jul 2024. Recruitment status is as the sponsor reported it: confirm with the study team.
- 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
- ClinicalTrials.gov ID
- NCT04933617
- Acronym / sponsor ID
- 10000193
- Conditions
- 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)
- Keywords
- Aliqopa, BAY 80-6946, Monoclonal Antibody, PI3K Target
- Phase
- Phase 1
- Study type
- Interventional
- Recruitment status
- TerminatedReason stopped: The study was terminated early because copanlisib was removed from the market by the Food and Drug Administration (FDA) and the manufacturer.
- Enrolment
- 8 participants (actual)
- Lead sponsor
- National Cancer Institute (NCI)US National Institutes of Health
- Study start
- 24 Mar 2022 (actual)
- Primary completion
- 30 Nov 2023 (actual)
- Study completion
- 30 Nov 2023 (actual)
- First posted
- 22 Jun 2021 (actual)
- Results
- Posted 9 Jul 2024
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
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 dose-adjusted etoposide, prednisone, vincristine, cyclophosphamide, doxorubicin, and rituximab (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 diffuse large B-cell lymphoma (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
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 myelocytomatosis (MYC) gene rearrangement as well as those that have transformed from an underlying indolent lymphoma have a lower cure rate.
Dose-adjusted dose-adjusted etoposide, prednisone, vincristine, cyclophosphamide, doxorubicin, and rituximab (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 myelocytomatosis (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 follicular lymphoma (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, National Cancer Institute (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, not otherwise specified (NOS), High-grade B-cell lymphoma, with MYC and B-cell lymphoma 2 (BCL2) and/or B-cell lymphoma 6 (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
Eastern Cooperative Oncology Group (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 recommended phase 2 dose (RP2D) and maximum tolerated dose (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.
Study design
- Primary purpose
- Treatment
- Allocation
- Non-randomised
- Intervention model
- Sequential
- Masking
- None (open label)
- Number of arms
- 2
| Arm | Type | Receives |
|---|---|---|
| Arm 1- Dose Escalation, Original Copanlisib Intravenous (IV) | Experimental | Biological: Rituximab, Drug: Etoposide, Biological: Copanlisib, Drug: Cyclophosphamide, Drug: Doxorubicin, Drug: Vincristine, Drug: Prednisone, Diagnostic Test: ECHO, Diagnostic Test: EKG, Diagnostic Test: MRI Brain, Diagnostic Test: 18F-FDG - PET, Diagnostic Test: CT Scan, Procedure: Bone Marrow Aspiration, Procedure: Bone Marrow Biopsy, Diagnostic Test: Lumbar Puncture (LP)Copanlisib intravenous (IV) per dose level (30 mg, 45 mg, or 60 mg) on day 1 of each 21-day cycle in combination with standard dosing dose adjusted rituximab, etoposide, prednisolone, vincristine, cyclophosphamide, doxorubicin (DA-EPOCH-R) to determine recommended phase 2 dose (RP2D) and maximum tolerated dose (MTD) of copanlisib. Up to 6 cycles total. |
| Arm 2 - Dose Expansion, Modified Copanlisib Intravenous (IV) | Experimental | Biological: Rituximab, Drug: Etoposide, Biological: Copanlisib, Drug: Cyclophosphamide, Drug: Doxorubicin, Drug: Vincristine, Drug: Prednisone, Diagnostic Test: ECHO, Diagnostic Test: EKG, Diagnostic Test: MRI Brain, Diagnostic Test: 18F-FDG - PET, Diagnostic Test: CT Scan, Procedure: Bone Marrow Aspiration, Procedure: Bone Marrow Biopsy, Diagnostic Test: Lumbar Puncture (LP)Copanlisib intravenous (IV) at the recommended phase 2 dose (RP2D) or maximum tolerated dose (MTD) on day 1 of each 21-day cycle in combination with standard dosing dose adjusted rituximab, etoposide, prednisolone, vincristine, cyclophosphamide, doxorubicin (DA-EPOCH-R). Up to 6 cycles total. |
Who may qualify
- Ages
- 18 years and older
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Adult, Older adult
Key inclusion criteria (30 listed)
- Subjects must have a histologic diagnosis, confirmed by the Laboratory of Pathology, National Cancer Institute (NCI) with one of the following subtypes and prior therapy, as follows:
- OR
- --Must have had at least 2 prior regimens, 1 of which must have been anthracycline containing regimen OR be primary refractory to frontline therapy:
- ---Diffuse large B-cell lymphoma (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)
Key exclusion criteria (25 listed)
- Subjects previously exposed to, intolerant of, or ineligible for phosphoinositide 3-kinases (PI3K) inhibitors and/or their combination
- Brain parenchymal involvement
- Patients who have been treated with prior chimeric antigen receptor (CAR)-T therapy or any regimen containing fludarabine.
- Cytomegalovirus (CMV)-positive polymerase chain reaction (PCR) at screening
- History of diabetic ketoacidosis
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| RituximabAlso: RituxanRituximab 375 mg/m^2 intravenous (IV) per protocol on Day 1 of each cycle up to 6 cycles | Biological | Arm 1- Dose Escalation, Original Copanlisib Intravenous (IV), Arm 2 - Dose Expansion, Modified Copanlisib Intravenous (IV) |
| EtoposideAlso: Toposar, EtopophosEtoposide 50 mg/m^2/day continuous intravenous infusion (CIVI) on Days 1-4 of each cycle up to 6 cycles | Drug | Arm 1- Dose Escalation, Original Copanlisib Intravenous (IV), Arm 2 - Dose Expansion, Modified Copanlisib Intravenous (IV) |
| CopanlisibAlso: AliqopaCopanlisib intravenous (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 | Biological | Arm 1- Dose Escalation, Original Copanlisib Intravenous (IV), Arm 2 - Dose Expansion, Modified Copanlisib Intravenous (IV) |
| CyclophosphamideAlso: CytoxanCyclophosphamide 750 mg/m^2 intravenous (IV) on Day 5 of each cycle up to 6 cycles | Drug | Arm 1- Dose Escalation, Original Copanlisib Intravenous (IV), Arm 2 - Dose Expansion, Modified Copanlisib Intravenous (IV) |
| DoxorubicinAlso: AdriamycinDoxorubicin 10 mg/m^2/day continuous intravenous infusion (CIVI) on Days 1-4 of each cycle up to 6 cycles | Drug | Arm 1- Dose Escalation, Original Copanlisib Intravenous (IV), Arm 2 - Dose Expansion, Modified Copanlisib Intravenous (IV) |
| VincristineAlso: Marqibo, Vincasar PFSVincristine 0.4 mg/m^2/day (no cap) continuous intravenous infusion (CIVI) on Days 1-4 of each cycle up to 6 cycles | Drug | Arm 1- Dose Escalation, Original Copanlisib Intravenous (IV), Arm 2 - Dose Expansion, Modified Copanlisib Intravenous (IV) |
| PrednisoneAlso: Deltasone, Rayos, Prednisone IntensolPrednisone 60 mg/m^2 by mouth (PO) twice a day (BID) Days 1-5 (total 120mg/m^2/day) | Drug | Arm 1- Dose Escalation, Original Copanlisib Intravenous (IV), Arm 2 - Dose Expansion, Modified Copanlisib Intravenous (IV) |
| ECHOAlso: EchocardiogramAt screening. | Diagnostic test | Arm 1- Dose Escalation, Original Copanlisib Intravenous (IV), Arm 2 - Dose Expansion, Modified Copanlisib Intravenous (IV) |
| EKGAlso: ElectrocardiogramAt screening. | Diagnostic test | Arm 1- Dose Escalation, Original Copanlisib Intravenous (IV), Arm 2 - Dose Expansion, Modified Copanlisib Intravenous (IV) |
| MRI BrainAlso: Magnetic resonance imaging of the brainAt screening. | Diagnostic test | Arm 1- Dose Escalation, Original Copanlisib Intravenous (IV), Arm 2 - Dose Expansion, Modified Copanlisib Intravenous (IV) |
| 18F-FDG - PETAlso: Fludeoxyglucose F18At screening, baseline, after cycle 1, 3, and 6, and end of treatment. | Diagnostic test | Arm 1- Dose Escalation, Original Copanlisib Intravenous (IV), Arm 2 - Dose Expansion, Modified Copanlisib Intravenous (IV) |
| CT ScanAlso: Computed tomography scanAt screening, baseline, after cycle 1, 3, and 6, end of treatment and follow-up. | Diagnostic test | Arm 1- Dose Escalation, Original Copanlisib Intravenous (IV), Arm 2 - Dose Expansion, Modified Copanlisib Intravenous (IV) |
| Bone Marrow AspirationAt screening and end of treatment. | Procedure or surgery | Arm 1- Dose Escalation, Original Copanlisib Intravenous (IV), Arm 2 - Dose Expansion, Modified Copanlisib Intravenous (IV) |
| Bone Marrow BiopsyAt screening and end of treatment. | Procedure or surgery | Arm 1- Dose Escalation, Original Copanlisib Intravenous (IV), Arm 2 - Dose Expansion, Modified Copanlisib Intravenous (IV) |
| Lumbar Puncture (LP)Also: Spinal tapBaseline and end of treatment. | Diagnostic test | Arm 1- Dose Escalation, Original Copanlisib Intravenous (IV), Arm 2 - Dose Expansion, Modified Copanlisib Intravenous (IV) |
Primary outcome
Maximum Tolerated Dose (MTD) and Recommended Phase II Dose (RP2D)
Time frame: 21 days
MTD and RP2D is defined as the dose level at which no more than 1 of up to 6 participants experience dose limiting toxicity (DLT) during the DLT period, and the dose below that at which at least 2 (of ≤6) participants have DLT as a result of treatment. A DLT is any treatment-emergent, clinically relevant, and related severe (grade ≥ 3) toxicity that is possibly, probably, or definitely related to copanlisib.
6 secondary outcomes
Overall Response Rate (ORR)
Time frame: Response was assessed after cycles 1, 3 and 6 (each cycle is 21 days), approximately 63 days.
Progression-free Survival (PFS)
Time frame: Time from enrollment to progression or death, approximately 9 months.
Complete Response Rate
Time frame: Response was assessed after cycles 1, 3 and 6 (each cycle is 21 days). Approximately 63 days.
Overall Survival (OS)
Time frame: Time from enrollment to death, approximately 1 year
Event-free Survival (EFS)
Time frame: Time from enrollment to next line of anti-lymphoma therapy, progressive disease, or death. Approximately 6 months.
Number of Serious and/or Non-serious Grades 3-5 Adverse Events Related to Copanlisib
Time frame: An average of 245.5 days
Results and safety
Loading the posted results from ClinicalTrials.gov…
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 9 Jul 2024.
- Posted resultsParticipant flow, baseline, all outcome measures and adverse events.
- NIH Clinical Center Detailed Web PageLink provided by the sponsor.
- Individual participant dataSharing planned: Yes. All individual participant data (IPD) recorded in the medical record will be shared with intramural investigators upon request. All large- scale genomic sequencing data will be shared with subscribers to the database of Genotypes and Phenotypes (dbGaP).
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Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
Mark J Roschewski, M.D. principal investigator
National Cancer Institute (NCI)
1 site in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A Phase 1 study testing Rituximab, Etoposide and Copanlisib in people with Burkitt Lymphoma and High-grade B-cell Lymphoma, run by National Cancer Institute (NCI) at 1 site in United States.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 30 inclusion and 25 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: stopped early, as of the sponsor's last update on 9 Jul 2024. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 1 site in United States. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
What does this phase mean?
Phase 1 studies test a treatment in a small group of people for the first time or in a new way, mainly to check safety and find the right dose.
Not every study follows the same path, and some studies (observational studies, device studies) have no phase.
Are results available for this study?
Yes. Results are posted in the registry (first posted 9 Jul 2024). A summary is in the For doctors view, and the full results are on ClinicalTrials.gov.
How can a doctor refer a patient or contact the research team?
The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
Maximum Tolerated Dose (MTD) and Recommended Phase II Dose (RP2D) (time frame: 21 days). It is what the study was designed to measure, not a finding.
Where can I read the original study information?
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 9 Jul 2024.