Copanlisib With Dose-Adjusted EPOCH-R in Relapsed and Refractory Burkitt Lymphoma and Other High-Grade B-cell Lymphomas
- Conditions
- High-grade B-cell LymphomaT-cell/Histocyte-rich Large B-cell LymphomaDiffuse Large B-Cell Lymphoma (DLBCL)Germinal Center B-cell Type (GCB)Burkitt Lymphoma
- Interventions
- Biological: RituximabBiological: CopanlisibDiagnostic Test: ECHODiagnostic Test: EKGDiagnostic Test: MRI BrainDiagnostic Test: 18F-FDG - PETDiagnostic Test: CT ScanProcedure: Bone Marrow AspirationProcedure: Bone Marrow BiopsyDiagnostic Test: Lumbar Puncture (LP)
- Registration Number
- NCT04933617
- Lead Sponsor
- 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 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.
Recruitment & Eligibility
- Status
- TERMINATED
- Sex
- All
- Target Recruitment
- 8
Not provided
Not provided
Study & Design
- Study Type
- INTERVENTIONAL
- Study Design
- SEQUENTIAL
- Arm && Interventions
Group Intervention Description Arm 1- Dose Escalation, Original Copanlisib Intravenous (IV) Copanlisib 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 1- Dose Escalation, Original Copanlisib Intravenous (IV) EKG 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) 18F-FDG - PET 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. Arm 1- Dose Escalation, Original Copanlisib Intravenous (IV) Rituximab 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 1- Dose Escalation, Original Copanlisib Intravenous (IV) MRI Brain 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 1- Dose Escalation, Original Copanlisib Intravenous (IV) 18F-FDG - PET 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 1- Dose Escalation, Original Copanlisib Intravenous (IV) CT Scan 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 1- Dose Escalation, Original Copanlisib Intravenous (IV) Bone Marrow Aspiration 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 1- Dose Escalation, Original Copanlisib Intravenous (IV) Bone Marrow Biopsy 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 1- Dose Escalation, Original Copanlisib Intravenous (IV) 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) Rituximab 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. Arm 1- Dose Escalation, Original Copanlisib Intravenous (IV) ECHO 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) ECHO 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. Arm 2 - Dose Expansion, Modified Copanlisib Intravenous (IV) Copanlisib 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. Arm 2 - Dose Expansion, Modified Copanlisib Intravenous (IV) Cyclophosphamide 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. Arm 2 - Dose Expansion, Modified Copanlisib Intravenous (IV) EKG 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. Arm 2 - Dose Expansion, Modified Copanlisib Intravenous (IV) CT Scan 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. Arm 2 - Dose Expansion, Modified Copanlisib Intravenous (IV) Bone Marrow Biopsy 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. Arm 2 - Dose Expansion, Modified Copanlisib Intravenous (IV) MRI Brain 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. Arm 2 - Dose Expansion, Modified Copanlisib Intravenous (IV) Bone Marrow Aspiration 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. Arm 2 - Dose Expansion, Modified Copanlisib Intravenous (IV) 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. Arm 1- Dose Escalation, Original Copanlisib Intravenous (IV) Etoposide 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 1- Dose Escalation, Original Copanlisib Intravenous (IV) Cyclophosphamide 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 1- Dose Escalation, Original Copanlisib Intravenous (IV) Doxorubicin 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 1- Dose Escalation, Original Copanlisib Intravenous (IV) Vincristine 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 1- Dose Escalation, Original Copanlisib Intravenous (IV) Prednisone 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) Etoposide 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. Arm 2 - Dose Expansion, Modified Copanlisib Intravenous (IV) Doxorubicin 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. Arm 2 - Dose Expansion, Modified Copanlisib Intravenous (IV) Vincristine 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. Arm 2 - Dose Expansion, Modified Copanlisib Intravenous (IV) Prednisone 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.
- Primary Outcome Measures
Name Time Method Maximum Tolerated Dose (MTD) and Recommended Phase II Dose (RP2D) 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.
- Secondary Outcome Measures
Name Time Method Progression-free Survival (PFS) Time from enrollment to progression or death, approximately 9 months. 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.
Overall Survival (OS) Time from enrollment to death, approximately 1 year 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.
Overall Response Rate (ORR) Response was assessed after cycles 1, 3 and 6 (each cycle is 21 days), approximately 63 days. 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.
Complete Response Rate Response was assessed after cycles 1, 3 and 6 (each cycle is 21 days). Approximately 63 days. 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.
Event-free Survival (EFS) Time from enrollment to next line of anti-lymphoma therapy, progressive disease, or death. Approximately 6 months. 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.
Number of Serious and/or Non-serious Grades 3-5 Adverse Events Related to Copanlisib An average of 245.5 days 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.
Trial Locations
- Locations (1)
National Institutes of Health Clinical Center
🇺🇸Bethesda, Maryland, United States