Phase 1 Study of Copanlisib With Dose-adjusted EPOCH-R in Relapsed and Refractory Burkitt Lymphoma and Other High-Grade B-cell Lymphomas
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.
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.
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.
INCLUSION CRITERIA:
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:
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:
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.
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.
EXCLUSION CRITERIA:
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:
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:
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.