Clinical trial NCT04933617: Copanlisib With Dose-Adjusted EPOCH-R in Relapsed and Refractory Burkitt Lymphoma and Other High-Grade B-cell Lymphomas
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
Study type: INTERVENTIONAL
Overall status: TERMINATED
Phase: PHASE1
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
Lead sponsor: National Institutes of Health Clinical Center (CC)
Sponsor class: NIH
First posted: 2021-06-22
Enrollment: 8
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NON_RANDOMIZED
Intervention model: SEQUENTIAL
Primary purpose: TREATMENT

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.

Eligibility criteria: * 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:

    * 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

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

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:

      * 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.

Primary outcomes:
measure: Maximum Tolerated Dose (MTD) and Recommended Phase II Dose (RP2D)
timeFrame: 21 days
Secondary outcomes:
measure: Overall Response Rate (ORR)
timeFrame: Response was assessed after cycles 1, 3 and 6 (each cycle is 21 days), approximately 63 days.
measure: Progression-free Survival (PFS)
timeFrame: Time from enrollment to progression or death, approximately 9 months.
measure: Complete Response Rate
timeFrame: Response was assessed after cycles 1, 3 and 6 (each cycle is 21 days). Approximately 63 days.
measure: Overall Survival (OS)
timeFrame: Time from enrollment to death, approximately 1 year
measure: Event-free Survival (EFS)
timeFrame: Time from enrollment to next line of anti-lymphoma therapy, progressive disease, or death. Approximately 6 months.
measure: Number of Serious and/or Non-serious Grades 3-5 Adverse Events Related to Copanlisib
timeFrame: An average of 245.5 days
Other outcomes:
measure: Number of Participants With Serious and/or Non-serious Adverse Events Assessed by the Common Terminology Criteria for Adverse Events (CTCAE v5.0)
timeFrame: Date treatment consent signed to date off study, an average of 245.5 days
measure: Number of Participants With Dose Limiting-toxicity (DLT)
timeFrame: 21 days
Locations:
city: Bethesda
country: United States
facility: National Institutes of Health Clinical Center
state: Maryland
Study officials:
affiliation: National Cancer Institute (NCI)
name: Mark J Roschewski, M.D.
role: PRINCIPAL_INVESTIGATOR
References: