Background: The disease follicular lymphoma (FL) develops when the body makes abnormal B-cells. These cells usually build up in the lymph nodes, but can also affect other parts of the body. Researchers want to see if a combination of drugs can attack the cancer cells in people with FL. Objective: To see if copanlisib plus rituximab is effective at slowing the growth of FL. Eligibility: People with FL who have not had prior treatment for their disease Design: Participants will be screened with: * Medical and cancer history * Physical exam * Review of symptoms and ability to perform daily activities * Blood and urine tests * Small amount of bone marrow removed by needle in the hip bone * Scans of the chest, abdomen, and pelvis. Some scans will use a radioactive tracer. Participants will get the study drugs in 28-day cycles for up to 13 cycles. Both are given as an intravenous (IV) infusion. Copanlisib is given over about 1 hour. Rituximab is given over several hours. * For 1 cycle, they will get 3 weekly doses of copanlisib. * For the next cycle, they will get 3 weekly doses of copanlisib and 4 weekly doses of rituximab. * For all other cycles, they will get 2-3 weekly doses of copanlisib and 1 dose of rituximab. Participants will repeat some screening tests during the cycles. They will give a cheek swab and/or saliva sample and may have a tumor sample taken. After treatment, some participants will have a few follow-up visits each year for 5 years, then 1 each year. They will repeat screening tests. Other participants will be contacted by phone every few months.
Background: * Follicular lymphoma (FL) is the most common indolent non-Hodgkins lymphoma (NHL) with a highly variable clinical course across patients * Standard frontline therapy for FL includes a monoclonal anti-cluster of differentiation 20 (CD20) antibody with or without chemotherapy that can induce durable remissions but is generally not curable * The 20% of patients who relapse within 2 years of frontline chemotherapy have an inferior overall survival; molecular profiles and gene-expression signatures can identify patients at high-risk of early treatment failure but are incomplete and require further validation * The phosphoinositide 3-kinase (PI3K) pathway is critically important in FL; agents that target PI3K show good clinical activity in patients who relapse early after chemotherapy * Copanlisib is an intravenous therapy targeting both PI3K-alpha and PI3K-delta isoforms and is Food and Drug Administration (FDA)-approved for use in adults with relapsed and refractory FL * Induction therapy with copanlisib and rituximab may produce deep and durable remissions in patients with FL without the use of cytotoxic agents * Circulating tumor deoxyribonucleic acid (DNA) circulating tumor DNA (ctDNA) is a promising modality for monitoring therapy Objective: \- To determine the complete response (CR) rate after copanlisib and rituximab as induction therapy for patients with untreated follicular lymphoma Eligibility: * Patients with histologically confirmed stage II-IV follicular lymphoma, grade 1-2 or 3a that meet criteria for initiation of systemic therapy * No previous systemic therapy; prior local radiation permitted * Eastern Cooperative Oncology Group (ECOG) performance status 0-2 * Adequate bone marrow and organ function Design: * Phase 2 study of up to 65 patients with untreated FL who meet standard criteria for treatment * Patients will first be treated with a window of copanlisib monotherapy, followed by induction therapy with copanlisib and rituximab for up to 6 cycles * Patients who achieve a CR after 6 cycles of induction therapy will stop treatment and be monitored with computed tomography (CT) scans and plasma assays for circulating tumor DNA (ctDNA). Patients who relapse \> 6 months from the end of induction can be re-treated with 6 additional cycles of copanlisib and rituximab * Patients who achieve a partial response after 6 cycles of induction therapy will receive an additional 6 cycles of extended induction therapy with copanlisib and rituximab * Patients who do not achieve at least a partial response after 6 cycles of induction therapy will stop treatment and be monitored with CT scans and peripheral blood assays for ctDNA * Patients who progress or relapse after induction therapy and meet criteria for salvage therapy will be treated with standard chemotherapy and a monoclonal anti-CD20 antibody
Study Type
INTERVENTIONAL
Allocation
NA
Purpose
TREATMENT
Masking
NONE
Enrollment
33
Rituximab is administered at a dose of 375 mg/m\^2 via intravenous (IV) weekly for the first 4 weeks on Days 1, 8, 15, and 22 during cycle 1. With subsequent cycles (cycles 2-6), rituximab will be dosed only once on Day 1 of the cycle.
Copanlisib is administered at a fixed dose of 60 mg via intravenous (IV) weekly for the first 3 weeks on Days 1, 8, and 15 followed by a 1-week break (no infusion on Day 22)
Screening. Cycles 6 \& 12, last 7 days of the cycle (disease evaluations). Follow-up (prior to progressive disease) every 3 or 6 months. Bone marrow aspiration with flow cytometry and biopsy (within 12 months prior to starting treatment) if clinically indicated; repeat in follow-up to confirm response or progression.
Screening and Baseline. Copanlisib Window (Cycle 0/ore Cycle 1 Day 1) Day-28 to -1 (-14 scheduling window). Cycles 3 \& 9 and Cycles 6 \& 12, last 7 days of the cycle (disease evaluations). Follow-up (prior to progressive disease) every 3 or 6 months. End of treatment (discontinued/progressive disease). Follow-up (prior to progressive disease) every 3 or 6 months. CT scans (preferred) of chest, abdomen and pelvis at baseline; may be adjusted to assess additional known sites of disease, as needed. Scans performed after cycles 3 and 6 (last 7 days of each cycle) of both induction and maintenance, as applicable. Repeat also within last 7 days of copanlisib window. MRIs may be used instead of CT scans as necessary.
Screening and Baseline. Copanlisib Window (Cycle 0/ore Cycle 1 Day 1) Day-28 to -1 (-14 scheduling window). Cycles 6 \& 12, last 7 days of the cycle (disease evaluations). PET scans to be performed after cycles 6 and 12 (last 7 days of each cycle) of both induction and maintenance, as applicable. Repeat also within last 7 days of copanlisib window.
Baseline. Copanlisib Window (Cycle 0/ore Cycle 1 Day 1) Day-28 to -1 (-14 scheduling window). Cycles 3 \& 9 and Cycles 6 \& 12, last 7 days of the cycle (disease evaluations). End of treatment (discontinued/progressive disease). Follow-up (prior to progressive disease) every 3 or 6 months. Participants with prolonged QTc at baseline, participants with congenital prolonged QT syndrome, and participants chronically on medications as specified in the protocol will have ECG monitoring after copanlisib window, and every 3 cycles thereafter.
National Institutes of Health Clinical Center
Bethesda, Maryland, United States
Proportion of Participants Who Achieve Positron Emission Tomography (PET) - Negative Complete Response
The response rate will be determined and reported along with a 95% confidence interval. Complete Response was assessed by the Lugano Classification of Response Criteria and is defined as the proportion of participants who achieve a PET-negative complete response in accordance with the 2014 Lugano classification of the International Working Group Criteria for Non-Hodgkin's Lymphoma after induction therapy with copanlisib and rituximab. Under the Lugano criteria (2014), a Complete Response is defined by a Deauville score of 1-3 on PET and no evidence of disease in the bone marrow, with or without a residual mass.
Time frame: Within 2 months of induction therapy completion, up to 13 months since start of therapy
Proportion of Participants With Serious and/or Non-serious Adverse Events Leading to Discontinuation of Induction Therapy With Copanlisib and Rituximab
The proportion of participants with adverse events leading to discontinuation of induction therapy with copanlisib and rituximab.
Time frame: Through study induction therapy period and until 1 month after completion of induction
Proportion of Participants With a Continuous Complete Response Rate at 30 Months (CR30)
The response rate will be determined and reported along with a 95% confidence interval. Complete Response was assessed by the Lugano Classification of Response Criteria and is defined as the proportion of participants who achieve a positron emission tomography (PET)-negative complete response in accordance with the 2014 Lugano classification of the International Working Group Criteria for Non-Hodgkin's Lymphoma after induction therapy with copanlisib and rituximab. CR30 refers to the proportion of participants who remain in complete response at 30 months from study enrollment. Under the Lugano criteria (2014), a Complete Response is defined by a Deauville score of 1-3 on PET and no evidence of disease in the bone marrow, with or without a residual mass.
Time frame: Through 30 months from study enrollment
Complete Molecular Remission (CMR) Rate Defined as the Proportion of Participants Who Achieve Both a Complete Response and Are Negative on Molecular Assays for Minimal Residual Disease After Induction Therapy With Copanlisib and Rituximab
The proportion of participants who achieve both a complete response and are negative on molecular assays for minimal residual disease after induction therapy with copanlisib and rituximab. Under the Lugano criteria (2014), a Complete Response is defined by a Deauville score of 1-3 on positron emission tomography (PET) and no evidence of disease in the bone marrow, with or without a residual mass. Minimal residual disease was defined as detection of circulating tumor deoxyribonucleic acid (DNA) after completion of induction therapy in blood.
Time frame: Through study induction therapy period and until 1 month after completion of induction
Objective Response Rate (ORR) Defined as the Proportion of Participants Who Achieve at Least a Partial Response (PR) to Induction Therapy With Copanlisib and Rituximab
Objective response rate (ORR) defined as the proportion of participants who achieve at least a partial response (PR) to induction therapy with copanlisib and rituximab. Partial response was defined using the 2014 Lugano classification for lymphoma and defined as a decrease in the sum of the product of the diameters (SPD) of up to six of the largest nodes or nodal masses.
Time frame: Through study induction therapy period and until 1 month after completion of induction
Duration of Response (DOR)
DOR is defined as time from first documentation of tumor response to disease progression. Progression was defined as evidence of disease growth, recurrence, or new disease based on imaging (computed tomography (CT) or positron-emission tomography (PET/CT) and clinical evaluation.
Time frame: 6 years
Time to Next Treatment (TTNT)
TTNT is the time from the end of induction therapy with copanlisib and rituximab until initiation of next treatment. Induction therapy is combination therapy with copanlisib and rituximab, and next treatment is start of any systemic therapy after completion of induction therapy with copanlisib and rituximab.
Time frame: time from the end of induction therapy with copanlisib and rituximab until initiation of next treatment, up to 6 years
Progression Free Survival (PFS)
PFS is the time from study enrollment until disease progression or death from any cause. Disease progression was defined as evidence of disease growth, recurrence, or new disease based on imaging (computed tomography (CT) or positron-emission tomography (PET/CT) and clinical evaluation.
Time frame: time from study enrollment until disease progression or death from any cause, up to 6 years
Overall Survival (OS)
OS is the time from study enrollment until death from any cause.
Time frame: time from study enrollment until death from any cause, up to 6 years
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