Response-Adapted Therapy With Copanlisib and Rituximab in Untreated Follicular Lymphoma

A Phase 2 Study of Response-Adapted Therapy With Copanlisib and Rituximab in Untreated Follicular Lymphoma

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.

Study Overview

• Status: Active, not recruiting
• Conditions: Follicular Lymphoma; Non-Hodgkin's Lymphoma; NHL
• Intervention / Treatment: Biological: Rituximab; Drug: Copanlisib; Procedure: Bone Marrow Aspiration/Biopsy; Diagnostic test: CT Scans; Diagnostic test: 18F-FDG-PET/CT Scan15; Diagnostic test: Electrocardigram

Detailed Description

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
• Enrollment (Actual): 33
• Phase: Phase 2

Contacts and Locations

Study Locations

• United States
  • Maryland
    • Bethesda, Maryland, United States, 20892
      • National Institutes of Health Clinical Center

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

• INCLUSION CRITERIA:
• Patients must have a confirmed histologic diagnosis of Follicular Lymphoma (FL), grade 1-2 or 3a, according to the criteria established by the most recent version of the World Health Organization (WHO) classification system. Pathologic diagnosis must be confirmed by Laboratory of Pathology, National Cancer Institute (NCI)
• Stage II-IV disease. NOTE: Patients with stage I FL who have been treated with radiation therapy and have subsequently relapsed are eligible.
• No prior systemic treatment for FL with chemotherapy, targeted small molecule therapy, or monoclonal antibody therapy prior to the first dose of copanlisib treatment. Patients may have received prior radiation therapy only; radiation therapy must have been completed >12 weeks prior to the first dose of copanlisib. NOTE: Prior shortterm (less than or equal to 7 days) use of corticosteroids for acute medical complications related to sites of FL involvement is permitted.

• Patients must meet standard criteria for initiation of systemic therapy as evidenced by presence of one of the following:

  • Development of symptomatic enlarged lymph nodes or spleen
  • Development of B symptoms (fever, night sweats, weight loss) or severe pruritus
  • Development of significant serous pleural or pericardial effusions (small effusions seen only on computed tomography (CT) scans are not indications for systemic therapy)
  • Development of bone marrow failure as a result of involvement by FL and not attributable to other causes; this would be manifest as a hemoglobin (Hgb) < 9 g/dl, absolute neutrophil count < 1 x 10^9/L, or platelet count < 75 x 10^9/L
  • Critical organ involvement, organ compression (e.g., ureteric obstruction or epidural compression), or significant risk of future organ compressions
  • Increase in the size of lymph nodes on CT scans indicating progression of disease from previous CT scans
• Adequate tissue from diagnostic biopsy; formalin fixed tissue block or 20 slides of tumor sample (archival or fresh) must be available for performance of correlative studies
• Be greater than or equal to 8 years of age on day of signing informed consent. NOTE: Because no dosing or adverse event data are currently available on the use of (copanlisib) in patients <18 years of age, children are excluded from this study
• Eastern Cooperative Oncology Group (ECOG) performance status 0-2

• Adequate organ function as evidenced by the following laboratory parameters:

  • Absolute neutrophil count (ANC): >= 1,500 /mm^3 (unless due to involvement by lymphoma or benign ethnic neutropenia)
  • Platelets: >=75,000 / mcL (unless due to involvement by lymphoma; transfusions not permitted)
  • Hemoglobin: >= 8 g/dL (transfusions permitted)
  • Renal function: Glomerular filtration rate (GFR) >= 40 mL/min/1.73 m^2 as estimated by the 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.
  • Serum total bilirubin: less than or equal to 1.5 X upper limit of normal (ULN) OR (< 3 x ULN for patients with Gilbert syndrome, patients with cholestasis due to compressive adenopathies of the hepatic hilum or documented liver involvement or with biliary obstruction due to lymphoma)
  • Aspartate aminotransferase (AST) serum glutamic-oxaloacetic transaminase (SGOT) and alanine aminotransferase (ALT) serum glutamic-pyruvic transaminase (SGPT): less than or equal to 2.5 x ULN (less than or equal to 5 x ULN for patients with liver involvement by lymphoma)
  • Lipase: less than or equal to 1.5 x ULN

• Women of childbearing potential (WOCBP) and men must agree to use effective contraception when sexually active. This applies for the time period between signing of the informed consent form and for at least 1 month after the last dose of copanlisib and

  12 months after the last dose of rituximab, whichever is later, for WOCBP and for men after the last administration of study 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 post-menopausal state in women not using hormonal contraception or hormonal replacement therapy. The investigator or a designated associate is requested to advise the patient 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. The use of condoms by male patients is required unless the female partner is permanently sterile.

• Ability of patient to understand and the willingness to sign a written informed consent document

EXCLUSION CRITERIA:

• Known lymphomatous involvement of the central nervous system
• History of any known primary or acquired immunodeficiency syndrome (e.g., human immunodeficiency virus (HIV))
• Cytomegalovirus (CMV) polymerase chain reaction (PCR) positive at baseline
• Hepatitis B surface antigen (HbsAg) or core antibody (HbcAb) positive with a positive Hep B DNA Quantitative, HBV Viral Load result.

NOTE: Subjects with positive hepatitis B serology (hepatitis B surface antigen (HbsAg) or Hepatitis B core antibody (HBcAb) may be enrolled onto the study but they must have a negative Hep B deoxyribonucleic acid (DNA) Quantitative, hepatitis B virus (HBV) Viral Load result before enrollment.

• Uncontrolled intercurrent illness including, but not limited to the following that may limit interpretation of results or that could increase risk to the patient at the discretion of the investigator:

  • Active autoimmune disease that has required systemic treatment in the past 12 months (i.e., with use of disease modifying agents, corticosteroids or immunosuppressive drugs). NOTE: Replacement therapy (e.g., thyroxine, insulin, or physiologic corticosteroid replacement therapy for adrenal or pituitary insufficiency, etc.) is not considered a form of systemic treatment.
  • History of (non-infectious) pneumonitis that required steroids, evidence of interstitial lung disease or active, non-infectious pneumonitis.
  • Active hepatitis C infection. NOTE: Subjects who are hepatitis C antibody positive will need to have a negative HCV PCR result before enrollment. Those with a positive PCR for hepatitis C are excluded.
  • Congestive heart failure > New York Heart Association (NYHA) class 2
  • Unstable angina
  • Myocardial infarction in the past 6 months
  • Uncontrolled hypertension despite optimal medical management
  • Arterial thromboembolic events such as cerebrovascular accident (including transient ischemic attacks), in prior 3 months
  • Uncontrolled Type I or II diabetes despite optimal medical management
  • Any second malignancy that requires active systemic therapy
  • 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 patient inappropriate for entry into the study.
• Severe hepatic impairment (Child-Pugh C)
• Requirement to continue on any of the medications that are excluded
• Organ compromise that, in the opinion of the principal investigator (PI), necessitates immediate cytoreductive therapy
• Pregnant or breast-feeding patients. 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
• Major surgical procedure or significant traumatic injury (as judged by the investigator) within 28 days before start of treatment, or have not recovered from major side effects, open biopsy within 7 days before start of treatment

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm

Intervention / Treatment

Experimental: Response-Adapted Therapy With Copanlisib and Rituximab in Untreated Follicular Lymphoma; Window of treatment with Copanlisib 60mg via intravenous (IV) for a single 28-day cycle, once weekly for the first 3 weeks and then a 1-week break followed by induction therapy with copanlisib and rituximab. Induction therapy will be 6 cycles (28 days) of: copanlisib dose and administration same as window, rituximab 375mg/m^2 via IV, once weekly for the first 4 weeks during cycle 1, subsequent cycles (cycles 2-6), rituximab will be dosed only once on day 1 of the cycle.

Biological: Rituximab; 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.; Other Names: Rituxan; Drug: Copanlisib; 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); Other Names: Aliqopa; Procedure: Bone Marrow Aspiration/Biopsy; 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.; Other Names: BM Aspiration/Bx; Diagnostic test: CT Scans; 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.; Other Names: Computed tomography scans; Diagnostic test: 18F-FDG-PET/CT Scan15; 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.; Other Names: Fludeoxyglucose F18 (FDG) positron emission tomography /Computed tomography Scan 15; Diagnostic test: Electrocardigram; 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.; Other Names: ECG

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
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.	Within 2 months of induction therapy completion, up to 13 months since start of therapy

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
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.	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.	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.	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.	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.	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 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 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 from study enrollment until death from any cause, up to 6 years

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Number of Participants With Serious and/or Non-serious Adverse Events Assessed by the Common Terminology Criteria for Adverse Events (CTCAE v5.0)	Here is the number of participants with serious and/or non-serious adverse events 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.	Adverse events were monitored/assessed from the first administration of study drug through 30 days post the last administration of study drug.

Collaborators and Investigators

• Sponsor: National Cancer Institute (NCI)
• Investigators: Principal Investigator: Rahul Lakhotia, M.B.B.S., National Cancer Institute (NCI)

Publications and helpful links

Helpful Links

• NIH Clinical Center Detailed Web Page

Study record dates

Study Major Dates

• Study Start (Actual): August 22, 2019
• Primary Completion (Actual): September 24, 2025
• Study Completion (Estimated): January 1, 2027

Study Registration Dates

• First Submitted: December 18, 2018
• First Submitted That Met QC Criteria: December 27, 2018
• First Posted (Actual): December 28, 2018

Study Record Updates

• Last Update Posted (Actual): March 3, 2026
• Last Update Submitted That Met QC Criteria: February 13, 2026
• Last Verified: February 1, 2026

More Information

Terms related to this study

• Keywords: Monoclonal Antibody; Aliqopa; BAY 80-6946; PI3K Target
• Additional Relevant MeSH Terms: Neoplasms; Immune System Diseases; Neoplasms by Histologic Type; Lymphatic Diseases; Lymphoproliferative Disorders; Immunoproliferative Disorders; Lymphoma; Hemic and Lymphatic Diseases; Lymphoma, Non-Hodgkin; Lymphoma, Follicular; Amino Acids, Peptides, and Proteins; Proteins; Investigative Techniques; Specimen Handling; Clinical Laboratory Techniques; Diagnostic Techniques and Procedures; Diagnosis; Surgical Procedures, Operative; Cytological Techniques; Cytodiagnosis; Antibodies, Monoclonal; Antibodies; Immunoglobulins; Immunoproteins; Blood Proteins; Serum Globulins; Globulins; Diagnostic Techniques, Surgical; Tomography; Diagnostic Imaging; Antibodies, Monoclonal, Murine-Derived; Diagnostic Techniques, Cardiovascular; Radiography; Heart Function Tests; Electrodiagnosis; Image Interpretation, Computer-Assisted; Radiographic Image Enhancement; Image Enhancement; Photography; Tomography, X-Ray; Tomography, Emission-Computed; Radionuclide Imaging; Diagnostic Techniques, Radioisotope; Rituximab; Biopsy; copanlisib; Electrocardiography; Tomography, X-Ray Computed; Positron-Emission Tomography
• Other Study ID Numbers: 190030; 19-C-0030

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES
• IPD Plan Description: 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).
• IPD Sharing Time Frame: Clinical data will be available during the study and indefinitely. Genomic data will be available once genomic data are uploaded per protocol Genomic Data Sharing (GDS) plan for as long as database is active.
• IPD Sharing Access Criteria: Clinical data will be made available via subscription to Biomedical Translational Research Information System (BTRIS) and with the permission of the study principal investigator (PI). Genomic data will be made available via the database of Genotypes and Phenotypes (dbGaP) through requests to the data custodians.
• IPD Sharing Supporting Information Type: STUDY_PROTOCOL; SAP; ICF

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No