Follicular Lymphoma, Non-Hodgkin's Lymphoma, NHL
Conditions
Keywords
BAY 80-6946, PI3K Target, Aliqopa, Monoclonal Antibody
Brief summary
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.
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
Interventions
BIOLOGICALRituximab
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.
DRUGCopanlisib
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)
PROCEDUREBone 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.
DIAGNOSTIC_TESTCT 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.
DIAGNOSTIC_TEST18F-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.
DIAGNOSTIC_TESTElectrocardigram
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.
Sponsors
National Cancer Institute (NCI)
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* 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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Proportion of Participants Who Achieve Positron Emission Tomography (PET) - Negative Complete Response | Within 2 months of induction therapy completion, up to 13 months since start of therapy | 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. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Proportion of Participants With Serious and/or Non-serious 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 | The proportion of participants with adverse events leading to discontinuation of induction therapy with copanlisib and rituximab. |
| Proportion of Participants With a Continuous Complete Response Rate at 30 Months (CR30) | Through 30 months from study enrollment | 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. |
| 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 | Through study induction therapy period and until 1 month after completion of induction | 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. |
| 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 | 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. 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. |
| Duration of Response (DOR) | 6 years | 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 to Next Treatment (TTNT) | time from the end of induction therapy with copanlisib and rituximab until initiation of next treatment, up to 6 years | 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. |
| Progression Free Survival (PFS) | time from study enrollment until disease progression or death from any cause, up to 6 years | 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. |
| Overall Survival (OS) | time from study enrollment until death from any cause, up to 6 years | OS is the time from study enrollment until death from any cause. |
Countries
United States
Contacts
PRINCIPAL_INVESTIGATORRahul Lakhotia, M.B.B.S.
National Cancer Institute (NCI)
Baseline characteristics
| Characteristic | — |
|---|---|
| Age, Categorical <=18 years | 0 Participants |
| Age, Categorical >=65 years | 10 Participants |
| Age, Categorical Between 18 and 65 years | 23 Participants |
| Age, Continuous | 55 years |
| Ethnicity (NIH/OMB) Hispanic or Latino | 2 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 31 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants |
| Race (NIH/OMB) Asian | 4 Participants |
| Race (NIH/OMB) Black or African American | 5 Participants |
| Race (NIH/OMB) More than one race | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 1 Participants |
| Race (NIH/OMB) White | 23 Participants |
| Region of Enrollment United States | 33 participants |
| Sex: Female, Male Female | 16 Participants |
| Sex: Female, Male Male | 17 Participants |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | 3 / 33 |
| other Total, other adverse events | 31 / 33 |
| serious Total, serious adverse events | 12 / 33 |
Outcome results
None listed