Clinical Trials /

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

NCT03789240

Description:

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.

Related Conditions:
  • Follicular Lymphoma
Recruiting Status:

Recruiting

Phase:

Phase 2

Trial Eligibility

Document

Title

  • Brief Title: Response-Adapted Therapy With Copanlisib and Rituximab in Untreated Follicular Lymphoma
  • Official Title: A Phase 2 Study of Response-Adapted Therapy With Copanlisib and Rituximab in Untreated Follicular Lymphoma

Clinical Trial IDs

  • ORG STUDY ID: 190030
  • SECONDARY ID: 19-C-0030
  • NCT ID: NCT03789240

Conditions

  • Follicular Lymphoma
  • Non-Hodgkin's Lymphoma
  • NHL

Interventions

DrugSynonymsArms
Rituximab1
Copanlisib1

Purpose

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-Hodgkin s lymphoma (NHL) with a
           highly variable clinical course across patients

        -  Standard frontline therapy for FL includes a monoclonal anti-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 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 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

        -  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
    

Trial Arms

NameTypeDescriptionInterventions
1ExperimentalWindow of treatment with Copanlisib 60mg via 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/m2 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.
  • Rituximab
  • Copanlisib

Eligibility Criteria

        -  INCLUSION CRITERIA:

          -  Patients must have a confirmed histologic diagnosis of 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, 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 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 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

          -  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 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)

               -  AST (SGOT) and ALT (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 6 months (180 days) 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 or Legally Authorized Representative (LAR) 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., HIV)

          -  CMV PCR positive at baseline

          -  Hepatitis B surface antigen (HbsAg) or core antibody (HbcAb) positive

          -  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.

          -  Requirement to continue on any of the medications that are excluded

          -  Organ compromise that, in the opinion of the 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
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Acheivement of complete response
Time Frame:Within 6 months of induction therapy completion
Safety Issue:
Description:The response rate will be determined and reported along with a 95% confidence interval

Secondary Outcome Measures

Measure:Safety of study treatments when given in combination
Time Frame:Through study induction therapy period
Safety Issue:
Description:Incidence of adverse events
Measure:Continuous complete response rate
Time Frame:At 30 months from study enrollment
Safety Issue:
Description:The response rate will be determined and reported along with a 95% confidence interval

Details

Phase:Phase 2
Primary Purpose:Interventional
Overall Status:Recruiting
Lead Sponsor:National Cancer Institute (NCI)

Trial Keywords

  • BAY 80-6946
  • PI3K Target
  • Aliqopa
  • Monoclonal Antibody

Last Updated

February 6, 2020