Clinical Trials /

Copanlisib in Combination With Rituximab and CHOP Chemotherapy in Patients With Previously Untreated DLBCL

NCT04263584

Description:

This is a prospective, multicenter, non-randomized, open-label, phase II study to describe the efficacy of R-CHOP plus copanlisib including a safety run-in phase in order to detect early and common unexpected toxicities caused by the addition of copanlisib to the standard immuno-chemotherapy R-CHOP in patients with diffuse large B-cell lymphoma (DLBCL)

Related Conditions:
  • Diffuse Large B-Cell Lymphoma
  • Diffuse Large B-Cell Lymphoma, Not Otherwise Specified
  • Double-Hit Lymphoma
  • Grade 3b Follicular Lymphoma
  • High Grade B-Cell Lymphoma, Not Otherwise Specified
  • Triple-Hit Lymphoma
Recruiting Status:

Not yet recruiting

Phase:

Phase 2

Trial Eligibility

Document

Title

  • Brief Title: Copanlisib in Combination With Rituximab and CHOP Chemotherapy in Patients With Previously Untreated DLBCL
  • Official Title: A Prospective Multicenter Phase 2 Study of Copanlisib in Combination With Rituximab and CHOP Chemotherapy (COPA-R-CHOP) in Patients With Previously Untreated Diffuse Large B-cell Lymphoma (DLBCL)

Clinical Trial IDs

  • ORG STUDY ID: UKM18-0021
  • NCT ID: NCT04263584

Conditions

  • Diffuse Large B Cell Lymphoma

Interventions

DrugSynonymsArms
CopanlisibCopanlisib and R-CHOP chemotherapy
R-CHOP ChemotherapyCopanlisib and R-CHOP chemotherapy

Purpose

This is a prospective, multicenter, non-randomized, open-label, phase II study to describe the efficacy of R-CHOP plus copanlisib including a safety run-in phase in order to detect early and common unexpected toxicities caused by the addition of copanlisib to the standard immuno-chemotherapy R-CHOP in patients with diffuse large B-cell lymphoma (DLBCL)

Detailed Description

      Patients diagnosed with DLBCL can be cured with a combined approach of CHOP chemotherapy and
      the anti-CD20 antibody rituximab in roughly 65% of cases. About one third of patients with
      DLBCL relapse or show primary progressive disease after modern first-line therapy. The
      outcome of these patients is poor in particular if first-line therapy contained rituximab.
      Novel therapeutic approaches are urgently warranted. Thus, it is the goal to further improve
      progression-free Survival (PFS) and overall Survival (OS) by combining R-CHOP with
      copanlisib. Copanlisib is a small molecule pan-class 1 PI3K inhibitor and approved by US FDA
      for the treatment of adult patients with relapsed follicular lymphoma who have received at
      least two prior systemic therapies.
    

Trial Arms

NameTypeDescriptionInterventions
Copanlisib and R-CHOP chemotherapyExperimentalAll patients will receive 6 cycles of R-CHOP immunochemotherapy every two weeks with the following doses per cycle: rituximab 375 mg/m², cyclophosphamide 750 mg/m², doxorubicin 50 mg/ m², vincristine 1.4 mg/m² (dose capped at 2 mg or 1 mg for individuals above 60 years of age), prednisolone 500 mg. In addition, copanlisib at a dose of 60 mg will be administered on days 1 and 8 of each 21-day cycle of R-CHOP in the first 6 patients. If dose limiting toxicity (DLT) occurs in no more than one out of these 6 patients during cycle 1, additional 6 patients at 60 mg will be enrolled and treated for at least 1 cycle before opening the phase II portion of the study. If a DLT is observed in 2 or more of the first 6 patients during cycle 1 the dose of copanlisib will be reduced to 45 mg on days 1 and 8 for the next 6 patients. The data of the safety run-in analysis (first 12 patients) will be presented to the Data Safety Monitoring Board and the recommended phase 2 dose will be determined.
  • Copanlisib
  • R-CHOP Chemotherapy

Eligibility Criteria

        Inclusion Criteria:

          1. Histologically confirmed

               1. DLBCL (NOS) or

               2. High-grade B-cell lymphoma with MYC and BCL2 and/or BCL6 rearrangements or

               3. High-grade B-cell lymphoma (NOS)

               4. Follicular lymphoma Grade 3B (primary diagnosis without history of indolent
                  lymphoma) with a diagnostic biopsy performed within 3 months before study entry
                  and with material available for central review and complimentary scientific
                  analyses

          2. 18-80 years of age

          3. International Prognostic Index (IPI) 2-5

          4. Eastern Cooperative Oncology Group Performance status (ECOG) 0-2

          5. Life expectancy of at least 3 months

          6. Women of childbearing potential 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 after the last administration of study treatment. 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,
             intrauterine hormone-releasing system, bilateral tubal occlusion, vasectomized partner
             and sexual abstinence. The use of condoms by male patients is required unless the
             female partner is permanently sterile.

             Adequate baseline laboratory values collected no more than 7 days before starting
             study treatment:

          7. Total bilirubin ≤ 1.5 x ULN (< 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)

          8. Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) ≤ 2.5 x ULN (≤ 5 x
             ULN for patients with liver involvement by lymphoma)

          9. Lipase ≤ 1.5 x ULN

         10. Glomerular filtration rate (GFR) ≥ 40 mL/min/1.73 m2 according to the Chronic Kidney
             Disease Epidemiology Collaboration (CKD-EPI) formula. If not on target, this
             evaluation may be repeated once after at least 24 hours either according to the
             CKD-EPI formula or by 24-hour sampling. If the later result is within acceptable
             range, it may be used to fulfill the inclusion criteria instead.

         11. INR and PTT ≤ 1.5 x ULN

         12. Platelet count ≥ 75,000 /mm3.

         13. Hemoglobin (Hb) ≥ 8 g/dL

         14. Absolute neutrophil count (ANC) ≥ 1,500/mm3

         15. Left ventricular ejection fraction ≥ 50%

         16. No prior lymphoma therapy

         17. Ability to understand and willingness to sign written informed consent. Signed
             informed consent must be obtained before any study specific procedure.

        Exclusion Criteria:

        Patients who meet any of the following criteria at the time of screening will be excluded.

          1. Previous assignment to treatment during this study. Patients permanently withdrawn
             from study participation will not be allowed to re-enter the study.

          2. Previous (within 28 days or less than 5 half-lives of the drug before start of study
             treatment) or concomitant participation in another clinical study with investigational
             medicinal product(s).

          3. Close affiliation with the investigational site; e.g. a close relative of the
             investigator, dependent persons (e.g. employee or student of the investigational
             site).

             Excluded medical conditions:

          4. Type I or II diabetes mellitus with HbA1c > 8.5% at screening or fasting plasma
             glucose > 160 mg/dL at screening

          5. History or concurrent condition of interstitial lung disease and/or severely impaired
             lung function (as judged by the investigator)

          6. Known lymphoma involvement of the central nervous system

          7. Human immunodeficiency virus (HIV) infection

          8. Hepatitis B (HBV) and C (HCV) infection. Patients with serologic markers of HBV
             immunization due to vaccination (HBsAg negative, Anti-HBc negative and Anti-HBs
             positive) will be eligible

          9. CMV-PCR positive at baseline

         10. Previous or concurrent history of malignancies within 5 years prior to study treatment
             except for curatively treated:

               1. Cervical carcinoma in situ

               2. Non-melanoma skin cancer

               3. Superficial bladder cancer (Ta [non-invasive tumor], Tis [carcinoma in situ] and
                  T1 [tumor invades lamina propria])

               4. Localized prostate cancer

         11. Patients with evidence or history of bleeding diathesis. Any hemorrhage or bleeding
             event ≥ CTCAE Grade 3 within 4 weeks prior to the start of study medication

         12. Patients with seizure disorder requiring medication

         13. Proteinuria of ≥ CTCAE Grade 3 as assessed by a 24h protein quantification or
             estimated by urine protein: creatinine ratio > 3.5 on a random urine sample

         14. Concurrent diagnosis of pheochromocytoma

         15. Congestive heart failure > New York Heart Association (NYHA) class 2

         16. Unstable angina (angina symptoms at rest), new-onset angina (begun within the last 3
             months)

         17. Myocardial infarction less than 6 months before start of test drug

         18. Arterial or venous thrombotic or embolic events such as cerebrovascular accident
             (including transient ischemic attacks), deep vein thrombosis or pulmonary embolism
             within 3 months before the start of study medication

         19. Non-healing wound, ulcer, or bone fracture

         20. Active, clinically serious infections > CTCAE Grade 2

         21. Uncontrolled hypertension (systolic blood pressure > 150 mmHg or diastolic pressure >
             90 mmHg despite optimal medical management)

         22. Known history of drug induced liver injury, alcoholic liver disease, non-alcoholic
             steatohepatitis, primary biliary cirrhosis, on-going extra-hepatic obstruction caused
             by cholelithiasis, cirrhosis of the liver or portal hypertension

         23. Ongoing inflammatory bowel disease

         24. History of, or current autoimmune disease

         25. Prior treatment with PI3K inhibitors

         26. Any other co-existing medical or psychological condition that will preclude
             participation in the study or compromise ability to give informed consent

         27. Patient is pregnant (β-HCG positive) or breast-feeding

         28. Known hypersensitivity to copanlisib or to any of the excipients of rituximab,
             cyclophosphamide, doxorubicine, vincristine, and/or prednisone
      
Maximum Eligible Age:80 Years
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:2-year progression-free survival
Time Frame:From the day of inclusion into the study until event (disease progression, relapse, death due to any other cause) occurs, assessed up to 4 years.
Safety Issue:
Description:Length of time that a patient lives without disease progression or relapse.

Secondary Outcome Measures

Measure:Overall survival
Time Frame:From the day of inclusion into the study to death due to any cause, assessed up to 4 years.
Safety Issue:
Description:The percentage of patients in this study who are still alive.
Measure:Event-free survival
Time Frame:From the day of inclusion into the study until event (disease progression, start of additional, unplanned anti-tumor therapy, relapse, death due to any other cause) occurs, assessed up to 4 years.
Safety Issue:
Description:Length of time that a patient remains free of certain events (disease progression, start of additional, unplanned antitumor therapy, relapse, death due to any other cause).
Measure:Rate of complete remission
Time Frame:From the day of inclusion into the study until date of complete remission, assessed up to 4 years.
Safety Issue:
Description:Rate of complete remission measured as number of complete remissions divided by the number of patients included.
Measure:Rate of partial remission
Time Frame:From the day of inclusion into the study until date of partial remission, assessed up to 4 years.
Safety Issue:
Description:Rate of partial remission measured as number of partial remissions divided by the number of patients included.
Measure:Overall response rate
Time Frame:From the day of inclusion into the study until date of complete or partial remission, assessed up to 4 years.
Safety Issue:
Description:Overall response rate measured as number of complete and partial remissions divided by the number of patients included.
Measure:Progression rate
Time Frame:From the day of inclusion into the study until date of progression during therapy or within 2 months after last treatment course.
Safety Issue:
Description:Progression rate measured as number of progressions divided by the number of patients included.
Measure:Relapse rate
Time Frame:From the day of inclusion into the study until date of relapse during therapy or within 2 months after last treatment course.
Safety Issue:
Description:Relapse rate measured as number of relapses divided by the number of patients included.
Measure:Duration of response
Time Frame:From documentation of tumor response to relapse, assessed up to 4 years.
Safety Issue:
Description:The time between the initial response to therapy and subsequent disease progression or relapse.
Measure:Adverse events and serious adverse events
Time Frame:The documentation of adverse events, including serious adverse events, starts with first study treatment after patient inclusion and ends 100 days after the last application of copanlisib or any component of R-CHOP
Safety Issue:
Description:Frequency of adverse events and serious adverse events
Measure:Rate of treatment-related deaths
Time Frame:From the start of therapy up to 2 months after the end of therapy.
Safety Issue:
Description:The number of deaths during therapy or up to 2 months after the end of therapy divided by the number of patients included.
Measure:Therapy cycles (number)
Time Frame:From the start of therapy (copanlisib and R-CHOP) until the end of therapy (last application of copanlisib or any component of R-CHOP), assessed up to 0.5 years.
Safety Issue:
Description:Number of therapy cycles
Measure:Therapy cycles (duration)
Time Frame:From the start of therapy (copanlisib and R-CHOP) until the end of therapy (last application of copanlisib or any component of R-CHOP), assessed up to 0.5 years.
Safety Issue:
Description:Duration of therapy cycles
Measure:Used drugs
Time Frame:From the start of therapy (copanlisib and R-CHOP) until the end of therapy (last application of copanlisib or any component of R-CHOP), assessed up to 0.5 years.
Safety Issue:
Description:Cumulative doses of R-CHOP (cyclophosphamide, doxorubicin, vincristine, prednisone, rituximab) and copanlisib.
Measure:Outcome according to lymphoma biology
Time Frame:From the start of study until the end of study, assessed up to 4 years.
Safety Issue:
Description:Lymphoma tissue from all patients will be characterized.

Details

Phase:Phase 2
Primary Purpose:Interventional
Overall Status:Not yet recruiting
Lead Sponsor:University Hospital Muenster

Trial Keywords

  • Copanlisib

Last Updated

February 6, 2020