Copanlisib and Rituximab in Marginal Zone Lymphoma Patients - A MULTICENTER OPEN LABEL SINGLE-ARM PHASE II STUDY (COUP-1)
- Trial ID
- 2022-500674-34-00
- Protocol
- COUP-1
Trial statistics
Objectives
The primary objective of this study is to evaluate the **efficacy** and **toxicity** of a treatment regimen combining **Copanlisib** and **Rituximab** in patients with **Marginal Zone Lymphoma** (MZL) who require treatment but have either failed or are ineligible for local therapy, or have experienced a relapse. Efficacy will be primarily assessed by analyzing the rate of complete remissions at 12 months, using the GELA criteria for gastric MALT lymphoma and the Cheson 2007 criteria for non-gastric extranodal, nodal, and splenic MZL. The clinical relevance of this objective lies in its potential to provide an effective treatment option for MZL patients who have limited therapeutic alternatives. Additionally, the study will document treatment-associated adverse events, quality of life, and the cumulative incidence of secondary malignancies to assess the safety profile of the treatment regimen.
Participants
The clinical trial involves participants diagnosed with **Marginal Zone Lymphoma** (MZL), specifically targeting those who have either relapsed or are not eligible for local therapy. The study population includes both male and female subjects, aged 18 years and older. The trial does not specify the total number of participants, as this information was not provided by the sponsor. Participants were selected based on their confirmed diagnosis of CD20 positive MALT Lymphoma, nodal MZL, or splenic MZL, with symptomatic disease requiring treatment. The trial includes individuals with a life expectancy greater than three months and specific baseline laboratory values. Participants must be willing to comply with study procedures and have provided informed consent. The study population is characterized by a diverse range of health statuses, including those with chronic HBV or HCV infections, provided certain criteria are met. Lifestyle considerations such as diet and physical activity are not specified in the trial data. The trial includes a vulnerable population, indicating a need for careful ethical considerations in the study's conduct.
Plans and Procedures
The clinical trial is designed to evaluate the **efficacy** and **toxicity** of a combination treatment involving **copanlisib dihydrochloride** and **rituximab** in patients diagnosed with **Marginal Zone Lymphoma** (MZL) who have either failed or are not eligible for local therapy. This is a multicenter, open-label, single-arm Phase II study. The trial will primarily assess the complete remission rate at 12 months, using the GELA criteria for gastric MALT or the Cheson 2007 criteria for non-gastric extranodal, nodal, and splenic MZL. Secondary endpoints include response rates, progression-free survival, and overall survival, among others. The trial is expected to run from November 20, 2019, to November 20, 2027, with participants involved for a maximum treatment period of 30 days.
Participants will undergo a series of study visits, beginning with an inclusion (screening) visit to confirm eligibility based on criteria such as confirmed CD20 positive MZL, life expectancy greater than three months, and specific laboratory values. Following the screening, participants will receive treatment through **intravenous infusion** of the study drugs. Follow-up visits will occur at regular intervals to monitor response and adverse events, with a final end-of-study visit to assess the primary and secondary endpoints. The expected length of participant involvement is up to 12 months, with conditions for early termination including disease progression, unacceptable toxicity, or withdrawal of consent.
Treatment
The clinical trial involves the administration of **Copanlisib dihydrochloride**, marketed under the product name BAY 80-6946. This experimental medication is provided in the form of a **powder for concentrate for solution for infusion**. The active substance, copanlisib dihydrochloride, is of chemical origin. The medication is administered via **intravenous infusion**. The maximum daily dose is 60 mg, with a total maximum dose of 2520 mg over a treatment period of 30 days. Compliance with the dosing schedule is monitored throughout the trial to ensure adherence to the protocol.
In addition to the experimental treatment, the study includes the administration of **Rituximab**, which is provided in two formulations: Truxima 500 mg and Truxima 100 mg, both as a **concentrate for solution for infusion**. Rituximab is a protein-based therapeutic agent. The administration route for both formulations is **intravenous infusion**. The maximum daily dose for rituximab is 375 mg/m², with a total maximum dose of 6750 mg/m² over a 30-day treatment period. The rituximab formulations are used as standard-of-care therapy in this trial, and participant compliance is closely monitored to ensure accurate dosing and administration.
Efficacy
The efficacy of the clinical trial involving **Marginal Zone Lymphoma (MZL)** patients treated with Copanlisib and Rituximab will be primarily assessed by evaluating the rate of complete remissions. This will be determined according to the GELA criteria for gastric MALT or the Cheson 2007 criteria for non-gastric extranodal, nodal, and splenic MZL at 12 months of therapy. The primary endpoint is the complete response rate (CRR) determined 12 months after the start of induction therapy, specifically at month 6 of maintenance. Patients who progress before 12 months after the start of treatment will be considered as CR='NO' and included in the calculation of the primary endpoint.
Secondary endpoints include various response rates, such as complete response (CR), partial response (PR), and overall response rate (CR or PR), evaluated 4 weeks after the end of induction treatment and 12 months after the start of treatment. Additional secondary endpoints are best response, time to best response, time to first response, progression-free survival (PFS), time to treatment failure (TTF), duration of response (DR), cause-specific survival (CSS), overall survival (OS), and quality of life during induction and maintenance therapy. Quality of life will be measured using the FACT-Lym scale before the start of treatment, during induction, and maintenance.
Inclusion and Exclusion Criteria
Inclusion Criteria
- Confirmed CD20 positive MALT Lymphoma de novo or relapsed following or being not eligible for local therapy (including surgery, radiotherapy) and antibiotics for H. pylori-positive gastric lymphoma arisen at any extranodal site. OR
- Confirmed CD20 positive de novo or relapsed splenic MZL following or not being eligible for local therapy (including surgery and antiviral therapy for Hepatitis C Virus) with symptomatic disease: In patients with splenic MZL without splenic tissue available for histologic review, the diagnosis may be confirmed by the presence of splenomegaly and typical morphologic and immunophenotypic findings in the blood and bone marrow. Bone marrow (acceptable up to 12 weeks before start of treatment) must be submitted for retrospective central confirmation. OR
- Confirmed CD20 positive de novo or relapsed nodal MZL
- Tissue diagnostic procedures must be performed within 12 months prior to study entry and have to include diagnostics by a reference pathology center.
- Patients in need of treatment: For patients with symptomatic splenic, nodal, or non-gastric extranodal MZL disease that is de novo or has relapsed following local therapy (i.e., surgery or radiotherapy) and requires therapy, as assessed by the investigator.
- For nodal MZL and EMZL: At least one bi-dimensionally measurable lesion (≥ 1.5 cm in its largest dimension by CT scan or MRI)
- For SMZL: For splenic MZL, an enlarged spleen on CT scan and lymphoma cell infiltration has to be seen in bone marrow and/or peripheral blood. At least one of the following criteria must be met: – Bulky progressive or painful splenomegaly – one of the following symptomatic/progressive cytopenias: Hb < 10 g/dL, or Plat < 80.000 /µL, or neutropenia < 1000/µL, whatever the reason (autoimmune or hypersplenism or bone marrow infiltration) – SMZL with concomitant hepatitis C infection which has not responded to or has relapsed after Interferon and/or Ribavirin and/or direct antiviral agents (patients positive for HCV antibody are eligible only if PCR is negative for HCV RNA). – splenectomised patients with rapidly raising lymphocyte counts, development of lymphadenopathy or involvement of extranodal sites if not being eligible for local therapy.
- For gastric MALT lymphoma, the clinical evidence of the MZL as seen by gastroendoscopy is sufficient. There is no need to show a measurable lesion by CT scan or MRI. Inclusion is possible for patients with: a) H. pylori-negative disease de novo or following or being not eligible for local therapy (i.e., surgery, radiotherapy or antibiotics) or after systemic therapy. b) H. pylori–positive disease that has remained stable, progressed, or relapsed following antibiotic therapy.
- Age >=18 years
- Life expectancy >3 months
- Baseline platelet count >=50 G/L (if not due to BM infiltration by the lymphoma), absolute neutrophil count >=0.75 G/L
- ASAT (SGOT): <=3 times the upper limit of institutional laboratory normal value
- ALAT (SGPT): <=3 times the upper limit of institutional laboratory normal value
- Total Bilirubin: <=2 mg/dL or 2 times the upper limit of institutional laboratory normal value, unless clearly related to the disease (except if due to Gilbert’s syndrome)
- GFR ≥ 40 mL/min/1.73 m²
- Negative HIV antibody
- Positive test results for chronic HBV infection (defined as positive HBsAg serology): patients with occult or prior HBV infection (defined as negative HBsAg and positive total HBcAb) may be included if HBV DNA is undetectable, provided that they are willing to undergo monthly DNA testing. Patients who have protective titers of HBsAb after vaccination or prior but cured hepatitis B are eligible.
- Positive test results for hepatitis C (hepatitis C virus [HCV] antibody serology testing): patients positive for HCV antibody are eligible only if PCR is negative for HCV RNA.
- Pregnancy β-HCG negative. For women of child-bearing potential only (i.e. fertile, following menarche and until becoming post-menopausal unless permanently sterile. Permanent sterilisation methods include hysterectomy, bilateral salpingectomy and bilateral oophorectomy); serum or urine β-HCG must be negative during screening and at study enrolment visit
- Premenopausal fertile females must agree to use a highly effective method of birth control for the duration of the therapy up to 12 months after end of therapy.
- Men must agree not to father a child for the duration of therapy and 6 months after (use of a condom) and must agree to advice a female partner to use a highly effective method of birth control.
- Willingness and ability to comply with scheduled visits, drug administration plan, imaging studies, laboratory tests, other study procedures, and study restrictions.
- Evidence of a personally signed informed consent indicating that the subject is aware of the neoplastic nature of the disease and has been informed of the procedures to be followed, the experimental nature of the therapy, alternatives, potential benefits, possible side effects, potential risks and discomforts, and other pertinent aspects of study participation.
Exclusion Criteria
- ECOG performance status ≥ 2
- History of a non-lymphoid malignancy except for the following: adequately treated local basal cell or squamous cell carcinoma of the skin, cervical carcinoma in situ, superficial bladder cancer, asymptomatic prostate cancer without known metastatic disease and with no requirement for therapy or requiring only hormonal therapy and with normal prostate specific antigen for ≥1 year prior to study enrollment visit, other Stage 1 or 2 cancer treated with a curative intent and currently in complete remission, for ≥3 years.
- Central nervous system lymphoma, leptomeningeal lymphoma, or histologic evidence of transformation to a high-grade or diffuse large B-cell lymphoma.
- Ongoing immunosuppressive therapy including corticosteroids (exception < 4 weeks administered at a dose equivalent to ≤ 40 mg/day prednisone is allowed)
- Evidence of ongoing systemic bacterial, fungal, or viral infection at the time of study enrolment visit
- Ongoing drug-induced liver injury, chronic active hepatitis B (HBV), alcoholic liver disease, non-alcoholic steatohepatitis, primary biliary cholangitis, extrahepatic obstruction caused by cholelithiasis, cirrhosis of the liver, or portal hypertension.
- Ongoing alcohol or drug addiction
- Treatment with any other investigational agent within 30 days or within 5 x the half life (t1/2) of the investigational product, whichever is longer, or participating in another trial within 30 days prior to entering this study
- Breastfeeding or pregnancy
- Prior treatment with Copanlisib
- Congestive heart failure > New York Heart Association (NYHA) class 2
- Unstable angina (angina symptoms at rest), new-onset angina (begun within the last 3 months).
- Myocardial infarction less than 6 months before start of test drug
- Uncontrolled arterial hypertension despite optimal medical management
- HbA1c>8.5%
- Prior or ongoing clinically significant illness, medical condition, surgical history, physical finding, electrocardiogram (ECG) finding, or laboratory abnormality that, in the investigator’s opinion, could adversely affect the safety of the subject or impair the assessment of study results.
- History of anaphylaxis in association with previous administration of monoclonal antibodies.
- Vaccination with a live vaccine within 28 days prior to start of therapy
- 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
- Non-healing wound, ulcer, or bone fracture
- History or concurrent interstitial lung disease of any severity and/or severely impaired lung function (as judged by the investigator).
Trial Status by Country
| Country | Status | Start of Recruitment | Planned Patients |
|---|---|---|---|
 Germany | Not Recruiting | 20 Nov 2019 | 36 |
Sites & Investigators
Investigational Products
Details about the medicinal products being studied in this clinical trial.
| Product Name | Role in Trial | Formulation | Administration | Max Daily Dose | Treatment Duration | EU MP Number |
|---|---|---|---|---|---|---|
Truxima 100 mg concentrate for solution for infusion | Test | CONCENTRATE FOR SOLUTION FOR INFUSION | IV INFUSION | 375 | 30 | PRD5065907 |
Truxima 500 mg concentrate for solution for infusion | Test | CONCENTRATE FOR SOLUTION FOR INFUSION | INTRAVENIOUS INFUSION | 375 | 30 | PRD4797328 |
BAY 80-6946 | Test | POWDER FOR CONCENTRATE FOR SOLUTION FOR INFUSION | INTRAVENIOUS INFUSION | 60 | 30 | PRD2732217 |