Copanlisib and Rituximab in Marginal Zone Lymphoma Patients

NCT03474744 | Active Not Recruiting Phase 2 DMC

• 1 other identifier: COUP-1
• Study Type: interventional
• Target: 36
• Locations: 2 countries
• Sites: 18

Brief Summary

For marginal zone lymphoma (MZL) Rituximab in combination with conventional chemotherapy is widely used for those patients who fail local therapy or do not qualify for such. Depending on the MZL subtype Rituximab/chemotherapy is able to induce in part long remissions, but do not prevent relapse later on. In addition, chemotherapy associated toxicity is often problematic in MZL patients, who are mostly of advanced age. Thus, chemotherapy - free approaches are highly attractive for this patient group. Rituximab single agent is a widely used chemotherapy - free approach in MZL, but was significantly inferior compared to Rituximab/chlorambucil in a large randomized prospective clinical trial in treatment naïve MZL with a CR rate of 56 % vs. 80%, respectively (P\<0.001). Thus, it is the major aim to develop chemotherapy - free approaches for MZL, which approach efficacy of Rituximab/chemotherapy combinations, but avoid chemotherapy associated toxicities. This in particular important in MZL as many physicians are reluctant to treat these often elderly patients with more intense treatments and prefer single agent therapies in these very often well and long responding lymphoma subtype. The PI3K inhibitor Copanlisib has shown high clinical activity in indolent B - cell lymphomas among them MZL. Based on these observations it is the aim of this study to test the toxicity and efficacy of Copanlisib in combination with the anti-CD20 antibody Rituximab in patients with newly diagnosed or relapsed MZL in need of treatment, who are not eligible or failed local therapy, following the assumption that this novel chemotherapy - free combination is significantly more effective than Rituximab single agent therapy and at least as efficient as Rituximab/chemotherapy, but avoids chemotherapy - related toxicity.

Conditions

Marginal Zone Lymphoma

Keywords

Copanlisib; Rituximab; Oncology

Outcome Measures

Primary Outcomes (1)

• Complete Response

  Primary endpoint is the complete response (CR rate (CRR) determined 12 months after start of induction therapy). Patients who progress before 12 months after start of treatment will be treated as CR='NO' and will be included in the calculation of the primary endpoint. No primary endpoint will be determined for patients who withdraw.

  12 months

Secondary Outcomes (10)

• Response rate

  12 months

• Best response

  8.5 years

• Time to best response

  8.5 years

• Time to first response

  12 months

• Progressioin free survival (PFS)

  12 months

Study Arms (1)

Experimental Arm

EXPERIMENTAL

Induction Phase: Cycle 1-6 (28 days cycle): Copanlisib: 60 mg i.v. fixed dose days 1, 8, 15. Rituximab: 375 mg/m2 day 1 i.v. Maintenance: Start 2 months after start of the last induction cycle for patients at least achieving a stable response after induction. Copanlisib: 60 mg i.v. fixed dose day 1 and day 15 every 4 weeks for a maximum of 12 cycles or until progression or study drug-related intolerable toxicity (month 2 to month 13 after end of induction). Rituximab: 375 mg/m2 i.v. day 1 every 8 weeks for a maximum of 12 infusions or until progression or study drug-related intolerable toxicity (month 2 to month 24 after end of induction)

Drug: Copanlisib; Drug: Rituximab

Interventions

Copanlisib DRUG

Solution for IV infusion

Also known as: Aliqopa

Experimental Arm

Rituximab DRUG

Solution for IV infusion

Also known as: Truxima

Experimental Arm

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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 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. Biopsy material from an excisional or core biopsy must be submitted for retrospective central confirmation. Tissue samples dated \> 12 months prior to informed consent can be accepted only if tissue material is available for retrospective confirmation, if there is no clinical indication for transformation of disease, and if the request for additional biopsy would be unethical treatment of the patient.
• 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.
• \- 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 extragastric MALT lymphoma:
• \- At least one bi-dimensionally measurable lesion (≥ 1.5 cm in its largest dimension by CT scan or MRI). Please refer to Appendix C.
• 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. Please refer also to Appendix E.
• 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:

You may not qualify if:

• The presence of any of the following will exclude a subject from enrolment:
• 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

Sponsors & Collaborators

• Christian Buske: lead
• University of Ulm: collaborator
• Optimapharm: collaborator
• X-act Cologne Clinical Research GmbH: collaborator
• Zentrum für Klinische Studien Ulm: collaborator
• Celltrion Healthcare Co., LTD: collaborator
• Bayer: collaborator

Study Sites (18)

Med. Uni Wien AKH, Klinische Abteilung für Onkologie, Innere Medizin I

Vienna, 1190, Austria

Location

St. Josef-Hospital, Medizinische Klinik I

Bochum, 44791, Germany

Location

Johanniter GmbH, Johanniter-Krankenhaus

Bonn, 53113, Germany

Location

ÜBAG MVZ Dr. Vehling-Kaiser GmbH Dingolfing

Dingolfing, 84113, Germany

Location

Kath. Karl-Leisner-Klinikum gGmbH, Betriebsstätte Wilhelm-Anton-Hospital

Goch, 47574, Germany

Location

MVZ Goslar, MVZ Onkologische Kooperation Harz

Goslar, 38642, Germany

Location

Universitätsklinikum Halle, Klinik und Poliklinik für Innere Medizin

Halle, 06120, Germany

Location

Rotes Kreuz Krankenhaus, Klinik für Interdisziplinäre Onkologie

Kassel, 34121, Germany

Location

ÜBAG MVZ Dr. Vehling-Kaiser GmbH

Landshut, 84036, Germany

Location

Gemeinschaftspraxis, Fachärzte für Innere Medizin

Mannheim, 68161, Germany

Location

Universitätsmedizin Mannheim, III. Medizinische Klinik

Mannheim, 68167, Germany

Location

Kliniken Ostalb Stauferklinikum Schwäbisch Gmünd, Zentrum für Innere Medizin

Mutlangen, 73557, Germany

Location

Klinikum der Universität München, Medizinische Klinik und Poliklinik III

München, 83177, Germany

Location

Sana Klinikum Offenbach GmbH

Offenbach, 63069, Germany

Location

Universitätsklinik PIUS Hospital, Innere Medizin

Oldenburg, 26121, Germany

Location

Elblandkliniken Stiftung & Co. KG, Innere Medizin II

Riesa, 01589, Germany

Location

Universitätsmedizin Rostock

Rostock, 18051, Germany

Location

University Hospital Ulm

Ulm, 89081, Germany

Location

Related Publications (1)

• Grunenberg A, Kaiser LM, Woelfle S, Schmelzle B, Viardot A, Moller P, Barth TFE, Muche R, Dreyhaupt J, Raderer M, Kiesewetter B, Buske C. A phase II study of the PI3K inhibitor copanlisib in combination with the anti-CD20 monoclonal antibody rituximab for patients with marginal zone lymphoma: treatment rationale and protocol design of the COUP-1 trial. BMC Cancer. 2021 Jun 29;21(1):749. doi: 10.1186/s12885-021-08464-6.

  PMID: 34187401 DERIVED

MeSH Terms

Conditions

Lymphoma, B-Cell, Marginal Zone; Neoplasms

Interventions

copanlisib; Rituximab

Condition Hierarchy (Ancestors)

Lymphoma, B-Cell; Lymphoma, Non-Hodgkin; Lymphoma; Neoplasms by Histologic Type; Lymphoproliferative Disorders; Lymphatic Diseases; Hemic and Lymphatic Diseases; Immunoproliferative Disorders; Immune System Diseases

Intervention Hierarchy (Ancestors)

Antibodies, Monoclonal, Murine-Derived; Antibodies, Monoclonal; Antibodies; Immunoglobulins; Immunoproteins; Blood Proteins; Proteins; Amino Acids, Peptides, and Proteins; Serum Globulins; Globulins

Study Officials

• Christian Buske, MD

  University Hospital of Ulm

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: NA
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: OTHER
• Responsible Party: SPONSOR INVESTIGATOR
• PI Title: Prof. Dr. med.

Study Record Dates

• First Submitted: February 28, 2018
• First Posted: March 23, 2018
• Study Start: December 15, 2019
• Primary Completion (Estimated): December 30, 2027
• Study Completion (Estimated): December 31, 2027
• Last Updated: May 6, 2026

Record last verified: 2026-04

Locations

DE (17); AU (1)