Copanlisib and Rituximab in Marginal Zone Lymphoma Patients
Copanlisib and Rituximab in Marginal Zone Lymphoma Patients
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.
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.

 The objective of the trial is to test the efficacy and toxicity of the treatment of
 Copanlisib/Rituximab in patients with MZL in need of treatment, who have failed or are not
 eligible for local therapy or relapsed after local or systemic therapy. For efficacy the rate
 of complete remissions (according to the GELA criteria for gastric MALT or to the Cheson 2007
 criteria for non-gastric extranodal, nodal and splenic MZL) after induction therapy will be
 primarily analysed. For toxicity treatment associated adverse events, quality of life and
 cumulative incidence of secondary malignancies will be documented.
Inclusion Criteria:

 Patients must meet all of the following inclusion criteria to be eligible for participation
 in this study:

 -  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:

 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. Please refer to
 Appendix D.

 Inclusion is possible for patients with:

 -  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.

 -  H. pylori-positive disease that has remained stable, progressed, or relapsed following
 antibiotic therapy.

 Others:

 -  Age >= 18 years

 -  Life expectancy >3 months.

 -  Baseline platelet Count >= 50 x 109/L (if not due to BM infiltration by the lymphoma),
 absolute neutrophil Count >= 0.75 x 109/L.

 -  Meet the following pretreatment laboratory criteria at the Screening visit conducted
 within 28 days of study enrollment (unless due to underlying lymphoma):

 -  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. A highly
 effective method of birth control is defined as those which result in a low failure
 rate (i.e. less than 1% per year) when used consistently and correctly such as
 combined (estrogen and progestogen containing) hormonal contraception associated with
 inhibition of ovulation (oral, intravaginal or transdermal), progestogen-only hormonal
 contraception associated with inhibition of ovulation (oral, injectable or
 implantable), intrauterine device (IUD), intrauterine hormone-releasing system ( IUS),
 bilateral tubal occlusion, vasectomised partner or sexual abstinence. Contraception
 and pregnancy testing are required according the CTFG recommendations
 (http://www.hma.eu/fileadmin/dateien/Human_Medicines/01-About_HMA/Working_Groups/CTFG/
 2014_09_HMA_CTFG_Contraception.pdf).

 -  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:

 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

 -  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).