Copanlisib and Rituximab in Marginal Zone Lymphoma Patients

  • STATUS
    Recruiting
  • End date
    Dec 31, 2029
  • participants needed
    56
  • sponsor
    Christian Buske
Updated on 21 April 2022
ct scan
platelet count
remission
rituximab
measurable disease
interferon
cytopenia
neutrophil count
tositumomab
chlorambucil
gastric malt lymphoma
splenic marginal zone lymphoma

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.

Description

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.

Details
Condition Marginal Zone Lymphoma
Treatment Rituximab, Copanlisib
Clinical Study IdentifierNCT03474744
SponsorChristian Buske
Last Modified on21 April 2022

Eligibility

Yes No Not Sure

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
For nodal MZL and extragastric MALT lymphoma
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
For SMZL
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
At least one of the following criteria must be met
diagnosis may be confirmed by the presence of splenomegaly and typical morphologic and
Bulky progressive or painful splenomegaly
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
For gastric MALT lymphoma
(i.e., surgery or radiotherapy) and requires therapy, as assessed by the investigator
At least one bi-dimensionally measurable lesion (≥ 1.5 cm in its largest dimension by CT
scan or MRI). Please refer to Appendix C
Inclusion is possible for patients with
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
Others
Age >= 18 years
Life expectancy >3 months
one of the following symptomatic/progressive cytopenias: Hb < 10 g/dL, or Plat <
000 /µL, or neutropenia < 1000/µL, whatever the reason (autoimmune or hypersplenism
or bone marrow infiltration)
ASAT (SGOT): <= 3 times the upper limit of institutional laboratory normal value
SMZL with concomitant hepatitis C infection which has not responded to or has relapsed
ALAT (SGPT): <= 3 times the upper limit of institutional laboratory normal value
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
Negative HIV antibody
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. Please refer to
Appendix D
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
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)
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
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/>
_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
Ongoing alcohol or drug addiction
Breastfeeding or pregnancy
Prior treatment with Copanlisib
Congestive heart failure > New York Heart Association (NYHA) class 2
Myocardial infarction less than 6 months before start of test drug
Uncontrolled arterial hypertension despite optimal medical management
HbA1c>8.5%
Vaccination with a live vaccine within 28 days prior to start of therapy
Non-healing wound, ulcer, or bone fracture
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
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
Unstable angina (angina symptoms at rest), new-onset angina (begun within the last 3
months)
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
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
History or concurrent interstitial lung disease of any severity and/or severely
impaired lung function (as judged by the investigator)
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