Clinical Trials /

Obinutuzumab in Marginal Zone Lymphoma

NCT03322865

Description:

For marginal zone lymphoma (MZL) Rituximab in combination with conventional chemotherapy are 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 type II anti-CD20 antibody Obinutuzumab (OBINUTUZUMAB) has demonstrated remarkable activity in follicular lymphoma and superiority to Rituximab in combination with chemotherapy in treatment naïve (Gallium trial) and rituximab refractory follicular lymphoma (Gadolin trial) as well as in CLL in combination with chlorambucil. Based on these observations it is the aim of this study to test the toxicity and efficacy of the anti-CD20 antibody Obinutuzumab (OBINUTUZUMAB) in patients with newly diagnosed MZL in need of treatment, who are not eligible or failed local therapy, following the assumption that this novel anti-CD20 antibody is significantly more effective than Rituximab single agent therapy, and avoids chemotherapy - related toxicity.

Related Conditions:
  • Marginal Zone Lymphoma
Recruiting Status:

Recruiting

Phase:

Phase 2

Trial Eligibility

Document

Title

  • Brief Title: Obinutuzumab in Marginal Zone Lymphoma
  • Official Title: Obinutuzumab in Marginal Zone Lymphoma (OLYMP-1)

Clinical Trial IDs

  • ORG STUDY ID: OLYMP-1
  • SECONDARY ID: 2017-003149-56
  • NCT ID: NCT03322865

Conditions

  • Marginal Zone Lymphoma

Interventions

DrugSynonymsArms
ObinutuzumabGA101One Arm

Purpose

For marginal zone lymphoma (MZL) Rituximab in combination with conventional chemotherapy are 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 type II anti-CD20 antibody Obinutuzumab (OBINUTUZUMAB) has demonstrated remarkable activity in follicular lymphoma and superiority to Rituximab in combination with chemotherapy in treatment naïve (Gallium trial) and rituximab refractory follicular lymphoma (Gadolin trial) as well as in CLL in combination with chlorambucil. Based on these observations it is the aim of this study to test the toxicity and efficacy of the anti-CD20 antibody Obinutuzumab (OBINUTUZUMAB) in patients with newly diagnosed MZL in need of treatment, who are not eligible or failed local therapy, following the assumption that this novel anti-CD20 antibody is significantly more effective than Rituximab single agent therapy, and avoids chemotherapy - related toxicity.

Trial Arms

NameTypeDescriptionInterventions
One ArmExperimentalObinutuzumab i.v.
  • Obinutuzumab

Eligibility Criteria

        Inclusion Criteria:

        Patients must have a proven pathological diagnosis of MZL.

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

          -  Confirmed CD20 positive de novo MALT Lymphoma following or being not eligible for
             local therapy (including surgery, radiotherapy) and antibiotics for H. pylori-positive
             gastric lymphoma arisen at any extranodal site

          -  Confirmed CD20 positive de novo splenic MZL following or not being eligible for local
             therapy (including surgery and antiviral therapy for Hepatitis C Virus) with
             symptomatic disease

          -  Confirmed CD20 positive de novo nodal MZL

          -  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 patients with symptomatic gastric extranodal MZL: Helicobacter pylori-negative disease
        that is de novo or has relapsed following local therapy (i.e., surgery or radiotherapy) and
        requires therapy, as assessed by the investigator, or H. pylori-positive disease that has
        remained stable, progressed, or relapsed following antibiotic therapy and requires therapy,
        as assessed by the investigator - At least one bi-dimensionally measurable lesion (> 2 cm
        in its largest dimension by CT scan or MRI).

        In patients with splenic MZL, an enlarged spleen on CT scan or extending at least 2 cm
        below the costal margin by physical examination will constitute measurable disease
        providing that no explanation other than lymphomatous involvement is likely. For an
        enlarged liver to constitute the only measurable disease parameter, a liver biopsy showing
        proof of NHL in the liver is required.

        For SMZL:

          -  Bulky progressive or painful splenomegaly

          -  one of the following symptomatic/progressive cytopenias : Hb < 10 g/dL, or Plat <
             80.000 /microL, or neutropenia < 1000 /microL, whatever the reason (autoimmune or
             hypersplenism or bone marrow infiltration)

          -  enlarged lymphoadenopathy or involvement of extranodal sites with or without cytopenia

          -  splenectomised patients with rapidly raising lymphocyte counts, development of
             lymphadenopathy or involvement of extranodal sites

          -  SMZL with concomitant hepatitis C infection who have not responded to or are relapsed
             after Interferon and/or Ribavirin (patients positive for HCV antibody are eligible
             only if PCR is negative for HCV RNA.

        For gastric MALT Lymphoma:

        - H. pylori-negative cases following or being not eligible for local therapy (i.e.,
        surgery, radiotherapy or antibiotics).

        Others:

          -  Age greater than 18 years

          -  Life expectancy >3 months.

          -  Baseline platelet Count 50, 109/L, if not due to BM Infiltration by the lymphoma,
             absolute neutrophil Count 0.75, 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: 20 mg/L or 2 times the upper limit of institutional laboratory normal
             value, unless clearly related to the disease (except if due to Gilbert's syndrome)

          -  Serum creatininie <= 2mg/dl

          -  Pregnancy beta-HCG negative. For women of child-bearing potential only; serum or urine
             beta-HCG must be negative during screening and at study enrolment visit

          -  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.

          -  Premenopausal fertile females must agree to use a highly effective method of birth
             control for the duration of the therapy up to 6 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
             implants, injectables, combined oral contraceptives, some IUDs, sexual abstinence or
             vasectomised partner.

          -  Men must agree not to father a child for the duration of therapy and 6 months after
             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.

        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.

          -  Ann Arbor Stage I disease

          -  Ongoing immunosuppressive therapy other than corticosteroids

          -  Evidence of ongoing systemic bacterial, fungal, or viral infection at the time of
             study enrollment visit

          -  Ongoing drug-induced liver injury, chronic active hepatitis B (HBV), alcoholic liver
             disease, non-alcoholic steatohepatitis, primary biliary cirrhosis, extrahepatic
             obstruction caused by cholelithiasis, cirrhosis of the liver, or portal hypertension.

          -  Ongoing alcohol or drug addiction

          -  Treatment with any other investigational agent or participating in another trial
             within 30 days prior to entering this study

          -  Breastfeeding or pregnancy

          -  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

        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.

          -  Ann Arbor Stage I disease

          -  Ongoing immunosuppressive therapy other than corticosteroids

          -  Evidence of ongoing systemic bacterial, fungal, or viral infection at the time of
             study enrollment visit

          -  Ongoing drug-induced liver injury, chronic active hepatitis B (HBV), alcoholic liver
             disease, non-alcoholic steatohepatitis, primary biliary cirrhosis, extrahepatic
             obstruction caused by cholelithiasis, cirrhosis of the liver, or portal hypertension.

          -  Ongoing alcohol or drug addiction

          -  Treatment with any other investigational agent or participating in another trial
             within 30 days prior to entering this study

          -  Breastfeeding or pregnancy

          -  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
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Complete Remission/Response (CR) rate
Time Frame:24 weeks
Safety Issue:
Description:The complete Response rate (CR) is evaluated after the end of induction

Secondary Outcome Measures

Measure:Progression free survival
Time Frame:24 weeks
Safety Issue:
Description:Progression free survival (PFS) is defined as the time from registration to the first occurrence of progression or relapse as assessed by the investigator, or death from any cause. PFS for patients without disease progression, relapse, or death will be censored at the time of the last tumor assessment.
Measure:Overall survival
Time Frame:participants will be followed for their participation in the trial, an expected average of 8.6 years
Safety Issue:
Description:Overall survival is defined as the period from the induction registration to death from any cause. Patients who have not died until the time of the analysis will be censored at their last contact date.
Measure:Time to first response
Time Frame:participation will be followed for their participation in the trial, an expected average of 8.6 years
Safety Issue:
Description:Time to first response is defined as the time from the start of induction to first response (CR, PR).
Measure:Time to best response under treatment (induction and maintenance)Time
Time Frame:participation will be followed for their participation in the trial, an expected average of 8.6 years
Safety Issue:
Description:Time to best response is defined as the time from the start of induction to best response the patient achieves (CR, PR).
Measure:Response rate
Time Frame:24 weeks
Safety Issue:
Description:The response rates (CR, PR) and overall response rate (CR, PR) are evaluated 4 weeks after the end of induction treatment.
Measure:Best response
Time Frame:participation will be followed for their participation in the trial, an expected average of 8.6 years
Safety Issue:
Description:Best response is determined in the time interval from the start of induction therapy to end of follow-up.
Measure:Time to Treatment failure
Time Frame:participation will be followed for their participation in the trial, an expected average of 8.6 years
Safety Issue:
Description:Time to treatment failure (TTF) is defined as the time of registration to discontinuation of therapy for any reason including death from any cause, progression, toxicity or add-on of new anti-cancer therapy. Patients alive without treatment failure are censored at the latest tumor assessment date.
Measure:Remission duration
Time Frame:participation will be followed for their participation in the trial, an expected average of 8.6 years
Safety Issue:
Description:Remission duration will be calculated in patients with response (CR, PR) to induction from end of induction to the date of progression, relapse or death from any cause. Patients alive without progression and relapse will be censored at the latest tumor assessment date or the stopping date.
Measure:Cause specific survival
Time Frame:participation will be followed for their participation in the trial, an expected average of 8.6 years
Safety Issue:
Description:Cause specific survival is defined as the period from the induction registration to death from lymphoma or lymphoma related cause; death unrelated to MZoL is considered as a competing event.

Details

Phase:Phase 2
Primary Purpose:Interventional
Overall Status:Not yet recruiting
Lead Sponsor:Christian Buske

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