Clinical Trials /

Pembrolizumab in MarginalzoneLymphoma A MULTICENTER OPEN LABEL SINGLE-ARM PHASE II STUDY

NCT04268277

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 does 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 55.8% vs. 78.8%, respectively (P < 0.001). Thus, it is the major aim to develop chemotherapy-free approaches for MZL, which approach or surpass efficacy of rituximab/chemotherapy combinations, but avoid chemotherapy associated toxicities. Checkpoint inhibitors such as Pembrolizumab have revolutionized cancer treatment and have also shown first encouraging results in Non-Hodgkin lymphomas. Based on these observations it is the aim of this study to test the toxicity and efficacy of Pembrolizumab 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 efficient than Rituximab single agent therapy and at least as efficient as rituximab/chemotherapy, but avoids chemotherapy-related toxicity.

Related Conditions:
  • Marginal Zone Lymphoma
Recruiting Status:

Not yet recruiting

Phase:

N/A

Trial Eligibility

Document

Title

  • Brief Title: Pembrolizumab in MarginalzoneLymphoma A MULTICENTER OPEN LABEL SINGLE-ARM PHASE II STUDY
  • Official Title: Pembrolizumab in Marginalzone Lymphoma A MULTICENTER OPEN LABEL SINGLE-ARM PHASE II STUDY

Clinical Trial IDs

  • ORG STUDY ID: POLE-1
  • NCT ID: NCT04268277

Conditions

  • Marginal Zone Lymphoma

Interventions

DrugSynonymsArms
RituximabTruximaRituximab & Pembrolizumab
PembrolizumabKeytrudaRituximab & Pembrolizumab

Purpose

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 does 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 55.8% vs. 78.8%, respectively (P < 0.001). Thus, it is the major aim to develop chemotherapy-free approaches for MZL, which approach or surpass efficacy of rituximab/chemotherapy combinations, but avoid chemotherapy associated toxicities. Checkpoint inhibitors such as Pembrolizumab have revolutionized cancer treatment and have also shown first encouraging results in Non-Hodgkin lymphomas. Based on these observations it is the aim of this study to test the toxicity and efficacy of Pembrolizumab 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 efficient than Rituximab single agent therapy and at least as efficient as rituximab/chemotherapy, but avoids chemotherapy-related toxicity.

Detailed 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 does
      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 55.8% vs. 78.8%, respectively (P < 0.001). Thus, it is the major aim to
      develop chemotherapy-free approaches for MZL, which approach or surpass efficacy of
      rituximab/chemotherapy combinations, but avoid chemotherapy associated toxicities.

      Checkpoint inhibitors such as Pembrolizumab have revolutionized cancer treatment and have
      also shown first encouraging results in Non-Hodgkin lymphomas. Based on these observations it
      is the aim of this study to test the toxicity and efficacy of Pembrolizumab 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 efficient 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 treatment with
      Pembrolizumab and Rituximab in patients with MZL in need of treatment, who have failed or are
      not eligible for local therapy or relapsed. For efficacy the rate of complete remissions
      (according to the GELA criteria for gastric MALT or to the Cheson 2007 criteria for nodal and
      splenic MZL) after end of treatment (18 cycles) will be primarily analyzed. For toxicity
      assessment treatment associated adverse events, quality of life and cumulative incidence of
      secondary malignancies will be documented.

      This study is a European multicenter, single-arm, open-label, phase II trial of 18 cycles of
      Pembrolizumab and Rituximab in patients aged ≥ 18 years with previously untreated or relapsed
      MZL in need of treatment.

      Primary endpoint is the complete response (CR rate (CRR) determined after end of treatment
      (18 cycles).

      The study flow will be as follows:

        -  Previously untreated or relapsed patients will be screened for eligibility for the
           trial. If the patient is eligible for the study, the patient will be registered before
           the first cycle of treatment.

        -  Patients who progress at any time point during treatment are considered as treatment
           failure. They will be followed up for overall survival until end of follow up period or
           death.

        -  Patients, who achieve at least a SD after treatment will be followed up for response
           until progression/relapse and for overall survival until death.

      It is expected that a total of 56 patients at approximately 15 investigator sites in Germany
      and 3 centers in Austria will be registered. Every patient will receive treatment over a time
      period of 18 cycles (each cycle lasts 3 weeks). Subsequently, patients will be monitored
      every 3 months for 2 additional years, subsequently every 6 months for three additional
      years.
    

Trial Arms

NameTypeDescriptionInterventions
Rituximab & PembrolizumabExperimentalCycle 1 (21 days cycle): Rituximab: 375 mg/m2 day 1, 8, 15 Pembrolizumab: 200 mg IV fixed dose day 2 Cycle 2-18 (21 days cycle) or until progression or non-tolerable toxicity: Rituximab: 375 mg/m2 day 1 every second cycle Pembrolizumab: 200 mg IV fixed dose day 1
  • Rituximab
  • Pembrolizumab

Eligibility Criteria

        Inclusion Criteria:

        Patients must have a proven pathological diagnosis of MZL, diagnosed by a reference
        pathology center.

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

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

          -  Confirmed CD20 positive de novo or relapsed splenic MZL in need of treatment following
             or not being eligible for local therapy (including surgery and antiviral therapy for
             Hepatitis C Virus) OR

          -  Confirmed CD20 positive de novo or relapsed nodal MZL in need of treatment following
             or not being eligible for local therapy (radiotherapy) • At least one bi-dimensionally
             measurable lesion (a measurable node must have a longest transverse diameter of a
             lesion (LDi) > 1.5 cm. A measurable extranodal lesion should have an LDi > 1.0 cm by
             CT/ PET-CT scan or MRI)

        For splenic MZL (SMZL):

        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.
        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.

        At least one of the following criteria must be fulfilled:

          -  Bulky progressive or painful splenomegaly

          -  one of the following symptomatic/progressive cytopenias: Hb < 10 g/dL, or Platelet
             count < 80.000 /µL, or neutropenia < 1000 /µL, 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) or after systemic therapy For an enlarged liver to
        constitute the only measurable disease parameter, a liver biopsy showing proof of NHL in
        the liver is required

        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

        Others:

          -  Age ≥ 18 years

          -  Life expectancy > 3 months

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

               -  Baseline platelet count ≥ 75 x 109/L (if not due to BM infiltration by the
                  lymphoma), absolute neutrophil count ≥ 1.5 x 109/L.

               -  Hemoglobin ≥ 9.0 g/dL or ≥ 5.6 mmol/L (Criteria must be met without
                  erythropoietin dependency and without packed red blood cell (pRBC) transfusion
                  within last 2 weeks)

               -  International Normalized Ratio (INR) or Prothrombin Time (PT): ≤ 1.5 × ULN unless
                  subject is receiving anticoagulant therapy as long as PT or PTT is within
                  therapeutic range of intended use of anticoagulants

               -  Activated Partial Thromboplastin Time (aPTT): ≤ 1.5 × ULN unless subject is
                  receiving anticoagulant therapy as long as PT or PTT is within therapeutic range
                  of intended use of anticoagulants

               -  ASAT (SGOT): ≤ 2.5 times the upper limit of institutional laboratory normal value
                  or ≤ 5 times the upper limit of institutional laboratory normal value in subjects
                  with lymphoma in the liver.

               -  ALAT (SGPT): ≤ 2,5 times the upper limit of institutional laboratory normal value
                  or ≤ 5 times the upper limit of institutional laboratory normal value in subjects
                  with lymphoma in the liver

               -  Serum total bilirubin: ≤ 1.5 × ULN OR Direct bilirubin ≤ ULN for subjects with
                  total bilirubin levels > 1.5 ULN (unless clearly related to the disease)

               -  Serum creatinine ≤ 1.5 × ULN OR ≥ 60 mL/min GFR or CrCl for subjects with
                  creatinine levels > 1.5 × institutional ULN

               -  Negative HIV antibody

               -  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.

               -  Patients positive for HCV antibody are eligible only if PCR is negative for HCV
                  RNA.

               -  For women of child-bearing potential only: Pregnancy β-HCG negative. 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 the last dose of
             Rituximab and through 4 months after the last dose of Pembrolizumab. A highly
             effective method of birth control is defined as those which results 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
             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 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 enrolment visit, other malignancy 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

          -  Has had prior chemotherapy (systemic anti-cancer therapy), targeted small molecule
             therapy, or radiation therapy within 2 weeks prior to study Day 1 or who has not
             recovered (i.e., ≤ Grade 1 or baseline value) from AEs due to a previously
             administered agent

               -  Note: Subjects with ≤ Grade 2 neuropathy are an exception to this criterion and
                  may qualify for the study

               -  Note: If a subject received major surgery, they must have recovered adequately
                  from complications from the intervention prior to starting therapy

          -  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 or participating in another clinical
             trial with an investigational product within 4 weeks prior to entering this study or
             within 5 x the half-life (t1/2) of the investigational product, whichever is longer

          -  Breastfeeding or Pregnancy

          -  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 study medication

          -  Uncontrolled arterial hypertension despite optimal medical management

          -  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

          -  Vaccination with a live vaccine within 30 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)

          -  Has received prior therapy with an anti-PD-1, anti-PD-L1, or anti PD L2 agent or with
             an agent directed to another stimulatory or co-inhibitory T-cell receptor (e.g.,
             CTLA-4, OX 40, CD137)

          -  Has received prior radiotherapy within 2 weeks of start of study treatment.
             Participants must have recovered from all radiation-related toxicities, not require
             corticosteroids, and not have had radiation pneumonitis. A 1-week washout is permitted
             for palliative radiation (≤2 weeks of radiotherapy) to non-CNS disease

          -  Has known active CNS metastases and/or carcinomatous meningitis. Participants with
             previously treated brain metastases may participate provided they are radiologically
             stable, i.e. without evidence of progression for at least 4 weeks by repeat imaging
             (note that the repeat imaging should be performed during study screening), clinically
             stable and without requirement of steroid treatment for at least 14 days prior to
             first dose of study treatment

          -  Has a history of non-infectious pneumonitis that required steroids, or current
             pneumonitis

          -  History of anaphylaxis in association with previous administration of monoclonal
             antibodies or severe hypersensitivity (≥Grade 3) to the investigational medicinal
             products and/or any of its excipients

          -  Has active autoimmune disease that has required systemic treatment in the past 2 years
             (i.e. with use of disease modifying agents, corticosteroids or immunosuppressive
             drugs). Replacement therapy (e.g., thyroxine, insulin, or physiologic corticosteroid
             replacement therapy for adrenal or pituitary insufficiency, etc.) is not considered a
             form of systemic treatment

          -  Has a known history of active TB (Bacillus Tuberculosis)

          -  Ongoing alcohol or drug addiction or known psychiatric or substance abuse disorders
             that would interfere with cooperation with the requirements of the trial

          -  Diagnosis of Stevens-Johnson Syndrome (SJS) and Toxic Epidermal Necrolysis (TEN)
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:CR rate
Time Frame:12 months
Safety Issue:
Description:CR rate (CRR) after end of treatment (18 cycles)

Secondary Outcome Measures

Measure:Response rate
Time Frame:58 weeks
Safety Issue:
Description:The response rates are evaluated 4 weeks after the end of treatment
Measure:Best response
Time Frame:54 weeks
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 best response
Time Frame:54 weeks
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:Time to first response
Time Frame:54 weeks
Safety Issue:
Description:Time to first response is defined as the time from the start of induction to first response (CR, PR)
Measure:Progression free survival (PFS)
Time Frame:54 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:Time to treatment failure (TTF)
Time Frame:54 weeks
Safety Issue:
Description:Time to treatment failure 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:Duration of Response (DR)
Time Frame:54 weeks
Safety Issue:
Description:Duration of response 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 (CSS)
Time Frame:54 weeks
Safety Issue:
Description:Cause specific survivial is defined as the period from the induction registration to death from lymphoma or lymphoma related cause; death unrelated to MZL is considered as a competing event.
Measure:Overall survival (OS)
Time Frame:54 weeks
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:Quality of life during trial
Time Frame:54 weeks
Safety Issue:
Description:Quality of life will be measured by the FACT Lym before start of treatment and during trial participation.

Details

Phase:N/A
Primary Purpose:Interventional
Overall Status:Not yet recruiting
Lead Sponsor:University of Ulm

Trial Keywords

  • Hematology
  • Oncology
  • Relapse
  • MALT
  • Pembrolizumab
  • Rituximab

Last Updated

February 17, 2020