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

NCT04268277 | Terminated Phase 2 Results DMC

• 1 other identifier: POLE-1
• Study Type: interventional
• Target: 22
• Locations: 1 country
• Sites: 12

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 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.

Conditions

Marginal Zone Lymphoma

Keywords

Hematology; Oncology; Relapse; MALT; Pembrolizumab; Rituximab

Outcome Measures

Primary Outcomes (1)

• CR Rate

  CR rate (CRR) 4 weeks after end of treatment (18 cycles) according to the GELA (Copie-Bergman C, Gaulard P, Lavergne-Slove A, Brousse N, Flejou JF, Dordonne K, et al. Proposal for a new histological grading system for post-treatment evaluation of gastric MALT lymphoma. Gut 2003 Nov; 52(11): 1656.) criteria for gastric MALT or to the Cheson 2007 (Cheson BD, Pfistner B, Juweid ME, Gascoyne RD, Specht L, Horning SJ, et al. Revised response criteria for malignant lymphoma. J Clin Oncol 2007 Feb 10; 25(5): 579-586.) criteria for non-gastric extranodal, nodal and splenic MZL: Complete Response (CR): Complete disappearance of all detectable clinical evidence of disease and disease-related symptoms if present prior to therapy.

  4 weeks after end of treatment (18 cycles), approx. 58 weeks

Secondary Outcomes (10)

• Response Rate

  4 weeks after end of treatment (18 cycles), approx. 58 weeks

• Best Response

  2.1 - 33.2 months

• Time to Best Response

  2.1 - 33.2 months

• Time to First Response

  2.1 - 33.2 months

• Progression Free Survival (PFS)

  12 months

Study Arms (1)

Rituximab & Pembrolizumab

EXPERIMENTAL

Cycle 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

Drug: Rituximab; Drug: Pembrolizumab

Interventions

Rituximab DRUG

100 mg concentrate for solution for infusion

Also known as: Truxima

Rituximab & Pembrolizumab

Pembrolizumab DRUG

100 mg/ 4mL concentrate for solution for infusion

Also known as: Keytruda

Rituximab & Pembrolizumab

Eligibility Criteria

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

You may qualify if:

• Patients must have a proven pathological diagnosis of MZL, diagnosed by a reference pathology center.
• 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). The need of treatment is applicable in the case of B symptoms, deterioration of peripheral blood counts due to lymphoma infiltration of the bone marrow, rapid enlargement of lymph nodes or compression of vital organs by bulky disease.
• For nodal MZL and extragastric MALT lymphoma:
• At least one bi-dimensionally measurable lesion (\>=1.5 cm in its largest dimension by CT/PET-CT scan or MRI)
• For splenic MZL (SMZL):
• In patients with splenic MZL, an enlarged spleen on CT scan and lymphoma cell infiltration has to be seen in bone marrow and/or peripheral blood.
• 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)
• splenectomised patients with rapidly raising lymphocyte counts, development of lymphadenopathy or involvement of extranodal sites if not being eligible for local therapy
• 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)
• 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.

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 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

Sponsors & Collaborators

• University of Ulm: lead
• X-act Cologne Clinical Research GmbH: collaborator
• Zentrum für Klinische Studien Ulm: collaborator
• Merck Sharp & Dohme LLC: collaborator
• Celltrion Healthcare Co., LTD: collaborator

Study Sites (12)

Universitätsklinikum Ulm; Klinik für Innere Medizin Innere Medizin III

Ulm, Baden-Wurttemberg, 89081, Germany

Location

Charité Universitätsmedizin Berlin; Hämatologie - Onkologie - Tumorimmunologie

Berlin, 12200, Germany

Location

Klinikum Chemnitz gGmbH, Klinik für Innere Medizin III

Chemnitz, 09116, Germany

Location

Gemeinschaftspraxis Dr. med. Johannes Mohm, Dr. med. Gabriele Prange-Krex

Dresden, 01307, Germany

Location

Kliniken Maria Hilf GmbH; Klinik für Hämatologie, Onkologie und Gastroenterologie

Mönchengladbach, 41063, Germany

Location

Klinikum rechts der Isar der TU München, Klinik und Poliklinik für Innere Medizin III

München, 81675, Germany

Location

Gemeinschaftspraxis für Hämatologie und Onkologie

Münster, 48149, Germany

Location

Klinikum Oldenburg AöR, Universitätsklinik für Innere Medizin, Onkologie und Hämatologie

Oldenburg, 26133, Germany

Location

Brüderkrankenhaus St. Josef, Klinik für Hämatologie und Onkologie

Paderborn, 33098, Germany

Location

Klinikum Passau, II. Medizinische Klinik - Hämatologie, Onkologie und Palliativmedizin

Passau, 94032, Germany

Location

RoMed Klinikum Rosenheim, Med. Klinik II / OTK

Rosenheim, 83002, Germany

Location

Robert-Bosch-Krankenhaus; Hämatologie, Onkologie und Palliativmedizin

Stuttgart, 70376, Germany

Location

MeSH Terms

Conditions

Lymphoma, B-Cell, Marginal Zone; Neoplasms; Recurrence

Interventions

Rituximab; pembrolizumab

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; Disease Attributes; Pathologic Processes; Pathological Conditions, Signs and Symptoms

Intervention Hierarchy (Ancestors)

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

Limitations and Caveats

The study was terminated preliminary with only 22 of 56 planned participants.

Results Point of Contact

• Title: Coordinating Investigator
• Organization: Universitätsklinikum Ulm

christian.buske@uni-ulm.de

+49 731 500 65801

Study Officials

• Christian Buske, Prof. Dr.

  University Hospital of Ulm Department of Internal Medicine III

  PRINCIPAL INVESTIGATOR

Publication Agreements

• PI is Sponsor Employee: No
• Restriction Type: OTHER
• Restrictive Agreement: Yes

Study Design

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

Study Record Dates

• First Submitted: February 11, 2020
• First Posted: February 13, 2020
• Study Start: March 1, 2022
• Primary Completion: December 6, 2024
• Study Completion: December 6, 2024
• Last Updated: February 27, 2026
• Results First Posted: February 27, 2026

Record last verified: 2026-02

Locations

DE (12)