| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
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| E.1.1.1 | Medical condition in easily understood language |
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| E.1.1.2 | Therapeutic area | Diseases [C] - Cancer [C04] |
| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 20.0 |
| E.1.2 | Level | PT |
| E.1.2 | Classification code | 10076596 |
| E.1.2 | Term | Marginal zone lymphoma |
| E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
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| E.1.3 | Condition being studied is a rare disease | Yes |
| E.2 Objective of the trial |
| E.2.1 | Main objective of the trial |
| The objective of this trial is to test the efficacy and toxicity of the treatment of Pembrolizumab/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 therapy will be primarily analysed. For toxicity assessment treatment associated adverse events, quality of life and cumulative incidence of secondary malignancies will be documented. |
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| E.2.2 | Secondary objectives of the trial |
Response rate (CR, PR, CR or PR)
Best response
Time to best response
Time to first response
Progression free survival (PFS)
Time to treatment failure (TTF)
Duration of Response (DR)
Cause specific survival (CSS)
Overall survival (OS)
Quality of life during therapy
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| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal 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). 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). Please refer to Appendix D.
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. Please refer also to Appendix F.
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 are 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. Please refer to Appendix E.
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
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.
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| E.4 | Principal exclusion criteria |
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)
Medical history of allogeneic stem cell transplant
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)
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| E.5 End points |
| E.5.1 | Primary end point(s) |
| CR rate (CRR) after end of treatment (18 cycles) |
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| E.5.1.1 | Timepoint(s) of evaluation of this end point |
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| E.5.2 | Secondary end point(s) |
Response rate (CR, PR, CR or PR)
Best response
Time to best response
Time to first response
Progression free survival (PFS)
Time to treatment failure (TTF)
Duration of Response (DR)
Cause specific survival (CSS)
Overall survival (OS)
Quality of life during therapy
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| E.5.2.1 | Timepoint(s) of evaluation of this end point |
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| E.6 and E.7 Scope of the trial |
| E.6 | Scope of the trial |
| E.6.1 | Diagnosis | No |
| E.6.2 | Prophylaxis | No |
| E.6.3 | Therapy | Yes |
| E.6.4 | Safety | Yes |
| E.6.5 | Efficacy | Yes |
| E.6.6 | Pharmacokinetic | No |
| E.6.7 | Pharmacodynamic | No |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | No |
| E.6.10 | Pharmacogenetic | No |
| E.6.11 | Pharmacogenomic | No |
| E.6.12 | Pharmacoeconomic | No |
| E.6.13 | Others | No |
| E.7 | Trial type and phase |
| E.7.1 | Human pharmacology (Phase I) | No |
| E.7.1.1 | First administration to humans | No |
| E.7.1.2 | Bioequivalence study | No |
| E.7.1.3 | Other | No |
| E.7.1.3.1 | Other trial type description | |
| E.7.2 | Therapeutic exploratory (Phase II) | Yes |
| E.7.3 | Therapeutic confirmatory (Phase III) | No |
| E.7.4 | Therapeutic use (Phase IV) | No |
| E.8 Design of the trial |
| E.8.1 | Controlled | No |
| E.8.1.1 | Randomised | No |
| E.8.1.2 | Open | Yes |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | No |
| E.8.1.5 | Parallel group | No |
| E.8.1.6 | Cross over | No |
| E.8.1.7 | Other | No |
| E.8.2 | Comparator of controlled trial |
| E.8.2.1 | Other medicinal product(s) | No |
| E.8.2.2 | Placebo | No |
| E.8.2.3 | Other | No |
| E.8.2.4 | Number of treatment arms in the trial | 1 |
| E.8.3 |
The trial involves single site in the Member State concerned
| No |
| E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
| E.8.4.1 | Number of sites anticipated in Member State concerned | 2 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 18 |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.1 | Trial being conducted both within and outside the EEA | No |
| E.8.6.2 | Trial being conducted completely outside of the EEA | No |
| E.8.7 | Trial has a data monitoring committee | Yes |
| E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
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| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 7 |
| E.8.9.1 | In the Member State concerned months | 6 |
| E.8.9.1 | In the Member State concerned days | |
| E.8.9.2 | In all countries concerned by the trial years | 7 |
| E.8.9.2 | In all countries concerned by the trial months | 6 |
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