E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
relapsed or refractory Primary Mediastinal Large B-Cell Lymphoma relapsed or refractory Richter Syndrome (rrRS) |
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E.1.1.1 | Medical condition in easily understood language |
relapsed or refractory Primary Mediastinal Large B-Cell Lymphoma relapsed or refractory Richter Syndrome (rrRS) |
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E.1.1.2 | Therapeutic area | Diseases [C] - Cancer [C04] |
MedDRA Classification |
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 |
- rrPMBCL: to estimate the ORR of pembrolizumab by independent central review according to the IWG response criteria (Cheson, 2007) - rrRS: Estimate the ORR of pembrolizumab by independent central review according to the IWG response criteria (Cheson, 2007) with special considerations for RS. |
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E.2.2 | Secondary objectives of the trial |
In subjects with rrPMBCL or rrRS: -To estimate the ORR of pembrolizumab by investigator assessment according to the IWG response criteria (Cheson, 2007) or IWG with special considerations for RS. - To evaluate PFS, DOR, and DCR of pembrolizumab by independent central review and investigator assessment according to the IWG response criteria (Cheson, 2007) or IWG with special considerations for RS. -To evaluate the OS of pembrolizumab. - To determine the safety and tolerability of pembrolizumab. |
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E.2.3 | Trial contains a sub-study | Yes |
E.2.3.1 | Full title, date and version of each sub-study and their related objectives |
Merck will conduct future Biomedical Research on DNA (blood and tissue) specimens collected during this clinical trial. Such research is for biomarker testing to address emergent questions not described elsewhere in the protocol (as part of the main trial) and will only be conducted on specimens from appropriately consented subjects. The objective of collecting specimens for Future Biomedical Research is to explore and identify biomarkers that inform the scientific understanding of diseases and/or their therapeutic treatments. The overarching goal is to use such information to develop safer, more effective drugs, and/or to ensure that subjects receive the correct dose of the correct drug at the correct time. |
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E.3 | Principal inclusion criteria |
PMBCL: - Diagnosis of PMBCL, according to the World Health Organization (WHO) classification of neoplasms of the hematopoietic and lymphoid tissues (WHO Criteria 2008). - Subject must be able to provide an evaluable core or excisional lymph node biopsy for evaluation of PMBCL diagnosis from an archival or newly obtained biopsy at Screening. (Central review is not required before enrolment. Enrolment can be done on local pathologic review for diagnosis.) - Have relapsed or refractory PMBCL and: * Have relapsed after auto-SCT or have failed to achieve a CR or PR within 60 days of auto-SCT. Subjects may have received intervening therapy after auto-SCT for relapsed or refractory disease, in which case they must have relapsed after or be refractory to their last treatment. OR * For subjects who are ineligible for auto-SCT, have received at least ≥ 2 lines of prior therapy and have failed to respond to or relapsed after their last line of treatment. For subjects who received consolidative local radiotherapy after systemic therapy, local radiotherapy will not be considered as a separate line of treatment. - Must have been previously exposed to rituximab as part of prior lines of treatment. Richter Syndrome: - Pathologic diagnosis per local institutional review of Richter syndrome that transformed from CLL. - Have relapsed or refractory RS and has received at least 1 previous treatment for RS. All Subjects: - Have radiographically measureable disease by independent central review, defined as at least one lesion that can be accurately measured in at least two dimensions with appropriate anatomic imaging (CT scan or magnetic resonance imaging [MRI]). Minimum measurement must be > 15 mm in the longest diameter. a. RS subjects must also be PET positive at screening, defined as having at least one lesion, attributable to malignancy and with appropriate correlation to anatomic imaging, with uptake greater than that of normal liver tissue. - Must have a performance status of 0 or 1 on the Eastern Cooperative Oncology Group (ECOG) Performance Scale - Life expectancy > 3 months
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E.4 | Principal exclusion criteria |
- Is currently participating and receiving study therapy or has participated in a study of an investigational agent and received study therapy or used an investigational device within 4 weeks of the first dose of treatment. - Is receiving systemic steroid therapy < 3 days before the first dose of trial treatment or receiving any other form of immunosuppressive medication. Note: a. Corticosteroid use on study after Cycle 1 for management of adverse events, serious adverse events, and events of clinical interest, as a premedication for IV contrast allergies/reactions, or if considered necessary for a subject's welfare is allowed. b. Subjects who receive daily steroid replacement therapy are an exception. Daily prednisone at doses of 5 to 7.5 mg is an example of replacement therapy. c. Equivalent hydrocortisone doses are also permitted if administered as replacement therapy. - Has had a prior monoclonal antibody within 4 weeks prior to study Day 1 or who has not recovered (i.e. ≤ Grade 1 or at baseline) from adverse events due to agents administered more than 4 weeks earlier. - Has had prior chemotherapy or targeted small molecule therapy within 2 weeks prior to study Day 1 or has had prior radiation therapy within 4 weeks prior to study Day 1 or who has not recovered (i.e. ≤ Grade 1 (2 weeks for RS subjects) or at baseline) from adverse events due to agents administered more than 4 weeks earlier (2 weeks for RS subjects).. Exception: Subjects with RS with CLL may receive ibrutinib (or similar for CLL) up to 24 hours before first dose. - Has undergone prior allogeneic hematopoietic stem cell transplantation within the last 5 years. (Subjects who have had a transplant greater than 5 years ago are eligible as long as there are no symptoms of Graft versus Host Disease (GVHD). - Has a known additional malignancy (except underlying CLL for RS) that is progressing or requires active treatment. Exceptions include basal cell carcinoma of the skin, squamous cell carcinoma of the skin, or in situ cervical cancer that has undergone potentially curative therapy. - Has known active central nervous system (CNS) involvement. Subjects with prior CNS involvement are eligible if their CNS disease is in radiographic, cytological (for cerebrospinal fluid disease) and clinical remission. - Has active autoimmune disease that has required systemic treatment in 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 history of (non-infectious) pneumonitis that required steroids, or current pneumonitis. - Has an active infection requiring intravenous systemic therapy. - Has received prior therapy with an anti-PD-1, anti-PD-L1, anti-PD-L2, anti-CD137, or anti-CTLA-4 antibody (including ipilimumab or any other antibody or drug specifically targeting T-cell co-stimulation or checkpoint pathways). - Has a known history of Human Immunodeficiency Virus (HIV 1 and 2 antibodies), or known active Hepatitis B (Hepatitis B surface antigen reactive), or Hepatitis C (Hepatitis C virus RNA [qualitative] is detected). - Has received a live vaccine within 30 days prior to first dose. |
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E.5 End points |
E.5.1 | Primary end point(s) |
The primary efficacy endpoint is the Objective Response Rate (ORR), defined as the proportion of subjects in the analysis population who have complete remission (CR) or partial remission (PR) using International Working Group (IWG) criteria, Cheson 2007 at any time during the study. Response for the primary analysis will be determined by central review. |
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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) |
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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 | No |
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 | Yes |
E.6.11 | Pharmacogenomic | No |
E.6.12 | Pharmacoeconomic | Yes |
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
| Yes |
E.8.4 | The trial involves multiple sites in the Member State concerned | No |
E.8.4.1 | Number of sites anticipated in Member State concerned | 1 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 21 |
E.8.6 Trial involving sites outside the EEA |
E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
E.8.6.2 | Trial being conducted completely outside of the EEA | No |
E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
Australia |
Brazil |
Canada |
Chile |
Colombia |
France |
Germany |
Italy |
Netherlands |
New Zealand |
Poland |
Russian Federation |
Spain |
Sweden |
Switzerland |
Turkey |
United Kingdom |
United States |
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E.8.7 | Trial has a data monitoring committee | No |
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 | 2 |
E.8.9.1 | In the Member State concerned months | 7 |
E.8.9.1 | In the Member State concerned days | 0 |
E.8.9.2 | In all countries concerned by the trial years | 3 |
E.8.9.2 | In all countries concerned by the trial months | 0 |
E.8.9.2 | In all countries concerned by the trial days | 0 |