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MK-3475-170

AcronymISRCTNEudraCTClinicaltrials.govDRKS
MK-3475-1702015-002406-37NCT02576990

A Phase II Study of Pembrolizumab (MK-3475) in Subjects with Relapsed or Refractory Primary Mediastinal Large B-cell Lymphoma (rrPMBCL) or Relapsed or Refractory Richter Syndrome (rrRS)

Status: Active (Recruitment Closed)

Purpose / Objectives

Primary Outcome

In subjects with Relapsed or Refractory Primary Mediastinal Large B-cell Lymphoma (rrPMBCL) or relapsed or refractory Richter syndrome (rrRS):

  1. Objective: rrPMBCL: Estimate the Objective Response Rate (ORR) of pembrolizumab by independent central review according to the International Working Group (IWG) response criteria.
  2. Objective: rrRS: Estimate the ORR of pembrolizumab by independent central review according to the IWG response criteria (Cheson, 2007) with Special considerations for RS.

 

 

Secondary Outcomes

In subjects with rrPMBCL or rrRS:

  1. Objective: To estimate the Objective Response Rate (ORR) of pembrolizumab by investigator assessment according to the IWG response criteria (Cheson, 2007) or IWG with special considerations for RS.
  2. Objective: To evaluate Progression Free Survival (PFS), Duration of Response (DOR) and Disease Control Rate (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.
  3. Objective: To evaluate the Overall Survival (OS) of pembrolizumab.
  4. Objective: To determine the safety and tolerability of pembrolizumab.

Diagnosis

Primary Mediastinal Large B-Cell Lymphoma

Non Hodgkin lymphomas (NHL) are a heterogeneous group of lymphoproliferative disorders originated in B-lymphocytes, T-lymphocytes or natural killer cells. In the United States, (US) B-cell lymphomas comprise 80 to 85% of NHL subjects. It is estimated that in 2015 around 71,850 new NHL cases will be diagnosed in United States, with approximately 19,790 deaths due to the disease. Diffuse Large B-Cell lymphoma (DLBCL) is the most common type of adult NHL in both North America and Europe, making up 30% to 40% of NHL. Primary Mediastinal B-Cell Lymphoma (PMBCL) is a distinct subtype of NHL that histologically can be indistinguishable from DLBCL and account only for 2% to 3% of all cases. This subtype tends to occur in young adults with a median age of 35 years with a slight female predominance. Interestingly, gene expression profiling has revealed that the pattern of gene expression in PMBCL is more similar to classical Hodgkin lymphoma (CHL) than DLBCL.

Richter syndrome

The 2008 World Health Classification of hematopoietic tumors defines RS as the transformation of CLL into a more aggressive lymphoma. Approximately 2% to 10% of CLL patients will experience transformation to a more aggressive lymphoma during the course of their disease, with a transformation rate of 0.5% to 1% per year. The vast majority of these transformations are DLBCL; transformation to HL is reported rarely. Diagnosis of RS follows an investigation of apparently rapidly progressing underlying disease per signs and symptoms, and assessed by PET/CT. An SUV > 5 is suggestive of RS, which may be confirmed by lymph node biopsy demonstrating DLBCL (or HL).

 

 

Patient attributes

Age

18-99

Inclusion criteria

In order to be eligible for participation in this trial, the subject must:

1. Be willing and able to provide written informed consent for the trial. The subject may also provide consent for Future Biomedical Research. However, the subject may participate in the main trial without participating in Future Biomedical Research.

2. Be ≥ 18 years of age on day of signing informed consent.

PMBCL:

3. Diagnosis of Primary Mediastinal Large B-cell lymphoma, according to the 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 lymph node biopsy at Screening. (Central review is not required before enrollment. Enrollment can be done on local pathologic review for diagnosis.)

4. Have relapsed or refractory Primary Mediastinal Large B-cell lymphoma and: Have relapsed after auto-SCT or have failed to achieve a Complete Response or Partial Response 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.

5. Must have been previously exposed to rituximab as part of prior lines of treatment.

Richter syndrome:

6. Pathologic diagnosis per local institutional review of Richter syndrome that transformed from CLL.

7. Have relapsed or refractory Richters syndrome and has received at least 1 previous treatment for RS.

All Subjects:

8. 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 MRI). Minimum measurement must be > 15 mm in the longest diameter.

9. Must have a performance status of 0 or 1 on the Eastern Cooperative Oncology Group (ECOG) Performance Scale.

10. Life expectancy > 3 months

11. Must demonstrate adequate organ functions; all screening labs should be performed within 7 days of treatment initiation. (Subjects may be enrolled based on local laboratory results pending central laboratory results.)

12. Female subjects of childbearing potential must have a negative urine or Serum pregnancy test within 72 hours prior to receiving the first dose of study medication. If the urine test is positive or cannot be confirmed as negative, a serum pregnancy test will be required.

13. Female subjects of childbearing potential must be willing to use an adequate method of contraception.Contraception, for the course of the study through 120 days after the last dose of study medication. Note: Abstinence is acceptable if this is the usual lifestyle and preferred contraception for the subject.

14. Male subjects of childbearing potential must agree to use an adequate method of contraception. Contraception, starting with the first dose of study therapy through 120 days after the last dose of study therapy. Note: Abstinence is acceptable if this is the usual lifestyle and preferred contraception for the subject.

 

 

 

 

Exclusion criteria

The subject must be excluded from participating in the trial if the subject:

1. 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.

2. 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.

3. 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.

4. 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 or at baseline) from adverse events due to a previously administered agent.

Exception: Subjects with RS with CLL may receive ibrutinib (or similar for CLL) up to 7 days before study Day 1.

Note: If subject received major surgery, they must have recovered adequately from the toxicity and/or complications from the intervention prior to starting therapy.

Note: Toxicity that has not recovered to ≤Grade 1 is allowed if it meets the inclusion requirements for laboratory parameters.

5. Has undergone prior allogeneic hematopoetic 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).

6. 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.

7. Has known active CNS involvement. Subjects with prior CNS involvement are eligible if their CNS disease is in radiographic, cytological (for CSF disease) and clinical remission.

8. 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.

9. Has a history of (non-infectious) pneumonitis that required steroids, or current pneumonitis.

10. Has an active infection requiring intravenous systemic therapy.

11. Has known psychiatric or substance abuse disorders that would interfere with cooperation with the requirements of the trial.

12. Is pregnant or breastfeeding, or expecting to conceive or father children within the projected duration of the trial, starting with the pre-screening or screening visit through 120 days after the last dose of trial treatment.

13. Has received prior therapy with an anti-PD-1, anti-PD-L1, anti-PD-L2, anti-CD137, or anti-Cytotoxic T-lymphocyte-associated antigen-4 (CTLA-4) antibody (including ipilimumab or any other antibody or drug specifically targeting T-cell co-stimulation or checkpoint pathways).

14. Has a known history of Human Immunodeficiency Virus (HIV)(HIV ½ antibodies).

15. Has known active Hepatitis B (e.g., HBsAg reactive) or Hepatitis C (e.g., HCV RNA [qualitative] is detected).

16. Has received a live vaccine within 30 days prior to first dose.

 

 

 

Trial design

  • Phase II
  • Multicenter
  • Prospective
  • One-arm
  • Open Label

Intervention

Approximately 106 subjects will be enrolled in this trial to examine the safety and efficacy of pembrolizumab 200 mg fixed dose administered Q3W. This will give a sample size of approximately 50 subjects in the analysis population of PMBCL, and approximately 50 subjects with RS, for safety and efficacy, assuming that approximately 6% of the total of 106 enrolled subjects will not be treated. Adverse events will be monitored throughout the Trial and graded in severity according to the guidelines outlined in the National Cancer Institute(NCI) Common Terminology Criteria for Adverse Events (CTCAE) version 4.0. Treatment will continue up to a maximum of 35 administrations of pembrolizumab (approximately 2 years) per subject or until documented disease progression by investigator assessment, unacceptable AE(s), intercurrent illness that prevents further administration of Treatment, subject withdraws consent, pregnancy of the subject, noncompliance with trial treatment or procedure requirements, or administrative reasons.

 

Documents (password protected)

Responsibilities in overall trial

Merck Sharp & Dohme Corp.

  • Tel. +1 (908) 740-4000

National Coordinating Investigator

Dr. med. Niels Murawski

Study Sites

Klinik I für Innere Medizin

Study office

  • Klinisches Studienzentrum der Klinik I für Innere Medizin Köln

Status

Active (Recruitment Closed)

Principal Investigator

Prof. Dr. med. Barbara Eichhorst

Deputy of Principal Investigator

  • Prof. Dr. med. Peter Borchmann
  • Prof. Dr. med. Christian Pallasch

Subinvestigator

  • Dr. med. Armin Tuchscherer

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