Pembrolizumab for T/NK-cell lymphomasNK-cell Lymphomas

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Brief Title

Pembrolizumab for T/NK-cell lymphomasNK-cell Lymphomas

Official Title

PD-1 Blockade With Pembrolizumab in Relapsed/Refractory Mature T-cell and NK-cell Lymphomas

Brief Summary

      Conventional chemotherapeutic regimens designed for aggressive B-cell lymphomas are generally
      less effective when applied to mature T-cell or NK-cell lymphomas. The treatment outcome for
      relapsed or refractory disease is especially poor.

      This is a single centre, prospective, non-randomized, open-label, phase II study to evaluate
      the efficacy of pembrolizumab in patients with relapsed or refractory mature T-cell or
      NK-cell lymphomas. Patients will receive pembrolizumab 200mg i.v. once every 3 weeks until
      disease progression or unacceptable toxicity.

      A baseline radiological assessment by positron emission tomography / computed tomography
      (PET/CT) scan is obtained before commencement of treatment. Tumor response and progression
      are evaluated by physical examination, standard laboratory tests, and PET/CT scan according
      to standard criteria. Standard response criteria for non-Hodgkin lymphomas are used for
      assessment . PET/CT scan will be done at week 12, week 24, week 36 and every 18 weeks
      thereafter.
    

Detailed Description

      Pembrolizumab is a potent and highly selective humanized monoclonal antibody (mAb) of the
      IgG4/kappa isotype against PD-1, designed to directly block its interaction with PD-L1 and
      PD-L2. KeytrudaTM (pembrolizumab) has recently been approved in the United Stated for the
      treatment of melanoma that is unresectable or metastatic, or has progressed following
      ipilumumab and, (if BRAF V600 mutation positive), a BRAF inhibitor.

      Mature T-cell and nature killer (NK)-cell lymphomas are lymphoid malignancies that are
      derived from T-cell and NK-cell lineages. They are less prevalent than B-cell lymphomas.
      Interestingly, there are distinct geographic differences in their distribution and
      prevalence. Nodal lymphomas including peripheral T-cell lymphoma, not otherwise specified
      (PTCL-NOS), angioimmunoblastic T-cell lymphoma (AITL), anaplastic large cell lymphoma (ALCL)
      and cutaneous T-cell lymphomas (CTCL) predominate in Western populations, accounting for
      about 10% of all lymphomas. In Asian countries, however, extranodal NK/T-cell lymphoma, nasal
      type, is much more prevalent, constituting 10% of all lymphomas; with AITL, ALCL and PTCL-NOS
      accounting for another 10%. Epstein Barr virus (EBV) infection is found in all cases of
      extranodal NK/T-cell lymphomas, the majority of AITL, and a significant proportion of
      PTCL-NOS, implying that it plays an important pathogenetic role.

      Conventional chemotherapeutic regimens designed for aggressive B-cell lymphomas are generally
      less effective when applied to mature T-cell or NK-cell lymphomas. The treatment outcome for
      relapsed or refractory disease is especially poor. In a recent retrospective analysis, the
      median overall survival (OS) and progression-free survival (PFS) in patients with disease
      relapse were found to be only 5.5 and 3.1 months respectively. The efficacy of newly approved
      agents such as pralatrexate and romidepsin for relapsed or refractory T-cell lymphomas is
      modest, with an average overall response rate (ORR) of around 20-30% only. Novel therapeutic
      approaches are therefore needed for this group of patients with dismal prognosis.

      PD-1 blockade using anti-PD1 monoclonal antibody has been shown to be highly effective for
      relapsed/refractory classical Hodgkin lymphoma. Furthermore, clinical response has also been
      seen in relapsed T-cell lymphomas after treatment with anti-PD-1 antibody in phase I studies.
      In addition, previous reports have shown that EBV infection may enhance the expression of
      PD-L1 in tumour cells, and that some EBV-associated lymphomas such as NK/T-cell lymphoma
      express high level of PD-L1, suggesting that EBV-associated mature T-cell and NK-cell
      lymphomas may be more susceptible to PD-1 blockade.
    

Study Phase

Phase 2

Study Type

Interventional


Primary Outcome

Complete remission rate (CR)

Secondary Outcome

 Overall response rate (ORR)

Condition

T-Cell Lymphoma

Intervention

pembrolizumab

Study Arms / Comparison Groups

 pembrolizumab
Description:  200mg i.v. once every 3 weeks Number of Cycles: until progression or unacceptable toxicity develops

Publications

* Includes publications given by the data provider as well as publications identified by National Clinical Trials Identifier (NCT ID) in Medline.

Recruitment Information


Recruitment Status

Drug

Estimated Enrollment

33

Start Date

December 1, 2016

Completion Date

December 2020

Primary Completion Date

June 2020

Eligibility Criteria

        Inclusion Criteria:

          1. Be willing and able to provide written informed consent/assent for the trial.

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

          3. Be willing to provide tissue from a newly obtained core or excisional biopsy of a
             tumor lesion. Newly-obtained is defined as a specimen obtained up to 6 weeks (42 days)
             prior to initiation of treatment on Day 1. Subjects for whom newly-obtained samples
             cannot be provided (e.g. inaccessible or subject safety concern) will be considered on
             a case-by-case basis.

          4. Have a performance status of 0 or 1 on the ECOG Performance Scale.

          5. Demonstrate adequate organ function , all screening labs should be performed within 10
             days of treatment initiation.

          6. Female subject of childbearing potential should have a negative urine or serum
             pregnancy 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.

          7. Female subjects of childbearing potential should be willing to use 2 methods of birth
             control or be surgically sterile, or abstain from heterosexual activity for the course
             of the study through 120 days after the last dose of study medication. Subjects of
             childbearing potential are those who have not been surgically sterilized or have not
             been free from menses for > 1 year.

          8. Male subjects should agree to use an adequate method of contraception starting with
             the first dose of study therapy through 120 days after the last dose of study therapy.

        Exclusion Criteria:

          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. Has a diagnosis of immunodeficiency or is receiving systemic steroid therapy or any
             other form of immunosuppressive therapy within 7 days prior to the first dose of trial
             treatment.

          3. Has undergone prior allogeneic HSCT

          4. Has a known history of active TB (Bacillus Tuberculosis)

          5. Has hypersensitivity to pembrolizumab or any of its excipients.

          6. Has had a prior anti-cancer monoclonal antibody (mAb) 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.

          7. Has had prior chemotherapy, 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 at
             baseline) from adverse events 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 subject received major surgery, they must have recovered adequately from
                  the toxicity and/or complications from the intervention prior to starting
                  therapy.

          8. Has a known additional malignancy that is progressing or requires active treatment.
             Exceptions include basal cell carcinoma of the skin or squamous cell carcinoma of the
             skin that has undergone potentially curative therapy or in situ cervical cancer.

          9. Has known active central nervous system (CNS) metastases and/or carcinomatous
             meningitis. Subjects with previously treated brain metastases may participate provided
             they are stable (without evidence of progression by imaging for at least four weeks
             prior to the first dose of trial treatment and any neurologic symptoms have returned
             to baseline), have no evidence of new or enlarging brain metastases, and are not using
             steroids for at least 7 days prior to trial treatment. This exception does not include
             carcinomatous meningitis which is excluded regardless of clinical stability.

         10. 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 (eg., thyroxine, insulin, or physiologic corticosteroid
             replacement therapy for adrenal or pituitary insufficiency, etc.) is not considered a
             form of systemic treatment.

         11. Has known history of, or any evidence of active, non-infectious pneumonitis.

         12. Has an active infection requiring systemic therapy.

         13. Has a history or current evidence of any condition, therapy, or laboratory abnormality
             that might confound the results of the trial, interfere with the subject's
             participation for the full duration of the trial, or is not in the best interest of
             the subject to participate, in the opinion of the treating investigator.

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

         15. 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.

         16. Has received prior therapy with an anti-PD-1, anti-PD-L1, or anti-PD-L2 agent.

         17. Has a known history of Human Immunodeficiency Virus (HIV) (HIV 1/2 antibodies).

         18. Has known active Hepatitis B virus or Hepatitis C virus infection.

         19. Has received a live vaccine within 30 days of planned start of study therapy.
      

Gender

All

Ages

18 Years - N/A

Accepts Healthy Volunteers

No

Contacts

Eric Tse, PhD(Cantab), 85222554361, [email protected]

Location Countries

Hong Kong

Location Countries

Hong Kong

Administrative Informations


NCT ID

NCT03021057

Organization ID

HKU-MK-NKT01


Responsible Party

Principal Investigator

Study Sponsor

The University of Hong Kong

Collaborators

 Merck Sharp & Dohme Corp.

Study Sponsor

Eric Tse, PhD(Cantab), Principal Investigator, The University of Hong Kong


Verification Date

April 2019