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Study of MK-3475 Alone or in Combination With Copanlisib in Relapsed or Refractory Peripheral T-cell Non-Hodgkin Lymphoma

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ClinicalTrials.gov Identifier: NCT02535247
Recruitment Status : Active, not recruiting
First Posted : August 28, 2015
Last Update Posted : January 15, 2019
Sponsor:
Collaborator:
Merck Sharp & Dohme Corp.
Information provided by (Responsible Party):
Fox Chase Cancer Center

Brief Summary:
This is a multicenter, single-arm, open label 2-stage phase 2 study exploring monotherapy with the PD-1 antibody pembrolizumab (or MK-3475) given intravenously at a fixed dose of 200mg every 3 weeks for up to 36 cycles for patients with relapsed or refractory Peripheral T-cell Lymphoma (PTCL), who have received at least 1 prior systemic therapy. The primary endpoint of the study is progression-free survival. Secondary outcomes are overall survival and response rate. Patients will be assessed for response with PET CT or CT every 12 weeks using the revised Cheson criteria. Correlative endpoints will be exploratory and assess PD-1 expression on peripheral blood lymphocytes; peripheral blood T-cell and NK-cell functional assays; PD-1 and PD-L1 expression on tumor tissue; and tumor infiltrating lymphocytes as prognostic and predictive biomarkers.

Condition or disease Intervention/treatment Phase
Lymphoma, T-Cell, Peripheral Drug: MK-3475 Drug: Copanlisib Phase 1 Phase 2

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 48 participants
Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Intervention Model Description: MK-3475 is given intravenously at a fixed dose of 200mg every 3 weeks. Copanlisib is given intravenously at RP2D determined from Phase I study 18 in cohort 1 (pembrolizumab alone; completed); 27 in Cohort 2; 4-12 in cohort 2a (phase I); 18 in cohort 2b (phase II). Total up to 48
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: A Phase I/II Study to Determine Feasibility and Safety MK-3475 Alone or in Combination With Copanlisib in Relapsed or Refractory NK and T-cell Non-Hodgkin Lymphoma
Actual Study Start Date : January 5, 2016
Estimated Primary Completion Date : December 2020
Estimated Study Completion Date : December 2022

Resource links provided by the National Library of Medicine

MedlinePlus related topics: Lymphoma

Arm Intervention/treatment
Experimental: Treatment
MK-3475 given intravenously at a fixed dose of 200mg every 3 weeks for up to 36 cycles
Drug: MK-3475
Other Name: Pembrolizumab

Active Comparator: Combination
MK-3475 is given intravenously at a fixed dose of 200mg every 3 weeks Copanlisib is given intravenously at RP2D determined from Phase I study
Drug: MK-3475
Other Name: Pembrolizumab

Drug: Copanlisib



Primary Outcome Measures :
  1. Progression Free Survival [ Time Frame: 3 Months ]

Secondary Outcome Measures :
  1. Overall Survival [ Time Frame: 6 Months ]
  2. Overall Survival [ Time Frame: 1 Year ]

Other Outcome Measures:
  1. PD-1 expression and leukocyte activation markers on circulating lymphocytes pre-treatment [ Time Frame: Week 3 ]
    PD-1 expression and leukocyte activation markers on circulating lymphocytes pre-treatment, at weeks 3 and 6, and at time of disease progression

  2. PD-1 expression and leukocyte activation markers on circulating lymphocytes pre-treatment [ Time Frame: Week 6 ]
    PD-1 expression and leukocyte activation markers on circulating lymphocytes pre-treatment, at weeks 3 and 6, and at time of disease progression



Information from the National Library of Medicine

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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  1. Have a histologically or cytologically confirmed relapsed/refractory mature T-cell lymphoma that has progressed after a minimum of 1 systemic therapy with any of the following T-cell histologies:

    • Peripheral T-cell NHL, not other wise specified (PTCL, NOS)
    • Anaplastic large cell T-cell lymphoma (ALCL)
    • Anaplastic lymphoma kinase positive or negative
    • Angioimmunoblastic T-cell lymphoma
    • Subcutaneous panniculitis like T-cell lymphoma
    • Follicular T-cell lymphoma
    • Nodal peripheral T-cell lymphoma with TFH phenotype
    • Monomorphic epitheliotropic intestinal T-cell lymphoma (MEITL)
    • Enteropathy associated T-cell lymphoma
    • Hepatosplenic T-cell lymphoma
    • Extranodal NK/T-cell lymphoma, nasal type
    • Unclassifiable PTCL
    • Transformed cutaneous T-cell lymphoma (CTCL) to PTCL with systemic involvement (not local skin transformation).
  2. Be willing and able to sign written informed consent for the trial.
  3. Be at least 18 years of age on day of signing informed consent.
  4. Have measurable disease based as defined by at least one lesion that can be measured in least 2 perpendicular dimensions and measures at least 1.5 cm in its long axis.
  5. Have provided tissue from an archival tissue sample or newly obtained core or excisional biopsy of a tumor lesion obtained within 28 days prior to study enrollment.
  6. Have a performance status of 0, 1 or 2 on the ECOG Performance Scale.
  7. Demonstrate adequate organ function as defined below, all screening labs should be performed within 10 days of treatment initiation.

    • Absolute neutrophil count (ANC) Greater than or equal to 1,500 /mcL, OR Greater than or equal to1,000 /mcL if lymphomatous bone marrow involvement Patients with documented marrow involvement may receive GCSF to achieve this value
    • Platelets greater than or equal to 100,000 / mcL, OR greater than or equal to 75,000 / mcL if lymphomatous bone marrow involvement Patients with documented marrow involvement may be transfused to this value.
    • Hemoglobin greater than or equal to 9 g/dL or greater than or equal to 5.6 mmol/L Patients with documented marrow involvement may be transfused to this value.
    • Serum creatinine OR Measured or calculated creatinine clearance (GFR can also be used in place of creatinine or CrCl) less than or equal to1.5 X upper limit of normal (ULN) OR greater than or equal to 40 mL/min for subject with creatinine levels greater than 1.5 X institutional ULN
    • Serum total bilirubin less than 1.5 X ULN OR Direct bilirubin less than the ULN for subjects with total bilirubin levels greater than 1.5 ULN
    • AST (SGOT) and ALT (SGPT) less than or equal to 2.5 X ULN OR less than or equal to 5 X ULN for subjects with liver involvement by lymphoma
    • Lipase less than or equal to 1.5 X ULN
    • International Normalized Ratio (INR) or Prothrombin Time (PT) less than or equal to 1.5 X ULN unless subject is receiving anticoagulant therapy
    • Activated Partial Thromboplastin Time (aPTT) less than or equal to 1.5 X ULN unless subject is receiving anticoagulant therapy as long as PT or PTT is within therapeutic range of intended use of anticoagulants
  8. 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 (Reference Section 5.5.2). Subjects of childbearing potential are those who have not been surgically sterilized or have not been free from menses for greater than 1 year.
  9. 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 in or has participated in a study of an investigational agent or using an investigational device within 2 weeks of the first dose of treatment.
  2. Patients diagnosed with Adult T-cell Leukemia/Lymphoma (ATLL) or T-cell PLL
  3. 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.
  4. Has had a prior monoclonal antibody within 4 weeks prior to study Day 1 or who has not recovered (i.e., worse than Grade 1 or at baseline) from adverse events due to agents administered more than 4 weeks earlier.
  5. 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 worse than 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.
  6. Has a known additional malignancy 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 intraparenchymal lymphomatous central nervous system (CNS) lesions and/or lymphomatous meningitis. Subjects with previously treated CNS involvement by lymphoma 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 lesions, and are not using steroids for at least 7 days prior to trial treatment.
  8. Has an active autoimmune disease requiring systemic treatment within the past 3 months or a documented history of clinically severe autoimmune disease, or a syndrome that requires systemic steroids or immunosuppressive agents. Subjects with vitiligo or resolved childhood asthma/atopy would be an exception to this rule. Subjects that require intermittent use of bronchodilators or local steroid injections would not be excluded from the study. Subjects with hypothyroidism stable on hormone replacement or Sjoegren's syndrome will not be excluded from the study.
  9. Has evidence of interstitial lung disease or active, non-infectious pneumonitis.
  10. Has an active infection requiring systemic therapy.
  11. 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.
  12. Has known psychiatric or substance abuse disorders that would interfere with cooperation with the requirements of the trial.
  13. 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.
  14. 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).
  15. Has a known history of Human Immunodeficiency Virus (HIV) (HIV 1/2 antibodies).
  16. Has known active Hepatitis B (e.g., HBsAg reactive) or Hepatitis C (e.g., HCV RNA [qualitative] is detected).
  17. Has received a live vaccine within 30 days prior to the first dose of trial treatment.
  18. Cohort 2a: Has received an allogeneic stem cell transplant. For cohort 2b, patients within the first 100 days of having undergone an allogeneic stem cell transplant will be excluded. Otherwise, patients who have received an allogeneic stem cell transplant are allowed as long as they have no evidence of active GVHD or are on immunosuppressive therapy
  19. Uncontrolled arterial hypertension despite optimal medical management
  20. Uncontrolled Type I or II diabetes mellitus as deemed appropriate by the investigator. Suggested guidelines for uncontrolled diabetes: HbA1c> 8.5%
  21. Anti-arrhythmic therapy (beta blockers or digoxin are permitted)
  22. Use of CYP3A4 inhibitors and inducers. Copanlisib is primarily metabolized by CYP3A4. Therefore concomitant use of strong inhibitors of CYP3A4 (e.g., ketoconazole, itraconazole, clarithromycin, ritonavir, indinavir, nelfinavir and saquinavir), and strong inducers of CYP3A (e.g. rifampin, phenytoin, carbamazepine, phenobarbital, St. John's Wort) are not permitted from Day -14 of Cycle 1 until the Safety follow up visit. See Table in Appendix 5 for complete list
  23. Concurrent diagnosis of pheochromocytoma
  24. 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
  25. Prior exposure to PI3K inhibitors, unless on PI3K inhibitor therapy more than 6 months ago AND reason for discontinuation of prior PI3K inhibitor therapy was other than progression or toxicity.
  26. Patients with detectable CMV viremia are excluded

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT02535247


Locations
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United States, Pennsylvania
Fox Chase Cancer Center
Philadelphia, Pennsylvania, United States, 19111
Sponsors and Collaborators
Fox Chase Cancer Center
Merck Sharp & Dohme Corp.

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Responsible Party: Fox Chase Cancer Center
ClinicalTrials.gov Identifier: NCT02535247     History of Changes
Other Study ID Numbers: HM-075
First Posted: August 28, 2015    Key Record Dates
Last Update Posted: January 15, 2019
Last Verified: January 2019

Additional relevant MeSH terms:
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Lymphoma
Lymphoma, Non-Hodgkin
Lymphoma, T-Cell
Lymphoma, T-Cell, Peripheral
Neoplasms by Histologic Type
Neoplasms
Lymphoproliferative Disorders
Lymphatic Diseases
Immunoproliferative Disorders
Immune System Diseases
Pembrolizumab
Antineoplastic Agents, Immunological
Antineoplastic Agents