Clinical Trials /

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

NCT02535247

Description:

This is a multicenter, single-arm, open label, study consisting of two cohorts. Cohort 2 explores the combination of copanlisib and pembrolizumab in patients with relapsed or refractory NKTCL, who have received at least 1 prior systemic therapy. Cohort 2 will include a phase 1 portion (cohort 2a) to determine the recommended phase 2 dose (RP2D) utilizing a standard 3+3 design, followed by a phase II portion where patients will be treated at the RP2D (cohort 2b). The primary endpoint for cohort 1 was progression-free survival; the primary endpoint for cohort 2a will be to determine RP2D for the combination therapy; and overall response rate at the end of 4 treatment cycles for cohort 2b. 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; tumor infiltrating lymphocytes and gene expression panels using the nanostring technology as prognostic and predictive biomarkers, as well as monitoring of minimal residual disease via high-throughput sequencing of cell free tumor DNA, and exosome analysis.

Related Conditions:
  • Mature T-Cell and NK-Cell Lymphoma/Leukemia
Recruiting Status:

Recruiting

Phase:

Phase 1/Phase 2

Trial Eligibility

Document

Title

  • Brief Title: Study of MK-3475 Alone or in Combination With Copanlisib in Relapsed or Refractory NK and T-cell Non-Hodgkin Lymphoma
  • 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

Clinical Trial IDs

  • ORG STUDY ID: HM-075
  • NCT ID: NCT02535247

Conditions

  • Lymphoma, T-Cell, Peripheral

Interventions

DrugSynonymsArms
MK-3475PembrolizumabCombination
CopanlisibCombination

Purpose

This is a multicenter, single-arm, open label, study consisting of two cohorts. Cohort 2 explores the combination of copanlisib and pembrolizumab in patients with relapsed or refractory NKTCL, who have received at least 1 prior systemic therapy. Cohort 2 will include a phase 1 portion (cohort 2a) to determine the recommended phase 2 dose (RP2D) utilizing a standard 3+3 design, followed by a phase II portion where patients will be treated at the RP2D (cohort 2b). The primary endpoint for cohort 1 was progression-free survival; the primary endpoint for cohort 2a will be to determine RP2D for the combination therapy; and overall response rate at the end of 4 treatment cycles for cohort 2b. 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; tumor infiltrating lymphocytes and gene expression panels using the nanostring technology as prognostic and predictive biomarkers, as well as monitoring of minimal residual disease via high-throughput sequencing of cell free tumor DNA, and exosome analysis.

Detailed Description

      Patients with relapsed or refractory (RR) NK and T-cell Lymphoma (NKTCL), who have received
      at least 1 prior systemic therapy, were enrolled in cohort 1. The study design for cohort 1
      was a single arm phase II 2-stage design, to explore 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. Enrollment to this cohort has been completed.
    

Trial Arms

NameTypeDescriptionInterventions
TreatmentExperimentalMK-3475 given intravenously at a fixed dose of 200mg every 3 weeks for up to 36 cycles
  • MK-3475
CombinationActive ComparatorMK-3475 is given intravenously at a fixed dose of 200mg every 3 weeks Copanlisib is given intravenously at RP2D determined from Phase I study
  • MK-3475
  • Copanlisib

Eligibility 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
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Progression Free Survival
Time Frame:3 Months
Safety Issue:
Description:

Secondary Outcome Measures

Measure:Overall Survival
Time Frame:6 Months
Safety Issue:
Description:
Measure:Overall Survival
Time Frame:1 Year
Safety Issue:
Description:
Measure:Maximum tolerated dose of pembrolizumab and copanlisib
Time Frame:6 months
Safety Issue:
Description:Defined as the highest dose tested in which none or only one patient experienced dose-limiting toxicity (DLT) attributable to the study drug(s), when 6 patients have been treated at that dose and are evaluable for toxicity.
Measure:expression of PD-1, PD-L1 and tumor infiltrating lymphocytes (TIL) in pre-treatment tumor specimens
Time Frame:1 year
Safety Issue:
Description:

Details

Phase:Phase 1/Phase 2
Primary Purpose:Interventional
Overall Status:Recruiting
Lead Sponsor:Fox Chase Cancer Center

Last Updated

August 20, 2019