Clinical Trials /

Pembrolizumab and Pralatrexate in Treating Patients With Relapsed or Refractory Peripheral T-Cell Lymphomas

NCT03598998

Description:

This phase I/II trial studies the side effects and best dose of pralatrexate when given together with pembrolizumab and how well they work in treating patients with peripheral T-cell lymphomas that has come back after a period of improvement or has not responded to treatment. Pralatrexate may stop the growth of cancer cells by blocking some of the enzymes needed for cell growth. Immunotherapy with monoclonal antibodies, such as pembrolizumab, may help the body's immune system attack the cancer, and may interfere with the ability of tumor cells to grow and spread. Giving pembrolizumab and pralatrexate may work better in treating patients with peripheral T-cell lymphomas.

Related Conditions:
  • Anaplastic Large Cell Lymphoma
  • Anaplastic Large Cell Lymphoma, ALK-Negative
  • Anaplastic Large Cell Lymphoma, ALK-Positive
  • Angioimmunoblastic T-Cell Lymphoma
  • Enteropathy-Associated T-Cell Lymphoma
  • Follicular T-Cell Lymphoma
  • Hepatosplenic T-Cell Lymphoma
  • Indolent T-Cell Lymphoproliferative Disorder of the Gastrointestinal Tract
  • Monomorphic Epitheliotropic Intestinal T-Cell Lymphoma
  • Nasal Type Extranodal NK/T-Cell Lymphoma
  • Nodal Peripheral T-Cell Lymphoma with TFH Phenotype
  • Peripheral T-Cell Lymphoma, Not Otherwise Specified
  • Subcutaneous Panniculitis-Like T-Cell Lymphoma
  • Transformed Lymphoma
Recruiting Status:

Recruiting

Phase:

Phase 1/Phase 2

Trial Eligibility

Document

Title

  • Brief Title: Pembrolizumab and Pralatrexate in Treating Patients With Relapsed or Refractory Peripheral T-Cell Lymphomas
  • Official Title: A Phase 1/2 Study of Pembrolizumab Plus Pralatrexate for Treatment of Relapsed or Refractory Peripheral T-Cell Lymphomas

Clinical Trial IDs

  • ORG STUDY ID: 17501
  • SECONDARY ID: NCI-2018-01420
  • SECONDARY ID: 17501
  • NCT ID: NCT03598998

Conditions

  • Anaplastic Large Cell Lymphoma
  • Nodal Peripheral T-Cell Lymphoma With TFH Phenotype
  • Recurrent Anaplastic Large Cell Lymphoma
  • Recurrent Angioimmunoblastic T-Cell Lymphoma
  • Recurrent Enteropathy-Associated T-Cell Lymphoma
  • Recurrent Follicular Lymphoma
  • Recurrent Hepatosplenic T-Cell Lymphoma
  • Recurrent Mature T- Cell and NK-Cell Non-Hodgkin Lymphoma
  • Recurrent Monomorphic Epitheliotropic Intestinal T-cell Lymphoma
  • Recurrent Mycosis Fungoides
  • Recurrent Peripheral T-Cell Lymphoma, Not Otherwise Specified
  • Refractory Anaplastic Large Cell Lymphoma
  • Refractory Angioimmunoblastic T-Cell Lymphoma
  • Refractory Enteropathy-Associated T-Cell Lymphoma
  • Refractory Follicular Lymphoma
  • Refractory Hepatosplenic T-Cell Lymphoma
  • Refractory Mature T-Cell and NK-Cell Non-Hodgkin Lymphoma
  • Refractory Mycosis Fungoides
  • Refractory Peripheral T-Cell Lymphoma, Not Otherwise Specified
  • Subcutaneous Panniculitis-Like T-Cell Lymphoma

Interventions

DrugSynonymsArms
PembrolizumabKeytruda, Lambrolizumab, MK-3475, SCH 900475Treatment (pralatrexate and pembrolizumab)
Pralatrexate10-propargyl-10-deazaaminopterin, Folotyn, PDXTreatment (pralatrexate and pembrolizumab)

Purpose

This phase I/II trial studies the side effects and best dose of pralatrexate when given together with pembrolizumab and how well they work in treating patients with peripheral T-cell lymphomas that has come back after a period of improvement or has not responded to treatment. Pralatrexate may stop the growth of cancer cells by blocking some of the enzymes needed for cell growth. Immunotherapy with monoclonal antibodies, such as pembrolizumab, may help the body's immune system attack the cancer, and may interfere with the ability of tumor cells to grow and spread. Giving pembrolizumab and pralatrexate may work better in treating patients with peripheral T-cell lymphomas.

Detailed Description

      PRIMARY OBJECTIVES:

      I. Evaluate the safety and tolerability of a regimen combining pembrolizumab and pralatrexate
      in patients with relapsed or refractory peripheral T-cell lymphoma (PTCL).

      II. Establish the maximum tolerated dose (MTD) and recommended phase II dose (RP2D) of the
      combined pralatrexate and pembrolizumab regimen.

      III. Estimate the overall response rate (ORR) according to the Lugano Classification in
      patients treated with pembrolizumab plus pralatrexate at the RP2D.

      SECONDARY OBJECTIVES:

      I. Estimate the complete response (CR) rate according to the Lugano Classification duration
      of response (DOR), overall survival (OS) and progression‐free survival (PFS) in patients
      treated with pembrolizumab plus pralatrexate.

      II. Estimate the ORR and CR rate according to the International Harmonization Project
      response criteria.

      III. Evaluate responses and disease progression according to the Lymphoma Response to
      Immunomodulatory therapy Criteria (LYRIC).

      EXPLORATORY OBJECTIVE:

      I. Explore immunologic and genomic biomarkers of response to pembrolizumab plus pralatrexate
      therapy.

      OUTLINE: This is a phase I, dose-escalation study of pralatrexate followed by a phase II
      study.

      Patients receive pralatrexate intravenously (IV) over 3-5 minutes on days 1 and 8 and
      pembrolizumab IV over 30 minutes on day 1. Courses repeat every 21 days for up to 24 months
      in the absence of disease progression or unacceptable toxicity.

      After completion of study treatment, patients are followed up at 30 and 90 days, every 12
      weeks for 1 year, and then every 18 weeks thereafter.
    

Trial Arms

NameTypeDescriptionInterventions
Treatment (pralatrexate and pembrolizumab)ExperimentalPatients receive pralatrexate IV over 3-5 minutes on days 1 and 8 and pembrolizumab IV over 30 minutes on day 1. Courses repeat every 21 days for up to 24 months in the absence of disease progression or unacceptable toxicity.
  • Pembrolizumab
  • Pralatrexate

Eligibility Criteria

        Inclusion Criteria:

          -  Documented willingness and ability to sign an informed consent of the participant
             and/or legally authorized representative.

          -  Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1.

          -  Patients must have a histologically confirmed diagnosis of mature peripheral T‐cell or
             natural killer (NK)‐cell lymphoma according to the World Health Organization (WHO)
             classification, with hematopathology review at the participating institution. Eligible
             histologies are:

               -  Peripheral T-cell lymphoma, not otherwise specified

               -  Anaplastic large cell lymphoma, ALK-negative

               -  Anaplastic large cell lymphoma, ALK-positive

               -  Angioimmunoblastic T-cell lymphoma

               -  Nodal peripheral T-cell lymphoma with TFH phenotype

               -  Follicular T-cell lymphoma

               -  Indolent T-cell lymphoproliferative disorder of the gastrointestinal (GI) tract

               -  Extranodal NK-/T-cell lymphoma

               -  Enteropathy-associated T cell lymphoma

               -  Monomorphic epitheliotropic intestinal T-cell lymphoma

               -  Hepatosplenic T-cell lymphoma

               -  Subcutaneous panniculitis-like T-cell lymphoma

               -  Transformed mycosis fungoides

          -  Patients must have failed at least one prior regimen, including:

               -  Recurrence of disease after a documented complete response (CR).

               -  Progression of disease after a partial response (PR) to the prior regimen.

               -  Partial response, stable disease (SD) or progressive disease (PD) at the
                  completion of the prior treatment regimen. If a patient has PR to prior regimen
                  without PD, there must be biopsy‐proven** residual disease that is measurable

                    -  Exception can be granted by the principal investigator (PI) if a biopsy is
                       not feasible and/or safe

          -  Patient must have measurable disease by computerized tomography (CT) or positron
             emission tomography (PET) scan, with one or more sites of disease >= 1.5cm in longest
             dimension.

          -  Be willing to provide tissue from a fresh core or excisional biopsy of a tumor lesion
             prior to starting study therapy or from archival tissue of a biopsy that was performed
             after the most recent systemic therapy. Exception can be granted by the PI if a biopsy
             is not feasible and/or safe

          -  Patients must have received one dose of vitamin B12 (1 mg intramuscularly [IM]) within
             10 weeks prior to first dose of pralatrexate, and must have begun folic acid
             supplementation (1 mg orally, once daily) within 10 days of first dose of
             pralatrexate. Note: If folic acid was not started but methylmalonic acid (MMA) and
             homocysteine (HCY) levels were checked and are in normal range at screening, the
             investigator can decide to start study therapy immediately. Vitamin B12 and folic acid
             supplementation is standard of care for pralatrexate therapy.

          -  Absolute neutrophil count (ANC) >= 1,000/mm^3. In Phase 2 portion of study, ANC <
             1000/mm^3 but >= 500/mm^3 is allowable if patients have demonstrated bone marrow
             involvement by lymphoma (within 14 days prior to day 1 of protocol therapy).

               -  Note: Growth factor is not permitted within 7 days of ANC assessment unless
                  cytopenia is secondary to disease involvement.

          -  Platelets >= 75,000/mm^3. In Phase 2 portion of study, Platelets < 75,000/mm^3 but >=
             25,000/mm^3 is allowable if patients have demonstrated bone marrow involvement by
             lymphoma (within 14 days prior to day 1 of protocol therapy)

               -  Note: Platelet transfusions are not permitted within 7 days of platelet
                  assessment unless cytopenia is secondary to disease involvement.

          -  Total serum bilirubin =< 1.5 X upper limit of norma (ULN) or =< 3X ULN for Gilbert's
             disease. Direct bilirubin =< ULN for subjects with total bilirubin levels > 1.5 ULN
             (within 14 days prior to day 1 of protocol therapy).

          -  Aspartate aminotransferase (AST) =< 2.5 x ULN (within 14 days prior to day 1 of
             protocol therapy)

          -  Alanine aminotransferase (ALT) =< 2.5 x ULN (within 14 days prior to day 1 of protocol
             therapy)

          -  Creatinine clearance of >= 60 mL/min per the Cockcroft‐Gault formula (within 14 days
             prior to day 1 of protocol therapy). If creatinine clearance (CrCl) is >= 60 mL/min as
             measured by 24 hour urine collection, this will be allowable.

          -  If not receiving anticoagulants: International normalized ratio (INR) OR prothrombin
             (PT) =< 1.5 x ULN (within 14 days prior to day 1 of protocol therapy).

               -  If on anticoagulant therapy: PT must be within therapeutic range of intended use
                  of anticoagulants.

          -  If not receiving anticoagulants: Activated partial thromboplastin time (aPTT) =< 1.5 x
             ULN (within 14 days prior to day 1 of protocol therapy)

               -  If on anticoagulant therapy: aPTT must be within therapeutic range of intended
                  use of anticoagulants.

          -  Female of childbearing potential: negative urine or serum pregnancy test within 72
             hours prior to receiving the first dose of study medication (within 14 days prior to
             day 1 of protocol therapy). If the urine test is positive or cannot be confirmed as
             negative, a serum pregnancy test will be required.

          -  Woman of childbearing potential (WOCBP): Use two effective methods of contraception
             (hormonal or barrier method) or be surgically sterile, or abstain from heterosexual
             activity for the course of the study through 120 days post last dose of pembrolizumab.
             WOCBP defined as not being surgically sterilized or have not been free from menses for
             >1 year.

               -  Male: Use two effective methods of contraception (barrier method) or abstain from
                  heterosexual activity with the first dose of study therapy through 120 days post
                  last dose of pembrolizumab.

        Exclusion Criteria:

          -  Patients with adult T-cell leukemia/lymphoma

          -  Prior allogeneic hematopoietic stem cell transplantation within the last 5 years.

          -  Prior autologous hematopoietic stem cell transplant within the last 60 days.

          -  Patients who received prior therapy with an anti‐PD‐1, anti-PD‐L1, or anti‐PD‐L2 agent
             without having had evidence of objective response.

          -  Patients who received prior therapy with pralatrexate without having had evidence of
             objective response.

          -  Investigational agent or anti‐cancer monoclonal antibody (mAb) within 21 days prior to
             day 1 of therapy or who has not recovered (i.e. =<1 or at baseline) from adverse
             events due to agents administered more than 21 days earlier.

          -  Prior chemotherapy, targeted small molecule therapy, or radiation therapy within 14
             days prior to day 1 of therapy or who has not recovered (i.e. =< 1 or at baseline)
             from adverse events due to a previously administered agent. * Note: Subjects with =<
             grade 2 neuropathy are an exception and may qualify for the study.

          -  Antineoplastic biologic therapy or major surgery within 21 days of the first dose of
             trial medication. If subjects received major surgery more than 21 days ago, they must
             have recovered adequately from the toxicity and/or complications from the intervention
             prior to starting therapy.

          -  Received live vaccine within 30 days prior to day 1 of protocol therapy.

          -  Systemic steroid therapy or on any other form of immunosuppressive therapy within 7
             days prior to the first dose of trial treatment.

          -  Diagnosis of immunodeficiency.

          -  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.

          -  Congestive heart failure class III/IV according to the New York Heart Association
             (NYHA) Functional classification.

          -  Known severe hypersensitivity reaction to pembrolizumab, pralatrexate, leucovorin or
             any excipients.

          -  Active autoimmune disease that has required systemic treatment in the past 2 years
             (replacement therapies for hormone deficiencies are allowed). Hemolytic anemia
             associated with the lymphoma does not exclude a patient from the study.

          -  Known history of human immunodeficiency virus (HIV) (HIV 1/2 antibodies).

          -  Known active hepatitis B (e.g., hepatitis B virus surface antigen (HBsAg) reactive) or
             hepatitis C (e.g., hepatitis C virus ribonucleic acid [HCV RNA] [qualitative] is
             detected).

          -  History of tuberculosis (TB) infection (Bacillus tuberculosis).

          -  Active central nervous system (CNS) involvement by lymphoma, including parenchymal
             and/or lymphomatous meningitis. Subjects with prior CNS involvement by lymphoma must
             have a baseline magnetic resonance imaging (MRI) and lumbar puncture at screening that
             demonstrate no active lymphoma in the CNS.

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

          -  Active, uncontrolled infection requires systemic therapy.

          -  Female: Pregnant or breastfeeding.

          -  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.

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

          -  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.

          -  Any other condition that would, in the investigator's judgment, contraindicate the
             patient's participation in the clinical study due to safety concerns with clinical
             study procedures.

          -  Perspective participants who, in the opinion of the investigator, may not be able to
             comply with all study procedures (including compliance issues related to
             feasibility/logistics).
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Maximum tolerated dose defined as the highest doe level at which < 2 out of 6 evaluable subjects experienced dose limiting toxicities (Phase I)
Time Frame:Up to 21 days
Safety Issue:
Description:Toxicities will be breaded according to National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) version 5.0.

Secondary Outcome Measures

Measure:Complete response (CR) rate according to Lugano classification
Time Frame:Up to 48 months
Safety Issue:
Description:
Measure:ORR according to the International Harmonization Project response criteria
Time Frame:Up to 48 months
Safety Issue:
Description:
Measure:CR rate according to the International Harmonization Project response criteria
Time Frame:Up to 48 months
Safety Issue:
Description:
Measure:Duration of response (DOR) based on Lymphoma Response to Immunomodulatory therapy Criteria (LYRIC) criteria
Time Frame:Up to 48 months
Safety Issue:
Description:
Measure:Overall survival (OS)
Time Frame:From initiation of study therapy to death from any cause, assessed up to 48 months
Safety Issue:
Description:
Measure:Progression‐free survival (PFS)
Time Frame:From initiation of study therapy to the first observation of disease relapse/progression or death from any cause, whichever occurs first, assessed up to 48 months
Safety Issue:
Description:
Measure:Incidence of adverse events assessed by NCI CTCAE version (v)5.0
Time Frame:Up to 90 days after last dose
Safety Issue:
Description:Observed toxicities will be summarized by type (organ affected or laboratory determination such as absolute neutrophil count, severity (by NCI CTCAE v5.0 and nadir or maximum values for lab measures), date of onset, duration, reversibility, and attribution.
Measure:Incidence of unacceptable toxicity assessed by NCI CTCAE version 5.0
Time Frame:Up to 90 days after last dose
Safety Issue:
Description:

Details

Phase:Phase 1/Phase 2
Primary Purpose:Interventional
Overall Status:Recruiting
Lead Sponsor:City of Hope Medical Center

Last Updated

November 18, 2019