Clinical Trials /

Mogamulizumab and Pembrolizumab in Treating Patients With Relapsed or Refractory Diffuse Large B Cell Lymphoma

NCT03309878

Description:

This phase I/II trial studies the best dose and side effects of mogamulizumab in combination with pembrolizumab and to see how well they work in treating patients with diffuse large B cell lymphoma that have come back after a period of improvement (relapsed) or does not respond to treatment (refractory). Immunotherapy with monoclonal antibodies, such as mogamulizumab and pembrolizumab, may help the body's immune system attack the cancer, and may interfere with the ability of tumor cells to grow and spread.

Related Conditions:
  • Diffuse Large B-Cell Lymphoma
  • Transformed Lymphoma
Recruiting Status:

Recruiting

Phase:

Phase 1/Phase 2

Trial Eligibility

Document

Title

  • Brief Title: Mogamulizumab and Pembrolizumab in Treating Patients With Relapsed or Refractory Diffuse Large B Cell Lymphoma
  • Official Title: A Phase I and Randomized Phase II Study of KW-0761 (Mogamulizumab) and MK-3475 (Pembrolizumab) in Relapsed, Refractory Diffuse Large B- Cell Lymphoma

Clinical Trial IDs

  • ORG STUDY ID: NCI-2017-01865
  • SECONDARY ID: NCI-2017-01865
  • SECONDARY ID: 19-018
  • SECONDARY ID: 10106
  • SECONDARY ID: 10106
  • SECONDARY ID: UM1CA186691
  • NCT ID: NCT03309878

Conditions

  • Recurrent Diffuse Large B-Cell Lymphoma
  • Recurrent High Grade B-Cell Lymphoma
  • Recurrent Transformed B-Cell Non-Hodgkin Lymphoma
  • Refractory Diffuse Large B-Cell Lymphoma
  • Refractory High Grade B-Cell Lymphoma
  • Refractory Transformed B-cell Non-Hodgkin Lymphoma

Interventions

DrugSynonymsArms
MogamulizumabImmunoglobulin G1, Anti-(CC Chemokine Receptor CCR4) (Human-Mouse Monoclonal KW-0761 Heavy Chain), Disulfide With Human-Mouse Monoclonal KW-0761 Kappa-Chain, Dimer, KM8761, KW-0761, Mogamulizumab-kpkc, PoteligeoArm I (pembrolizumab, mogamulizumab)
PembrolizumabKeytruda, Lambrolizumab, MK-3475, SCH 900475Arm I (pembrolizumab, mogamulizumab)

Purpose

This phase I/II trial studies the best dose and side effects of mogamulizumab in combination with pembrolizumab and to see how well they work in treating patients with diffuse large B cell lymphoma that have come back after a period of improvement (relapsed) or does not respond to treatment (refractory). Immunotherapy with monoclonal antibodies, such as mogamulizumab and pembrolizumab, may help the body's immune system attack the cancer, and may interfere with the ability of tumor cells to grow and spread.

Detailed Description

      PRIMARY OBJECTIVES:

      I. To determine the maximum tolerated dose (MTD) or recommended phase 2 dose (RP2D) of
      KW-0761 (mogamulizumab) when administered in combination with MK-3475 (pembrolizumab) in
      patients with relapsed, refractory diffuse large B-cell lymphoma. (Phase I) II. To assess the
      safety and tolerability of KW-0761 (mogamulizumab) when administered in combination with
      MK-3475 (pembrolizumab) in patients with relapsed, refractory diffuse large B-cell lymphoma.
      (Phase I) III. To assess the progression-free survival of KW-0761 (mogamulizumab) when
      administered in combination with MK-3475 (pembrolizumab) compared to MK-3475 (pembrolizumab)
      alone in patients with relapsed and refractory diffuse large B-cell lymphomas. (Phase II)

      SECONDARY OBJECTIVES:

      I. To observe and record anti-tumor activity. (Phase I) II. To assess the overall response
      rate, complete response rate, partial response rate, duration of response of KW-0761
      (mogamulizumab) and MK-3475 (pembrolizumab) compared to MK-3475 (pembrolizumab) alone in
      patients with relapsed and refractory diffuse large B-cell lymphomas. (Phase II)

      EXPLORATORY OBJECTIVES:

      I. To determine whether the progression-free survival of KW-0761 (mogamulizumab) and MK-3475
      (pembrolizumab) when administered to patients with relapsed and refractory diffuse large
      B-cell lymphomas differs based on the presence or absence of mutations in B2M or CD58 or
      amplifications in PD-L1.

      II. To determine whether the progression-free survival of KW-0761 (mogamulizumab) and MK-3475
      (pembrolizumab) when administered to patients with relapsed and refractory diffuse large
      B-cell lymphomas differs based on changes in CD8 T-cell, natural killer (NK) cell, and FoxP3+
      regulatory T cell (Treg) prevalence in response to therapy as measured by
      immunohistochemistry.

      III. To determine whether KW-0761 (mogamulizumab) and MK-3475 (pembrolizumab) alters the
      prevalence of peripheral blood CCR4+/FoxP3+ regulatory T-cells as well as effector CD4 and
      CD8 T-cells by multi-parametric flow cytometry.

      OUTLINE: This is a phase I, dose-escalation study of mogamulizumab followed by a phase II
      study. Patients are randomized to 1 of 2 arms.

      ARM I: Patients receive pembrolizumab intravenously (IV) over 30 minutes on day 1 and
      mogamulizumab IV over 60 minutes on days 1, 8, and 15 of cycle 1, then day 1 of subsequent
      courses.

      ARM II: Patients receive pembrolizumab IV over 30 minutes on day 1.

      In both arms, cycles repeat every 21 days for up to 2 years in the absence of disease
      progression or unacceptable toxicity.

      After completion of study treatment, patients are followed up for 4 weeks.
    

Trial Arms

NameTypeDescriptionInterventions
Arm I (pembrolizumab, mogamulizumab)ExperimentalPatients receive pembrolizumab IV over 30 minutes on day 1 and mogamulizumab IV over 60 minutes on days 1, 8, and 15 of cycle 1, then day 1 of subsequent courses. Cycles repeat every 21 days for up to 2 years in the absence of disease progression or unacceptable toxicity.
  • Mogamulizumab
  • Pembrolizumab
Arm II (pembrolizumab)ExperimentalPatients receive pembrolizumab IV over 30 minutes on day 1. Cycles repeat every 21 days for up to 2 years in the absence of disease progression or unacceptable toxicity.
  • Pembrolizumab

Eligibility Criteria

        Inclusion Criteria:

          -  Patients must have histologically confirmed diffuse large B-cell lymphoma; all
             subtypes of diffuse large B-cell lymphoma are eligible, including high-grade B-cell
             lymphoma and diffuse large B-cell lymphoma (DLBCL) that has transformed from a prior
             indolent B-cell non-Hodgkin lymphoma

          -  Patients must have measurable disease per 2014 Lugano Classification Criteria which is
             defined as at least one nodal lesion measuring > 1.5 cm in greatest diameter or at
             least one extranodal lesion measuring > 1.0 cm in greatest diameter

          -  For phase 2: patients and received at least 2 prior lines of therapy and must have
             previously received, refused, or been deemed ineligible for autologous stem cell
             transplantation

          -  Eastern Cooperative Oncology Group (ECOG) performance status =< 2 (Karnofsky >= 60%)

          -  Absolute neutrophil count >= 1,500/mcL (if neutropenia is related to bone marrow
             involvement with lymphoma, the absolute neutrophil count must be >= 1,000/mcL)

          -  Platelets >= 75,000/mcL (if thrombocytopenia is related to bone marrow involvement
             with lymphoma, the platelet count must be >= 50,000/mcL)

          -  Hemoglobin >= 9 g/dL (if anemia is related to bone marrow involvement with lymphoma,
             the hemoglobin must be >= 8 g/dL)

          -  Total bilirubin =< 1.5 x the institutional upper limit of normal (ULN) or < 3 x the
             ULN for indirect bilirubin in patients with Gilbert's disease

          -  Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) =< 2.5 x
             institutional upper limit of normal

          -  Creatinine =< 1.5 x institutional upper limit of normal OR measured or calculated
             creatinine clearance if creatinine > 1.5 x ULN then creatinine clearance >= 40
             mL/min/1.73 m^2 as calculated by Cockcroft and Gault equation

          -  Life expectancy of greater than 3 months

          -  The effects of MK-3475 (pembrolizumab) in combination with KW-0761 (mogamulizumab) on
             the developing human fetus are unknown; for this reason, women of child-bearing
             potential and men must agree to use adequate contraception (hormonal or barrier method
             of birth control; abstinence) prior to study entry and for the duration of study
             participation, and 6 months after completion of MK-3475 (pembrolizumab) in combination
             with KW-0761 (mogamulizumab) administration; should a woman become pregnant or suspect
             she is pregnant while she or her partner is participating in this study, she should
             inform her treating physician immediately; men treated or enrolled on this protocol
             must also agree to use adequate contraception prior to the study, for the duration of
             study participation, and 6 months after completion of MK-3475 (pembrolizumab) in
             combination with KW-0761 (mogamulizumab) administration

          -  Submit adequate archival tissue specimen (25+ unstained slides or 2 tissue blocks)
             from a biopsy performed after progression of disease on most recent therapy OR subject
             is willing to undergo a new core or excisional biopsy to obtain evaluable tumor tissue
             sample for immunohistochemical assessment and sequencing for B2M loss; repeat samples
             may be required if adequate tissue is not provided, however, patients may still be
             considered for enrollment on a case by case basis following consultation with the
             principal investigator (PI)

          -  Ability to understand and the willingness to sign a written informed consent document

          -  Subjects with prior history of chemotherapy-induced or radiation-induced pulmonary
             toxicity require confirmation of diffuse capacity of the lung for carbon monoxide
             (DLCO) over 60% (adjusted for hemoglobin) by a pulmonary function test prior to study
             enrollment

        Exclusion Criteria:

          -  Patients who have had previous systemic anti-cancer therapy within 3 weeks of
             registration or those who have not recovered from adverse events due to agents
             administered previously

               -  Note: Patients are considered enrolled on the study after protocol registration
                  and not after signing consent

          -  Patients who are receiving any other concurrent investigational agents

          -  Patient is receiving systemic steroid therapy or any other form of immunosuppressive
             therapy within 7 days prior to the first dose of trial treatment; the use of
             physiologic doses of corticosteroids (e.g. prednisone =< 20 mg/d) may be approved
             after consultation with the study PI; topical or inhaled corticosteroids are allowed

          -  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 that has undergone potentially curative therapy, or in situ cervical cancer

          -  Patients with active cerebral or meningeal involvement by lymphoma should be excluded
             from this clinical trial because of their poor prognosis and because they often
             develop progressive neurologic dysfunction that would confound evaluation of
             neurologic and other adverse events

          -  History of allergic reactions attributed to compounds of similar chemical or biologic
             composition to MK-3475 (pembrolizumab) or KW-0761 (mogamulizumab)

          -  Subject with active autoimmune disease; subjects with vitiligo, eczema, alopecia, type
             I diabetes mellitus, psoriasis not requiring systemic treatment, or endocrine
             deficiencies (such as hypothyroidism) managed with replacement hormones, including
             physiologic corticosteroid replacement therapy are eligible

          -  Has a history or currently active (non-infectious) pneumonitis that required steroids
             unless prior history of chemotherapy or radiotherapy induced pneumonitis meeting the
             eligibility criteria

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

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

          -  Prior allogeneic stem cell transplant (SCT)

          -  Patients who are planning to receive allogeneic SCT in the near future as preliminary
             reports suggest added toxicity in patients undergoing allogeneic stem cell
             transplantation after having received mogamulizumab

          -  Autologous SCT =< 90 days prior to first dose of study drug

          -  Uncontrolled intercurrent illness including, but not limited to, ongoing or active
             infection, interstitial lung disease or active, non-infectious pneumonitis,
             symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, or
             psychiatric illness/social situations that would limit compliance with study
             requirements

          -  Pregnant women are excluded from this study because MK-3475 (pembrolizumab) is an
             agent with the potential for teratogenic or abortifacient effects; because there is an
             unknown but potential risk for adverse events in nursing infants secondary to
             treatment of the mother with MK-3475 (pembrolizumab), breastfeeding should be
             discontinued if the mother is treated with MK-3475 (pembrolizumab); these potential
             risks may also apply to KW-0761 (mogamulizumab)

          -  MK-3475 (pembrolizumab) and KW-0761 (mogamulizumab) may have adverse effects on a
             fetus in utero; furthermore, it is not known if MK-3475 (pembrolizumab) or KW-0761
             (mogamulizumab) has transient adverse effects on the composition of sperm; patients
             are excluded from this study if pregnant or breastfeeding or expecting to conceive or
             father children within the projected duration of the trial, starting with the
             screening visit through 180 days after the last dose of trial treatment

          -  Patients with human immunodeficiency virus (HIV) are excluded if they have a
             detectable viral load, are not on a stable antiretroviral regimen, have a decreased
             CD4+ T-cell count (< 500), or require prophylactic antibiotics for the prevention of
             opportunistic infections

          -  Has known history of hepatitis B (defined as hepatitis B surface antigen [HBsAg]
             reactive) or known active hepatitis C virus (defined as HCV ribonucleic acid [RNA]
             [qualitative] is detected) infection

               -  Note: No testing for hepatitis B and hepatitis C is required unless mandated by
                  local health authority

          -  Has a known history of active tuberculosis (TB)

          -  Patients with significant cardiac disease (e.g., New York Heart Association [NYHA]
             class III-IV congestive heart failure, unstable angina, recent myocardial infarction
             within the last 6 months, etc.)
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Maximum tolerated dose (MTD) or recommended phase II dose (RP2D) of mogamulizumab in combination with pembrolizumab (Phase I)
Time Frame:Up to 6 weeks
Safety Issue:
Description:Will be determined by dose limiting toxicity (DLT). A standard 3+3 design will be used to find the MTD or RP2D for the combination of pembrolizumab and mogamulizumab.

Secondary Outcome Measures

Measure:Overall response rate
Time Frame:Up to 4 years
Safety Issue:
Description:Will be calculated along with exact 95% confidence intervals.
Measure:Complete response rate
Time Frame:Up to 4 years
Safety Issue:
Description:Will be calculated along with exact 95% confidence intervals.
Measure:Partial response rate
Time Frame:Up to 4 years
Safety Issue:
Description:Will be calculated along with exact 95% confidence intervals.
Measure:Duration of response
Time Frame:Up to 4 years
Safety Issue:
Description:Will be summarized by Kaplan-Meier method in patients who achieve CR or PR.

Details

Phase:Phase 1/Phase 2
Primary Purpose:Interventional
Overall Status:Recruiting
Lead Sponsor:National Cancer Institute (NCI)

Last Updated

December 19, 2019