Mogamulizumab and Pembrolizumab in Treating Patients with Relapsed or Refractory Lymphomas

Status: Active

Description

This randomized 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 lymphomas that have come back after a period of improvement or does not respond to treatment. Monoclonal antibodies, such as mogamulizumab and pembrolizumab, may interfere with the ability of cancer cells to grow and spread.

Eligibility Criteria

Inclusion Criteria

  • For phase 1 dose-escalation: patients must have histologically confirmed relapsed or refractory lymphoma for which standard curative or palliative measures do not exist or are no longer effective; this includes non-Hodgkin and Hodgkin lymphomas
  • For phase 2: 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 or been deemed ineligible for autologous stem cell transplantation
  • Eastern Cooperative Oncology Group (ECOG) performance status =< 2 (Karnofsky >= 60%)
  • Life expectancy of greater than 3 months
  • 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 within normal institutional limits of < 3X the upper limit of normal in patients with Gilbert’s disease
  • Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) =< 2.5x institutional upper limit of normal
  • Creatinine =< 1.5x institutional upper limit of normal OR measured or calculated creatinine clearance if creatinine > 1.5x upper limit of normal (ULN) then creatinine clearance >= 40 mL/min/1.73 m^2 as calculated by Cockcroft and Gault equation
  • Submit adequate archival tissue specimen 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
  • 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
  • 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; 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 4 months after completion of MK-3475 (pembrolizumab) in combination with KW-0761 (mogamulizumab) administration
  • Ability to understand and the willingness to sign a written informed consent document

Exclusion Criteria

  • Patients who have had chemotherapy or radiotherapy within 4 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 investigational agents
  • 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; the use of physiologic doses of corticosteroids may be approved after consultation with the study principal investigator (PI); topical or inhaled corticosteroids are allowed
  • Has had a prior monoclonal antibody within 4 weeks prior to study day 1
  • 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 known cerebral or meningeal involvement by lymphoma should be excluded from this clinical trial
  • 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
  • Subjects with active (non-infectious) pneumonitis
  • 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 future
  • 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; breastfeeding should be discontinued if the mother is treated with MK-3475
  • 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 120 days after the last dose of trial treatment
  • Subject has immunodeficiency disorder or who are human immunodeficiency virus (HIV) positive
  • Has known active hepatitis B (e.g., hepatitis B surface antigen [HBsAg] reactive) or active hepatitis C (e.g., hepatitis C virus [HCV] quantitative polymerase chain reaction [PCR] is detected)
  • Has a known history of active tuberculosis (TB)

Locations & Contacts

See trial information on ClinicalTrials.gov for a list of participating sites.

Trial Objectives and Outline

PRIMARY OBJECTIVES:

I. To determine the maximum tolerated dose (MTD) or recommended phase 2 dose (RP2D) of mogamulizumab when administered in combination with pembrolizumab in patients with relapsed, refractory lymphomas. (Phase I)

II. To assess the safety and tolerability of mogamulizumab when administered in combination with pembrolizumab in patients with relapsed, refractory lymphomas. (Phase I)

III. To assess the 12-month progression-free survival of mogamulizumab when administered in combination with pembrolizumab compared to 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 mogamulizumab and pembrolizumab compared to pembrolizumab alone in patients with relapsed and refractory diffuse large B-cell lymphomas. (Phase II)

TERTIARY OBJECTIVES:

I. To determine whether 12-month progression-free survival of mogamulizumab and 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 12-month progression-free survival of mogamulizumab and 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 mogamulizumab and pembrolizumab alters the prevalence, immunophenotype and function of peripheral blood regulatory T-cells as well as effector CD4 and CD8 T-cells by multi-parametric flow cytometry.

IV. To determine whether differences in tumor metabolism as measured by liquid chromatography–mass spectrometry (LC-MS) correlate with differences in baseline immune infiltration as measured by ribonucleic acid sequencing (RNA-seq) or with 12-month progression-free survival of mogamulizumab and pembrolizumab when administered to patients with relapsed and refractory diffuse large B-cell lymphomas.

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 course 1, then day 1 of subsequent courses.

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

In both arms, courses 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 Phase & Type

Trial Phase

Phase I/II

Trial Type

Treatment

Lead Organization

Lead Organization
JHU Sidney Kimmel Comprehensive Cancer Center LAO

Principal Investigator
Anita Kumar

Trial IDs

Primary ID 10106
Secondary IDs NCI-2017-01865
Clinicaltrials.gov ID NCT03309878