Study of the Effect NT-I7 on CD4 Counts in Patients With High Grade Gliomas

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Brief Title

Study of the Effect NT-I7 on CD4 Counts in Patients With High Grade Gliomas

Official Title

A Phase I and Pilot Study of the Effect of rhIL-7-hyFc (NT-I7) on CD4 Counts in Patients With High Grade Gliomas and Severe Treatment-related CD4 Lymphopenia After Concurrent Radiation and Temozolomide

Brief Summary

      The purpose of this study is to determine the maximum tolerated dose (MTD) and select optimal
      biological doses (OBD) of the study drug NT-I7 in High Grade Glioma patients with severe
      lymphopenia, as well as to test the effect of NT-I7 on the CD4 counts of patients in
      comparison to control participants. This study has both a Phase I and Pilot component.
    

Detailed Description

      PRIMARY OBJECTIVES:

      Phase I: To determine the MTD (Maximum Tolerated Dose) and select optimal biological doses
      (OBD) of NT-I7 in HGG patients with severe lymphopenia

      Pilot Study: To test the effect of NT-I7 on CD4 counts compared to control

      SECONDARY OBJECTIVES:

        1. To evaluate the optimal biological dose of NT-I7

        2. To evaluate the effect of concurrent dexamethasone

        3. To evaluate the duration of effect on CD4 counts (up to 6 months)

        4. To evaluate the total lymphocyte counts over time and serial T cell lymphocyte subtypes
           and the effect on T cell repertoire (up to 6 months)

        5. To evaluate the serial cytokine levels (up to 6 months)

        6. To evaluate the impact of adjuvant temozolomide on NT-I7 effects on CD4 counts

        7. To evaluate anti-drug antibodies

        8. To evaluate the pharmacokinetic profile of NT-I7 after intramuscular administration in
           this patient population

        9. To evaluate the safety and toxicity of NT-I7 in patients with high grade glioma

      OUTLINE: Patients are assigned to 1 of 2 groups depending on their use of dexamethasone.

      GROUP A: Patients not on dexamethasone (or equivalent of an alternative corticosteroid), or
      on a dose lower than a physiologic dose (=< 0.75 mg daily)

      GROUP B: patients who require dexamethasone (or equivalent of an alternative corticosteroid)
      => 4 mg daily

      Patients must have been on the group assignment dose of corticosteroids for at least 5 days
      prior to the dose of NT-I7. Corticosteroid dose changes prior to the start of treatment are
      allowed as long as they do not alter patient's group assignment.

      PHASE I TREATMENT PLAN

      All patients (both Groups A and B) will be given a single dose of NT-I7 by intramuscular
      injection starting at 60 μg/kg, within one week after completing concurrent RT+TMZ and before
      starting adjuvant TMZ treatment, during the standard post-radiation break. Following this
      period, as per standard treatment, patients will go on to receive adjuvant temozolomide on
      Days 1-5 of 28-day cycles for 6 cycles. There should be about six weeks between the study
      injection and the start of adjuvant temozolomide; thus the start of adjuvant TMZ will be
      approximately two weeks later than the usual start, which is 4 weeks post-end of radiation.
      Patients who are delayed from receiving or are not able to receive adjuvant TMZ treatment may
      continue on study; adjuvant TMZ treatment is not a requirement for participation.

      PILOT STUDY TREATMENT PLAN

      GROUP A: participants will be given either a placebo (NT-I7 diluent) or one dose of NT-I7 at
      the Phase I Group A OBD by intramuscular injection within one week after completing
      concurrent RT+TMZ and before starting adjuvant TMZ treatment, during the standard
      post-radiation break.

      GROUP B: participants will be given one dose of NT-I7 at the Phase I Group B OBD by
      intramuscular injection within one week after completing concurrent RT+TMZ and before
      starting adjuvant TMZ treatment, during the standard post-radiation break.

      After completion of study treatment, patients are followed up every 2 months for 2 years and
      then every 6 months thereafter.
    

Study Phase

Phase 1

Study Type

Interventional


Primary Outcome

Absolute total CD4 cell counts

Secondary Outcome

 Optimal dose of glycosylated recombinant human interleukin-7 determined by dose-limiting toxicities graded according to the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) version 5.0

Condition

Lymphopenia

Intervention

Laboratory Biomarker Analysis

Study Arms / Comparison Groups

 Arm A - Low Dexamethasone (LD)
Description:  Patients receive single dose of NT-I7 IM. Treatment continues in the absence of disease progression or unacceptable toxicity. Dose Escalation
Laboratory Biomarker Analysis Correlative Studies

Publications

* Includes publications given by the data provider as well as publications identified by National Clinical Trials Identifier (NCT ID) in Medline.

Recruitment Information


Recruitment Status

Other

Estimated Enrollment

12

Start Date

October 30, 2018

Completion Date

March 30, 2022

Primary Completion Date

March 30, 2022

Eligibility Criteria

        Inclusion Criteria:

          -  Patients must have histologically confirmed high grade glioma by pathology (World
             Health Organization [WHO] grade III and IV)

               -  Patients' post-operative treatment must have included at least 80% of standard
                  radiation and concomitant temozolomide; patients may not have received any other
                  prior chemotherapy, immunotherapy or therapy with biologic agent (including
                  immunotoxins, immunoconjugates, antisense, peptide receptor antagonists,
                  interferons, interleukins, tumor infiltrating lymphocytes [TIL],
                  lymphokine-activated killer [LAK] or gene therapy), or hormonal therapy for their
                  brain tumor; prior Gliadel wafers are allowed; glucocorticoid therapy is allowed

               -  Patients must have CD4 =< 300 cells/mm^3 in the last week (7 days) of standard
                  radiation + temozolomide treatment (58-60 Gy radiation with temozolomide 75 mg/m2
                  daily during radiation)

               -  Absolute neutrophil count >= 1,000/mcL

               -  Platelets >= 50,000/mcL (need to confirm before administering study drug)

               -  Hemoglobin >= 9 g/dL

               -  Total bilirubin =< institutional upper limit of normal

               -  Aspartate aminotransferase (AST) (serum glutamic oxaloacetic transaminase
                  [SGOT])/alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase
                  [SGPT]) =< 2.5 x institutional upper limit of normal

               -  Creatinine =< institutional upper limit of normal OR creatinine clearance >= 60
                  ml/min/1.73 m^2 for patients with creatinine levels above institutional normal

               -  Activated partial thromboplastin time (APTT) or partial thromboplastin time (PTT)
                  =< 1.5 x institutional upper limit of normal

               -  Patients must have a Karnofsky performance status (KPS) >= 60% (i.e. the patient
                  must be able to care for himself/herself with occasional help from others)

               -  Patients must be able to provide written informed consent

               -  Women of childbearing potential must have a negative serum pregnancy test prior
                  to study entry; women of childbearing potential and men must agree to use two
                  birth control methods (either two barrier methods or a barrier method plus a
                  hormonal method) or abstinence prior to study entry and for the duration of study
                  participation (through at least 90 days after the last study injection); should a
                  woman become pregnant or suspect she is pregnant while participating in this
                  study, she should inform her treating physician immediately

               -  Dexamethasone dose must be provided for treatment group assignment:

                    -  Group A: patients not on dexamethasone or on a dose =< 0.75 mg daily (or
                       equivalent of an alternative corticosteroid)

                    -  Group B: patients who require dexamethasone >= 4 mg daily (or equivalent of
                       an alternative corticosteroid) ** Patients must have been on the group
                       assignment dose of corticosteroids for at least 5 days prior to the dose of
                       NT-I7; corticosteroid dose changes prior to the start of treatment are
                       allowed as long as they do not alter patient's group assignment

        Exclusion Criteria

          -  Patients receiving any other investigational agents are ineligible

          -  Patients with known hypersensitivity to NT-I7 or any component used in the
             vehicle/formulation are ineligible

          -  Patients with uncontrolled intercurrent illness including, but not limited to, ongoing
             or active infection, symptomatic congestive heart failure, unstable angina pectoris,
             cardiac arrhythmia, or psychiatric illness/social situations that would limit
             compliance with study requirements, are ineligible

          -  Pregnant women are excluded from this study; breastfeeding should be discontinued if
             the mother is treated with NT-I7

          -  Patients with human immunodeficiency virus (HIV) are excluded

          -  Patients with a known or screening-period-determined corrected QT (QTc) interval > 450
             msec and patients who require a therapy with a drug known to prolong the QT/QTc
             interval, are ineligible

          -  Patients with a history of or who currently have evidence of autoimmune disease (other
             than autoimmune thyroid disease managed with thyroid hormone replacement or vitiligo)
             including: myasthenia gravis, Guillain Barre syndrome, systemic lupus erythematosus,
             multiple sclerosis, scleroderma, ulcerative colitis, Crohn's disease, autoimmune
             hepatitis, Wegener's etc., are ineligible
      

Gender

All

Ages

18 Years - N/A

Accepts Healthy Volunteers

No

Contacts

Jian L Campian, MD, PhD, , 

Location Countries

United States

Location Countries

United States

Administrative Informations


NCT ID

NCT02659800

Organization ID

ABTC 1403

Secondary IDs

UM1CA137443

Responsible Party

Sponsor

Study Sponsor

Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins

Collaborators

 National Cancer Institute (NCI)

Study Sponsor

Jian L Campian, MD, PhD, Study Chair, National Cancer Institute (NCI)


Verification Date

May 2022