Clinical trial NCT02659800: 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
Study type: INTERVENTIONAL
Overall status: TERMINATED
Phase: PHASE1
Conditions: Lymphopenia
Malignant Glioma
Lead sponsor: Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins
Sponsor class: OTHER
Collaborators: name: National Cancer Institute (NCI)
name: NeoImmuneTech
First posted: 2016-01-20
Enrollment: 12
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Intervention model description: Dose Escalation - 3 levels - Group A Dexamethasone less/equal 0.75mg/day; Group B Dexamethasone greater/equal 4mg/day. At MTD Group A - w/outDexamethasone randomized Arm 1 placebo and Arm 2 MTD; Group B MTD w/ Dexamethasone single arm
Primary purpose: SUPPORTIVE_CARE

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.

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

Primary outcomes:
measure: Absolute total CD4 cell counts
timeFrame: At 6 weeks (after standard radiation and temozolomide treatment completion)
Secondary outcomes:
measure: 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
timeFrame: 4 weeks
Other outcomes:
Locations:
city: Birmingham
country: United States
facility: UAB Comprehensive Cancer Center
state: Alabama
city: Baltimore
country: United States
facility: Johns Hopkins Oncology Center
state: Maryland
city: Boston
country: United States
facility: Dana Farber Cancer Institute
state: Massachusetts
city: Detroit
country: United States
facility: Josephine Ford Cancer Center at Henry Ford Hospital
state: Michigan
city: Saint Louis
country: United States
facility: Washington University
state: Missouri
city: New York
country: United States
facility: Memorial Sloan-Kettering Cancer Center
state: New York
city: Winston-Salem
country: United States
facility: Wake Forest University Comprehensive Cancer Center
state: North Carolina
city: Cleveland
country: United States
facility: Cleveland Clinic Taussig Cancer Center
state: Ohio
city: Philadelphia
country: United States
facility: Abrams Cancer Center of the University of Pennsylvania
state: Pennsylvania
city: Pittsburgh
country: United States
facility: Hillman Cancer Center at University of Pittsburgh Cancer Institute
state: Pennsylvania
Study officials:
affiliation: National Cancer Institute (NCI)
name: Jian L Campian, MD, PhD
role: STUDY_CHAIR
References: