rhIL-7-hyFc on Increasing Lymphocyte Counts in Patients With Newly Diagnosed Non-severe Lymphopenic Gliomas Following Radiation and Temzolomide

• ClinicalTrials.gov Identifier: NCT03687957
• Recruitment Status: Recruiting
• First Posted: September 27, 2018
• Last Update Posted: May 18, 2023
• Sponsor: Washington University School of Medicine
• Collaborators: NeoImmuneTech; The Foundation for Barnes-Jewish Hospital
• Information provided by (Responsible Party): Washington University School of Medicine

Tracking Information

• First Submitted Date: September 25, 2018
• First Posted Date: September 27, 2018
• Last Update Posted Date: May 18, 2023
• Actual Study Start Date: January 4, 2019
• Estimated Primary Completion Date: January 31, 2030 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: November 19, 2021)

• Phase I: Safety and tolerability of rhIL-7-hyFc as measured by the maximum tolerated dose (MTD) - Phase I only [ Time Frame: Completion of enrollment of phase I portion of study (estimated to be 1 year) ]
  -The maximum tolerated dose (MTD) is defined as the dose level immediately below the non-tolerated dose. A total of at least 6 patients must be treated at a dose level for it to be considered the MTD.
• Phase I: Safety and tolerability of rhIL-7-hyFc as measured by dose-limiting toxicities (DLTs) [ Time Frame: 30 days from the date when patients receive the 1st dose of rhIL-7-hyFc administration (estimated to be 29 weeks) ]
  -DLT will be defined as ≥ grade 3 non-dermatological and non-hematological AEs that occur within 30 days from the date when patients receive the 1st dose of rhIL-7-hyFc administration and are concluded to be possibly, likely or definitely related to the drug regimen that occurs during cycle 1, with severity graded according to the Common Terminology Criteria for Adverse Events (CTCAE) 5.0.
• Randomized Phase II: Percent increase of absolute lymphocyte count [ Time Frame: Prior to adjuvant TMZ (approximately week 4) ]
• Phase II Expansion Cohort: Progression-free survival (PFS) [ Time Frame: Through completion of follow-up (estimated to be 5 years and 6 months) ]
  -Defined from date of surgery to date of progression or death due to disease or date of last clinical follow up.

Original Primary Outcome Measures (submitted: September 25, 2018)

• Phase I portion: Safety and tolerability of rhIL-7-hyFc as measured by the maximum tolerated dose (MTD) - Phase I only [ Time Frame: Completion of enrollment of phase I portion of study (estimated to be 1 year) ]
  -The maximum tolerated dose (MTD) is defined as the dose of rhIL-7-hyFc that yields a dose limiting toxicity rate less than 33%. If an MTD is not reached, the highest administered dose will be the highest dose to test for safety.
• Phase I portion: Safety and tolerability of rhIL-7-hyFc as measured by the optimal biological dose (OBD) [ Time Frame: Completion of enrollment of phase I portion of study (estimated to be 1 year) ]
  -The optimal biological dose (OBD) is defined as the dose of rhIL-7hyFc that yields the highest level of ALC, if no toxicity is observed at the highest dose level tested.
• Phase I portion: Safety and tolerability of rhIL-7-hyFc as measured by dose-limiting toxicities (DLTs) [ Time Frame: 30 days from the date when patients receive the 1st dose of rhIL-7-hyFc administration (estimated to be 29 weeks) ]
  -DLT will be defined as ≥ grade 3 non-dermatological and non-hematological AEs that occur within 30 days from the date when patients receive the 1st dose of rhIL-7-hyFc administration and are concluded to be possibly, likely or definitely related to the drug regimen that occurs during cycle 1, with severity graded according to the Common Terminology Criteria for Adverse Events (CTCAE) 5.0.
• Phase II portion: Percent increase of absolute lymphocyte count [ Time Frame: Prior to adjuvant TMZ (approximately week 4) ]

Current Secondary Outcome Measures (submitted: November 19, 2021)

• Phase I and Randomized Phase II: Immunogenicity as measured by anti-drug antibodies [ Time Frame: Baseline through Week 14 ]
  -The formation of anti-drug antibodies (ADA) to rhIL-7-hyFc will be evaluated: BioAgilytix will perform both Elisa Binding (non-neutralizing) and neutralizing antibody assays according to their Standard Operating Procedure.
• Phase I: Absolute lymphocyte count (ALC) [ Time Frame: 1 year ]
• Phase I and Randomized Phase II: Immunogenicity as measured by neutralizing anti-drug antibodies [ Time Frame: Baseline through Week 14 ]
  -The formation of neutralizing anti-drug antibodies (NADA) to rhIL-7-hyFc will be evaluated: BioAgilytix will perform both Elisa Binding (non-neutralizing) and neutralizing antibody assays according to their Standard Operating Procedure.

Original Secondary Outcome Measures (submitted: September 25, 2018)

• Anti-drug antibodies [ Time Frame: Baseline through Week 14 ]
  -The formation of anti-drug antibodies (ADA) and neutralizing anti-drug antibodies (NADA) to rhIL-7-hyFc will be evaluated: BioAgilytix will perform both Elisa Binding (non-neutralizing) and neutralizing antibody assays according to their Standard Operating Procedure.
• Phase I portion: Absolute lymphocyte count (ALC) [ Time Frame: 1 year ]

• Current Other Pre-specified Outcome Measures: Not Provided
• Original Other Pre-specified Outcome Measures: Not Provided

Descriptive Information

• Brief Title: rhIL-7-hyFc on Increasing Lymphocyte Counts in Patients With Newly Diagnosed Non-severe Lymphopenic Gliomas Following Radiation and Temzolomide
• Official Title: Effect of rhIL-7-hyFc on Increasing Lymphocyte Counts in Patients With Newly Diagnosed Non-severe Lymphopenic Gliomas Following Radiation and Temzolomide

Brief Summary

The investigators have developed a phase I/II clinical trial to evaluate the effect of rhIL-7-hyFc on lymphocyte counts in patients with high grade glioma (HGG).

A phase I study will test whether rhIL-7-hyFc can be safely administered to patients with HGG. Six doses of rhIL-7-hyFc will be tested using a mix of Accelerated Phase and standard 3+3 dose-escalation design. The phase II portion to test effect of rhIL-7-hyFc on lymphocyte counts will use placebo-controlled randomization in HGG patients whose treatment include the standard radiation therapy (RT) and temozolomide (TMZ).

• Detailed Description: Not Provided
• Study Type: Interventional
• Study Phase: Phase 1; Phase 2

Study Design

Allocation: Randomized
Intervention Model: Sequential Assignment
Intervention Model Description:

-Phase I enrollment will be a sequential enrollment (patients will be stratified by concomitant use of steroids (yes/no). Phase II randomized portion will open with 2 arms being enrolled to in parallel. Phase II expansion cohort will not be randomized.

Masking: Triple (Participant, Care Provider, Investigator)
Masking Description:

Phase II only: This study is triple-blinded (participant, physician, and study coordinator are all blinded; pharmacist and study statistician are not blinded)

Primary Purpose: Treatment

• Condition: Glioma

Intervention

• Drug: rhIL-7-hyFc
  -Given by intramuscular injection
• Drug: Placebo
  -Given by intramuscular injection
• Drug: Temozolomide
  -Standard of care
  Other Name: TMZ
• Radiation: Radiation therapy
  -Standard of care
  Other Name: RT
• Procedure: Blood sample
  • Week 1 (prior to the 1st dose of rhIL-7-hyFc)
  • Week 2 (one week after rhIL-7-hyFc)
  • Week 3 (two weeks after rhIL-7-hyFc)
  • Week 4 (three weeks after rhIL-7-hyFc)
  • Week 13 (prior to the 2nd dose of rhIL-7-hyFc)
  • Week 14 (one week after rhIL-7-hyFc)
  • Week 16 (three weeks after rhIL-7-hyFc) - optional
  • Week 45 (eight weeks after the last dose of rhIL-7-hyFC)
  • If ADA or NADA is observed in week 45, additional blood collections will be required every 2 months in order to monitor ADA/NADA levels until it decreases to the basal level
  • At the time of tumor progression

Study Arms

• Experimental: Phase I: rhIL-7-hyFc
  • Per standard treatment, patients will receive concurrent RT/TMZ followed by adjuvant TMZ on Days 1-5 of a 28-day cycle for a total of 6 cycles. rhIL-7hyFc will be given by intramuscular injection starting at the end of RT/TMZ (within 7 days after last day of RT/TMZ). The 2nd injection will be administered 3-5 days after the last dose of cycle 3 TMZ treatment (~week 13). The 3rd injection will be given 3-5 days after the last dose of cycle 6 TMZ treatment (~week 25). Note the 2nd and 3rd injections should be administered once between Day 3 through 5 following the last dose of TMZ to achieve the strongest response. The 4th injection (last injection in the study) will be given after completion of monthly TMZ (~Week 37). A total of 4 doses of rhIL-7-hyFc injections are planned
  • The phase I part will begin with an Accelerated Phase with 1 patient per cohort at the first 2 doses (60 mcg/kg and 120 mcg/kg) followed by a standard 3+3 design on the remaining 4 dose levels
  Interventions:

  • Drug: rhIL-7-hyFc
  • Drug: Temozolomide
  • Radiation: Radiation therapy
  • Procedure: Blood sample
• Experimental: Randomized Phase II: Placebo
  -Per standard treatment, patients will receive concurrent RT/TMZ followed by adjuvant TMZ on Days 1-5 of a 28-day cycle for a total of 6 cycles. Placebo will be given by intramuscular injection starting at the end of RT/TMZ (within 14 days after last day of RT/TMZ). The 2nd injection will be administered 3-5 days after the last dose of cycle 3 TMZ treatment (~week 13). The 3rd injection will be given 3-5 days after the last dose of cycle 6 TMZ treatment (~week 25). Note the 2nd and 3rd injections should be administered once between Day 3 through 5 following the last dose of TMZ to achieve the strongest response. The 4th injection (last injection in the study) will be given after completion of monthly TMZ (~Week 37). A total of 4 doses of placebo injections are planned.
  Interventions:

  • Drug: Placebo
  • Drug: Temozolomide
  • Radiation: Radiation therapy
  • Procedure: Blood sample
• Experimental: Randomized Phase II: rhIL-7-hyFc
  Per standard treatment, patients will receive concurrent RT/TMZ followed by adjuvant TMZ on Days 1-5 of a 28-day cycle for a total of 6 cycles. rhIL-7hyFc will be given by intramuscular injection starting at the end of RT/TMZ (within 14 days after last day of RT/TMZ). The 2nd injection will be administered 3-5 days after the last dose of cycle 3 TMZ treatment (~week 13). The 3rd injection will be given 3-5 days after the last dose of cycle 6 TMZ treatment (~week 25). Note the 2nd and 3rd injections should be administered once between Day 3 through 5 following the last dose of TMZ to achieve the strongest response. The 4th injection (last injection in the study) will be given after completion of monthly TMZ (~Week 37). A total of 4 doses of rhIL-7-hyFc injections are planned.
  Interventions:

  • Drug: rhIL-7-hyFc
  • Drug: Temozolomide
  • Radiation: Radiation therapy
  • Procedure: Blood sample
• Experimental: Phase II Expansion Arm: rhIL-7-hyFc
  Per standard treatment, patients will receive concurrent RT/TMZ followed by adjuvant TMZ on Days 1-5 of a 28-day cycle for a total of 6 cycles. rhIL-7hyFc will be given by intramuscular injection starting at the end of RT/TMZ (within 14 days after last day of RT/TMZ). The 2nd injection will be administered 3-5 days after the last dose of cycle 3 TMZ treatment (~week 13). The 3rd injection will be given 3-5 days after the last dose of cycle 6 TMZ treatment (~week 25). Note the 2nd and 3rd injections should be administered once between Day 3 through 5 following the last dose of TMZ to achieve the strongest response. The 4th injection (last injection in the study) will be given after completion of monthly TMZ (~Week 37). A total of 4 doses of rhIL-7-hyFc injections are planned.
  Interventions:

  • Drug: rhIL-7-hyFc
  • Drug: Temozolomide
  • Radiation: Radiation therapy

• Publications *: Campian JL, Ghosh S, Kapoor V, Yan R, Thotala S, Jash A, Hu T, Mahadevan A, Rifai K, Page L, Lee BH, Ferrando-Martinez S, Wolfarth AA, Yang SH, Hallahan D, Chheda MG, Thotala D. Long-Acting Recombinant Human Interleukin-7, NT-I7, Increases Cytotoxic CD8 T Cells and Enhances Survival in Mouse Glioma Models. Clin Cancer Res. 2022 Mar 15;28(6):1229-1239. doi: 10.1158/1078-0432.CCR-21-0947.

Recruitment Information

• Recruitment Status: Recruiting
• Estimated Enrollment (submitted: November 19, 2021): 70
• Original Estimated Enrollment (submitted: September 25, 2018): 32
• Estimated Study Completion Date: January 31, 2030
• Estimated Primary Completion Date: January 31, 2030 (Final data collection date for primary outcome measure)

Eligibility Criteria

Inclusion Criteria:

• World Health Organization (WHO) grade III, grade IV, and high risk grade II gliomas that require RT and TMZ treatment.
• Phase 2 Expansion Cohort ONLY: Must be IDH1 wildtype, as defined by negative immunohistochemistry using an R132H-specific antibody and MGMT promoter unmethylated glioblastoma multiforme (WHO grade IV).
• Post-operative treatment must have included radiation and TMZ. Prior Gliadel Wafers are allowed. Glucocorticoid therapy is allowed. Tumor treating fields (TTF) device is allowed.

• Adequate organ and marrow function defined as follows:

  • Absolute neutrophil count ≥ 1,000/mcL
  • Platelets ≥ 75,000/mcL
  • Hemoglobin ≥ 8 g/dL
  • Total bilirubin ≤ 3.0 x institutional upper limit of normal
  • AST (SGOT)/ALT (SGPT) ≤ 3.0 × institutional upper limit of normal
  • Absolute lymphocyte count (ALC) ≥ 600/mcL (required for phase I and randomized phase II only)
• Karnofsky Performance Status (KPS) ≥ 60% (i.e. the patient must be able to care for himself/herself with occasional help from others).
• Able to provide written informed consent (or consent from a legally authorized representative).

• Women of childbearing potential must have a negative serum pregnancy test prior to study entry (within 14 days). Patients must be willing to be on adequate contraception during treatment.

  • 18 years of age.

Exclusion Criteria:

• Receiving any other investigational agents which may affect patient's lymphocyte counts.
• Pregnant women are excluded from this study because rhIL-7-hyFc has not been evaluated regarding its potential for teratogenic or abortifacients effects. There is a potential risk for adverse events in nursing infants secondary to treatment of the mother with the study drug, breastfeeding should be discontinued if the mother is treated with rhIL-7-hyFc.
• Has an active viral infection requiring systemic treatment at screening.
• Has active autoimmune disease or syndrome (i.e. moderate or severe rheumatoid arthritis, moderate or severe psoriasis, multiple sclerosis, myasthenia gravis, Guillain Barre syndrome, systemic lupus erythematosis, scleroderma, ulcerative colitis, Crohn's disease, autoimmune hepatitis, Wegener's etc.,) that requires systemic treatment at the time of screening. Replacement therapy (e.g., thyroxine, insulin, or physiologic corticosteroid replacement therapy for adrenal or pituitary insufficiency) is not considered a form of systemic treatment. Subjects are permitted to enroll if they have vitiligo, resolved childhood asthma/atopy, type I diabetes mellitus, residual hypothyroidism due to autoimmune condition only requiring hormone replacement, psoriasis not requiring systemic treatment, or conditions not expected to recur in the absence of an external trigger.
• Receipt of live attenuated vaccine within 30 days before the first dose of study treatment. Examples of live vaccines include, but are not limited to, the following: measles, mumps, rubella, chicken pox, yellow fever, rabies, Bacillus Calmette-Guérin (BCG), Zoster, and typhoid vaccine. Seasonal influenza vaccines for injection are generally killed virus vaccines and are allowed; however, intranasal influenza vaccines (e.g. FluMist) are live attenuated vaccines and are not allowed.
• Has abnormal cardiac enzymes ([Tnl or TnT] or CK-MD)
• Patients with a clinically significant EKG on screening triggering a echocardiogram which is also clinically significant

Sex/Gender

• Sexes Eligible for Study: All

• Ages: 18 Years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Contacts

Contact: Milan Chheda, M.D.; 314-747-2712; mchheda@wustl.edu

• Listed Location Countries: United States

Administrative Information

• NCT Number: NCT03687957
• Other Study ID Numbers: 201810185
• Has Data Monitoring Committee: Yes

U.S. FDA-regulated Product

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No
• Product Manufactured in and Exported from the U.S.: No

IPD Sharing Statement

• Plan to Share IPD: No

• Current Responsible Party: Washington University School of Medicine
• Original Responsible Party: Same as current
• Current Study Sponsor: Washington University School of Medicine
• Original Study Sponsor: Same as current

Collaborators

• NeoImmuneTech
• The Foundation for Barnes-Jewish Hospital

Investigators

• Principal Investigator: Milan Chheda, M.D.; Washington University School of Medicine

• PRS Account: Washington University School of Medicine
• Verification Date: May 2023